Genes and Immunity (1999) 1, 3–19 1999 Stockton Press All rights reserved 1466-4879/99 $15.00 http://www.stockton-press.co.uk REVIEW Cytokine gene polymorphism in human disease: on-line databases
J Bidwell1, L Keen1, G Gallagher2, R Kimberly3, T Huizinga4, MF McDermott5, J Oksenberg6,J McNicholl7, F Pociot8, C Hardt9 and S D’Alfonso101Department of Pathology and Microbiology, University of Bristol, Homoeopathic Hospital Site, Cotham, Bristol BS6 6JU, UK;2University of Glasgow Department of Surgery, Queen Elizabeth Building, Glasgow Royal Infirmary, Glasgow G31 2ER, Scotland;3Division of Clinical Immunology and Rheumatology, Tinsley Harrison Tower, Room 429, University of Alabama at Birmingham,1900 University Boulevard, Birmingham, AL 35294–0006, USA; 4Leiden University Medical Center, Department of Rheumatology,C4-R, P.O. Box 9600, 2300 RC Leiden, The Netherlands; 5Medical Unit, St. Bartholomew’s and the Royal London Hospital Schoolof Medicine and Dentistry, Whitechapel, London E1 1BB, UK; 6Department of Neurology, University of California San Francisco,513 Parnassus Ave., San Francisco, CA 94143–0435, USA; 7HIV Immunology and Diagnostics Branch, Division of AIDS, NationalCenter for Infectious Diseases, Centers for Disease Control, Mailstop A25, 1600 Clifton Road NE, Atlanta, GA 30333, USA; 8StenoDiabetes Center, Niels Steensensvej 2, DK-2820 Gentofte, Denmark; 9Institut fu¨r Humangenetik, Universita¨tsklinikum Essen,Hufelandstr. 55, 45122 Essen, Germany; 10Dipartimento Scienze Mediche, Via Solaroli 17, 28100 No¨vara, Italy
The pathologies of many infectious, autoimmune and malignant diseases are influenced by the profiles of cytokineproduction in pro-inflammatory (TH1) and anti-inflammatory (TH2) T cells. Interindividual differences in cytokine profilesappear to be due, at least in part, to allelic polymorphism within regulatory regions of cytokine gene. Many studies haveexamined the relationship between cytokine gene polymorphism, cytokine gene expression in vitro, and the susceptibilityto and clinical severity of diseases. A review of the findings of these studies is presented. An on-line version featuringappropriate updates is accessible from the World Wide Web site, http://www.pam.bris.ac.uk/services/GAI/cytokine4.htm. Keywords: cytokines; gene polymorphism; gene expression Introduction: cytokines, the cytokine
ollary that the cytokine network is highly flexible, since
network and the Th1–Th2 paradigm
there is considerable overlap and redundancy betweenthe function of individual cytokines.8–12 This feature con-
Cytokines are humoral immunomodulatory proteins or
tinues to complicate efforts to analyse both the function
glycoproteins which control or modulate the activities of
of individual cyokines and the influence of cytokine gene
target cells, generally those within the haematopoietic
polymorphism on gene expression and disease.
system. They act on target cells by binding to specific
Cytokine production by the cells of the immune system
cytokine receptor ligands, initiating signal transduction
may occur through antigen-specific and non-antigen spe-
and second messenger pathways within the target cell.1–5
cific stimuli. For example, monocytes when exposed to
This can result in gene activation, leading to mitotic
bacterial cell wall products, such as lipopolysaccharide,
division, growth and differentiation, migration, or
produce IL-12 and other cytokines which have multiple
functions including influencing the expression of cyto-
Cytokines are produced by a wide range of cell types
kines by other cells. Antigen-specific responses are gener-
ated by B and T cells through immunoglobulin and T cell
(produced by cells of the monocyte lineage) or lympho-
receptors respectively. B cell activation may result in the
kines (produced by lymphocytes), though this is arguably
production of IL-6 and other cytokines. T cells are central
an over-simplistic classification: other classifications are
players in linking non-antigen specific, B cell and T cell
based on functional or structural groupings.6,7 Cytokines
responses together. Two classes of T cells are recognized:
act in a highly complex coordinated network in which
␣, and ␥,␦ T cells, defined by their T cell receptor (TCR)
they induce or repress their own synthesis as well as that
chain usage. The majority of circulating ␣, T cells carry
of other cytokines and cytokine receptors. In addition,
either CD4 or CD8 molecules, which bind to MHC class
many cytokines appear to be pleiotropic, with the cor-
II or MHC class I molecules, respectively. The ligand of
␥,␦ T cells is not clearly known, and these cells typicallycarry neither CD4 nor CD8 molecules, hence the name‘double negative’ T cells. Functionally, CD8+ T cells, are
Correspondence: Dr JL Bidwell, University of Bristol Department of Path-ology and Microbiology, Homoeopathic Hospital Site, Cotham, Bristol
typically cytotoxic T cells and can kill target cells
presenting processed foreign peptide via HLA class I
Received 9 June 1999; accepted 21 June 1999
molecules; some CD8+ T cells secrete cytokines such as
Cytokine gene polymorphism in human disease
IFN␥. CD4+ T cells are typically helper T cells, although
Table 1 List of human cytokine gene polymorphisms
rare subsets have cytoxic function. Several TH subsets ofCD4+ T cells have been identified. In the mouse these
subsets are well defined and include Type 1 (TH1), whichpromote cell-mediated effector responses; and Type 2
CD4+ helper T cells (TH2), which promote B cell-
mediated humoral responses. Cytokines produced by
TH1 cells include interleukin-2 (IL-2), interferon gamma
(IFN␥) and tumour necrosis factor beta (TNF), and
constitute a pro-inflammatory cytokine profile; those pro-
duced by TH2 cells include IL-4, IL-5, IL-6, and IL-10, ie,
a predominantly anti-inflammatory cytokine profile. Both
TH1 and TH2 cells produce IL-3 and granulocyte-macro-
phage colony stimulating factor (GM-CSF).13–20 Recently
a TH3 subset (characterized by TGF) has been defined.
In humans, the distinction between TH1, TH2 and TH3
is less well defined, and a subset of TH0 cells, which pro-
duce some cytokines typical of TH1 and TH2 profiles can
be identified. The clinical outcome of many infectious,
autoimmune, or malignant diseases appears to be influ-
enced by the overall balance of production (profiles) of
pro-inflammatory and anti-inflammatory cytokines.21–31
Hence, much interest has focused upon the regulation of
genes expressing these cytokines. In particular, a signifi-
cant number of studies have addressed whether genetic
polymorphism within these genes might influence the
levels of expression, and therefore the overall immune
response. A review of the findings of these studies is
Cytokine gene polymorphism: influence on protein structure, expression and Cytokine gene polymorphism
Non-conservative mutation within the coding region of
genes can result in loss, abrogation, or change of function
in the expressed protein as a result of change in protein
structure. Cytokine and cytokine receptor genes are gen-
erally highly conserved in terms of exon sequences,32,33
although examples of amino acid sequence variation
have been found for IL-4 receptor, LT␣ (TNF), TGF
and GM-CSF receptor  in healthy individuals; and in the
IL-2 receptor ␥ gene for persons with severe combined
immunodeficiency (Tables 1 and 3). Although conserva-
tive (silent) mutations do not affect amino acid sequence,
they may influence protein expression in a variety of
other ways: for example, they can alter mRNA splicing,
mRNA stability, and levels of gene transcription. Poly-
morphisms within the 5Ј- and 3Ј-regulatory sequences or
introns of genes may have a significant effect on tran-
scription, since they may alter the structure of transcrip-
tion factor binding sites within gene promoters or the
structure of enhancers and silencers within introns or at
more remote regulatory sites. Finally, they may alter
binding sites within the nuclear matrix for architectural
geometry.34 Many of the reported polymorphisms within
cytokine genes occur within known or putative regulat-
The rationale for studying cytokine gene polymor-
phisms in human disease can be broadly summarised
Cytokine gene polymorphism in human disease J Bidwell et al Table 1 Continued Table 2 In vitro expression studies
LT␣ (TNF) Intron 1, NcoI RFLP (Thr26Asn)
Intron 1 (CA)n repeat, allele 2 Increased
• To enhance the understanding of the aetiology and
To identify potential markers of susceptibility, severity,
• To identify potential markers for responders vs non-
• To identify targets for therapeutic intervention.
studies attempt to determine a genetic basis for interindi-
To identify novel strategies to prevent disease or to
vidual differences in the immune response. This is achi-
improve existing preventions such as vaccines.
eved by examining the relationship between individual
The influence of cytokine gene polymorphisms on gene
polymorphic alleles or haplotypes of cytokine genes and
expression and disease has been addressed at two levels
the expression of the transcript or cytokine in vitro. The
of research: studies using in vitro gene expression, and
main approaches used to date include measuring the lev-
those involving in vivo disease association. Only a few
els of cytokine or cytokine receptor mRNA, or of cytokine
studies have thus far integrated both of these approaches.
or receptor protein, expressed as a result of in vitro stimu-lation of cells in culture with a mitogen; and isolation of
In vitro gene expression studies
individual alleles of gene promoters by cloning adjacent
Up-regulated and/or down-regulated expression and
to a reporter gene in an expression vector, followed by
production of cytokine mRNA and cytokines, or of their
transfection of an appropriate cell line and measurement
receptors, is a feature in most immune responses in
of reporter protein expression. The majority of studies to
human diseases. However, this response may differ sig-
date have followed the first approach. It is becoming
nificantly among individuals. In vitro gene expression
increasingly apparent that the results of expression stud-
Cytokine gene polymorphism in human disease Table 3 In vivo disease association studies
Early-onset pauciarticular juvenile chronic
Early-onset pauciatricular juvenile chronic
frequency of allele5; decreasedfrequency of allele2)
Inflammatory bowel disease and ulcerative
Graft-versus-host disease in allogeneic bone
Rheumatoid arthritis and Felty’s syndrome
IL-10 −1082A, −819C, −592C haplotype
IL-10 −1082A, −819T, −592A haplotype
IL-10 −1082G, −819C, −592C haplotype
Grave’s disease and Grave’s ophthalmopathy
Insulin-dependent diabetes mellitus, Non-
insulin-dependent diabetes mellitusnephropathy
Cytokine gene polymorphism in human disease J Bidwell et al Table 3 Continued
Early-onset pauciarticular juvenile chronic
Insulin-dependent diabetes mellitus (with
Insulin-dependent diabetes mellitus (DR3-
Low-grade squamous intraepithelial lesions
IL-1 −511 G→A (AvaI), IL-1␣ −889, IL-1Ra
Early-onset pauciarticular juvenile chronic
Severe combined immunodeficiency disease*
Early-onset pauciarticular juvenile chronic
Systemic-onset juvenile chronic arthritis
Rheumatoid arthritis, pauciarticular juvenile
rheumatoid arthritis, systemic lupuserythematosus
Cytokine gene polymorphism in human disease Table 3 Continued
TNFa, TNFb, TNFc, TNFd
TNFa1b5, a2b1, a2b3, a7b4, a6 b5
Campylobacter jejuni-related Guillain-Barre
Early-onset pauciarticular juvenile chronic
TNFa6, b5, c1, d3, e3
Graft-versus-host disease in allogeneic bone
TNF receptor-associated periodic syndromes
Early-onset pauciarticular juvenile chronic
Cytokine gene polymorphism in human disease J Bidwell et al Table 3 Continued
Early-onset pauciarticular juvenile chronic
Graft-versus-host disease in allogeneic bone
Systemic lupus erythematosus and nephritis
TNF␣ −308 and LT␣ (TNF) NcoI
TNF␣ −308 and LT␣ (TNF) NcoI
TNF␣ −308 and LT␣ (TNF) NcoI
TNF␣ −308 and LT␣ (TNF) NcoI
TNF␣ −308 and LT␣ (TNF) NcoI
TNF␣ −308 and LT␣ (TNF) NcoI
TNF␣ −308 and LT␣ (TNF) NcoI
TNF␣ −308 and LT␣ (TNF) NcoI
TNF␣ −308 and LT␣ (TNF) NcoI
TNF␣ −308 and LT␣ (TNF) NcoI
Cytokine gene polymorphism in human disease Table 3 Continued
Hyperinsulinaemia in coronary artery disease
Rheumatoid arthritis, pauciarticular juvenile
rheumatoid arthritis, systemic lupuserythematosus, Sjo¨gren’s
LT␣ (TNF) NcoI & EcoRI
LT␣ (TNF) NcoI, TNFa, b, c
*For other SCID-IL-2R␥ associations, information is available from the World Wide Web site:
http://www.nhgri.nih.gov/DIR/LGT/SCID/IL2RGbase.html
ies may be critically influenced by several factors such as
ficulty in selecting from among the many candidate
the cell lineage used in the assay and the therapeutic pre-
possibilities, and the likely modest effect of any single
conditioning or treatment of subjects prior to harvesting
disease susceptibility gene. The difficulty in identifying
cells for the assay. Therefore, the reader should refer to
a perfectly matched control group creates an additional
publications of individual studies in which apparent con-
limitation, increasing the possibility that a potentially
tradictions between results are evident. A review of the
positive association is biologically irrelevant because of
results of the principal studies is shown in Table 2.
population admixture. Furthermore, even when casesand controls are adequately matched, most study designs
In vivo disease association studies
involve relatively small sample sizes which lack the stat-
These studies attempt to identify immunogenetic mark-
istical power to detect small or moderate gene effects.
ers for a given disease. Association is sought between
Other approaches to identifying associations between
specific cytokine gene polymorphisms and clinical out-
complex traits and cytokine or cytokine receptor gene
come by direct comparison of individual cytokine geno-
polymorphism use a variety of family-based study
types and the clinical features of the disease (eg, suscepti-
designs. These include whole genome scanning using
bility, duration and severity). The a priori involvement
linkage analysis (LOD scores) and affected sib-pair (ASP)
of dysregulation of a specific cytokine or receptor in the
methods. With identification of specific chromosomal
disease is usually, though not always, the rationale for
regions, more precise localisation required the develop-
selecting a cytokine or cytokine receptor gene for analy-
ment of linkage disequilibrium mapping35 and trans-
sis. Such data may be generated using population-based
mission disequilibrium testing36,37 with the establishment
or family studies in humans or using animal models, and
of ancestral haplotypes among disease-associated chro-
may be from analysis of secreted, cell surface or intra-
cellular protein, or of cytokine mRNA. Using these and
Allelic association methods based on increased trans-
other clues, many studies have identified statistically sig-
mission of marker alleles will need to be employed for
nificant associations between cytokine alleles and disease.
the mapping of complex disease susceptibility genes.
However, in many of these studies the in vitro expression
However, because the extent of association of single
studies have not been attempted, or are the subject of
marker alleles with disease is a function of the relative
controversy, or by consensus have not indicated a con-
frequency of the allele on disease-associated chromo-
vincing functional rationale for the association.
somes vs non disease-predisposing chromosomes, the
The genetic analysis of cytokines in human disease has
most associated marker allele in a region will not neces-
traditionally focused on case-control association studies,
sarily be closest to the disease locus. Although this area
in which the frequencies of marker alleles in groups of
is controversial, the extended transmission/disequilbrium
patients and healthy controls are compared, and the dif-
ference is subjected to statistical analysis. The association
While combined analysis of data from several studies
is often expressed as the relative risk (or odds ratio) that
can be pooled to increase confidence in the strength of
an individual will develop the disorder if he or she car-
observed associations, biases in reporting positive or
ries the particular allele or marker, compared to an indi-
weak associations as opposed to lack of reporting nega-
vidual who does not carry the allele or marker. These
tive associations also influences interpretation of pub-
studies have met with only modest success in identifying
disease-causing cytokine genes, in part because of the dif-
One of the sometimes overlooked aspects of such dis-
Cytokine gene polymorphism in human disease J Bidwell et al
ease association studies is that the cytokine network is
Related World Wide Web sites
highly complex, containing interactive cascades of geneactivation and suppression. One consequence of mutual
Human cytokine gene nucleotide sequence alignments:
TH1–TH2 antagonism may be the predominance of one
http://www.pam.bris.ac.uk/services/cytokine2.htm
or the other subset, which might directly influence the
PubMed search engine, primed to search for cytokine
clinical outcome of disease. Therefore, genetic polymor-
phisms in cytokine genes and their receptors which regu-
http://www.gla.ac.uk/Acad/FacMed/Surgery/ggtemp/
late expression should not in all cases be studied strictly
in isolation. This is because individual associations maybe non-informative, whereas specific combinations of
On-line Mendelian Inheritance in Man (OMIM) Web site:
cytokine genotypes might predispose to disease suscepti-
http://www3.ncbi.nlm.nih.gov/Omim/searchomim.html
bility or outcome. Only a very few studies to date have
attempted to analyse the combined contribution of morethan one cytokine gene polymorphism to disease.
In addition, other elements which can influence the
A review of the results of the principal disease associ-
expression of cytokine (and other?) genes should not be
ation studies is shown in Table 3, both statistically sig-
forgotten. For example, the rigour with which Fishman
nificant (scored as ‘yes’) and statistically non-significant
et al64 approached the measurement of IL-6 production in
(scored as ‘no’). The statistical significance is recorded as
their control subjects, demonstrates the importance of the
interpreted by the originating authors: for details of the
natural metabolic variation which occurs daily. This sup-
statistical tests and corrections used, the reader should
ported earlier studies, for example that of Petrovsky and
refer to the papers cited. For certain combinations of
Harrison,313 who showed that the LPs induction of IL-10
polymorphisms and diseases, contradictory results have
and IFN-gamma varied throughout the day, observing
been published. In these cases, the discordancy may be
that the IFN-gamma/IL-10 ratio peaked early in the
attributable to differences in ethnicity of populations,
morning and concluding that both cortisol and melatonin
patient and/or control cohort selection or size, disease
could regulate diurnal immune variation. Although
classification or status, or methods of statistical analysis.
much has been made of the requirement for caution
Both in vitro expression studies and in vivo disease associ-
when interpreting genetic data from the TNF cluster
ation studies involving TNF␣ and LT␣ (TNF) polymor-
without due consideration of the MHC and linkage dis-
phisms are often complicated by their linkage disequilib-
equilibrium, MHC effects on cytokines off chromosome
rium (LD) with HLA genes and haplotypes within the
6 have not been so well documented. The evidence is
major histocompatibility complex. This has created diffi-
beginning to emerge, however. A study in 1997314 dem-
culties in dissecting the independent role of TNF in
onstrated that secreted levels of IFN-gamma varied
expression and disease (see Table 2 and 3 for examples).
markedly with class-II alleles, in an MLR. DR1, DR2 andDR6 were associated with high IFN-gamma secretion
On-line databases
while DR3, DR4 and DR7 were associated with lowerIFN-gamma production. Similar conclusions were drawn
Tables 1, 2 and 3 and associated citations are reproduced
for those DQ alleles in linkage disequilibrium with the
in electronic form on the World Wide Web. They are
DR alleles noted above. This pattern was reversed for
searchable using the appropriate ‘find’ command of Web
TNF secretion (ie, DR3 was high TNF and so on), mir-
browsers. It is the intention of the authors to issue regular
roring earlier work by Pociot et al115 who demonstrated
updates of these tables as part of an ongoing feature of
a DR-based hierarchy of TNF secretion which was of
this Journal. Notification and details of the revisions to
greater magnitude than the TNF-allele results for which
the tables will be published as appropriate.
they are more usually remembered. Similar data are
The Web site URL for Tables 1, 2 and 3 and associated
available for other aspects of the immune system, for
http://www.pam.bris.ac.uk/services/GAI/cytokine4.htm
In this regard, DR3 has received the greatest attention.
T cell activation varies in DR3-positive individuals, per-
Cytokine reviews database
haps because of diminished CD69 expression,316 as docytokines themselves317 particularly in regard to auto-
In addition to these databases, we have issued a search-
immune DR3 positive subjects.318 Apoptosis may differ
able reference database containing 1000 cytokine review
because these individuals have diminished expression of
citations, from 1990 to the present. This database is pro-
CD95 (FAS319) and indeed lower total lymphocyte counts
have been described in aassociation with B8-DR3.320 Little
insight to the mechanism of these various effects by the
Endnote version 3 (filename CYTOREVIEWS.ENL)
class-II on immune function was available until recently,
Tagged MEDLARS format (.TAG) file (filename
when it was demonstrated that different class-II mol-
ecules varied in the efficiency with which they transduce
The files contain both general and disease-specific reviews
signals from CD4 across the cell membrane, and that this
relating to cytokines and cytokine receptors. The Endnote
variation is carried with the intracellular portion of the
version may be searched using any criteria available
class-II molecule.321 As if this were not confusing enough,
within the Endnote application, eg, by author or
the age of the donors themselves has been shown to affect
keyword. The tagged MEDLARS version may be
T cell activation322,323 through various mechanisms. In
imported directly into other reference manager pro-
conclusion, the genetic effect seen to be acting on cytokine
grams. Both files may be downloaded directly from the
production, and implicating them as disease-associated loci
in their own right, are complicated by the MHC and age. Cytokine gene polymorphism in human disease
How well we as a research community deal with these
25 Karban A, Lerner A, Shapiro S. Th1/TH2 cytokine profile in
complications will determine how efficiently the influence
celiac disease. Israel J Med Sci 1997; 33: 209–214.
of cytokine immunogenetics on disease is elucidated.
26 Wu TC, Kurman RJ. Analysis of cytokine profiles in patients
with human papillomavirus-associated neoplasms. J Nat Cancer Inst 1997; 89: 185–187.
27 Rugtveit J, Nilsen EM, Bakka A, Carlsen H, Brandtzaeg P, Scott
References
H. Cytokine profiles differ in newly recruited and resident sub-sets of mucosal macrophages from inflammatory bowel dis-
1 Hibi M, Hirano T. Signal transduction through cytokine recep-
ease. Gastroenterology 1997; 112: 1493–1505.
tors. Int Rev of Immunol 1998; 17: 75–102.
28 Groux H, Rouleau M, Bacchetta R, Roncarolo MG. T-cell sub-
2 Onishi M, Nosaka T, Kitamura T. Cytokine receptors: struc-
sets and their cytokine profiles in transplantation and toler-
tures and signal transduction. Int Rev of Immunol 1998; 16:
ance. Annals of the New York Acad of Sci 1995; 770: 141–148.
29 Miossec P. Acting on the cytokine balance to control auto-
3 Rubinstein M, Dinarello CA, Oppenheim JJ, Hertzog P. Recent
immunity and chronic inflammation. Eur Cytokine Netw 1993;
advances in cytokines, cytokine receptors and signal transduc-
4: 245–251.
tion. Cytokine and Growth Factor Rev 1998; 9: 175–181.
30 Miossec P. Pro- and antiinflammatory cytokine balance in
4 Carpenter LR, Yancopoulos GD, Stahl N. General mechanisms
rheumatoid arthritis. Clin Exp Rheumatol 1995; 13 (Suppl 12):
of cytokine receptor signaling. Adv Protein Chem 1998; 52:
31 Rabinovitch A. Immunoregulatory and cytokine imbalances in
5 Ihle JN, Thierfelder W, Teglund S et al. Signaling by the cyto-
the pathogenesis of IDDM. Therapeutic intervention by immu-
kine receptor superfamily. Ann NY Acad Sci 1998; 865: 1–9.
nostimulation? Diabetes 1994; 43: 613–621.
6 Casciari JJ, Sato H, Durum SK, Fiege J, Weinstein JN. Reference
32 Bidwell JL, Wood NAP, Morse HR, Olomolaiye OO, Laundy
databases of cytokine structure and function. Cancer Chemother
GJ. Human cytokine gene nucleotide sequence alignments,
Biolog Response Modifiers 1996; 16: 315–346.
1998. Eur J Immunogenet 1998; 25: 83–266.
7 Minasian E, Nicola NA. A review of cytokine structures. Pro-
33 Bidwell JL, Wood NAP, Morse HR, Olomolaiye OO, Keen LJ,
tein Sequences and Data Analysis 1992; 5: 57–64.
Laundy GJ. Human cytokine gene nucleotide sequence align-
8 Balkwill FR, Burke F. The cytokine network. Immunology Today
ments: supplement 1. Eur J Immunogenet 1999; 26: 135–223.
1989; 10: 299–304.
34 Bidwell JP. Nuclear matrix proteins and osteoblast gene
9 Elias JA, Zitnik RJ. Cytokine-cytokine interactions in the con-
expression. J Bone Miner Res 1998; 13: 155–167.
text of cytokine networking. Am J Respirat Cell Molecul Biol
35 Escamilla MA, McInnes LA, Spesney M, Reus VI, Service SK,
1992; 7: 365–367.
Shimayoshi N. Assessing the feasibility of linkage disequilib-
10 Fraser JK, Lill MC, Figlin RA. The biology of the cytokine
rium methods for mapping complex traits: an initial screen for
sequence cascade. Seminars in Oncology 1996; 23: 2–8.
bipolar disorder loci on chromosome 18. Am J Hum Genet 1999;
11 Kunkel S, Standiford T, Chensue SW, Kasahara K, Strieter RM. 64: 1670–1678.
Cellular and molecular mechanisms of cytokine networking.
36 Spielman RS, McGinnis RE, Ewens WJ. Transmission test for
Agents And Actions. Supplements 1991; 32: 205–218.
linkage disequilibrium the insulin gene and insulin-dependent
12 Olsson I. The cytokine network. J Intern Med 1993; 233: 103–105.
diabetes mellitus (IDDM). Am J Hum Genet 1993; 52: 506–516.
13 Abbas AK, Williams ME, Burstein HJ, Chang TL, Bossu P,
37 Sham PC, Curtis D. An extended transmission/disequilbrium
Lichtman AH. Activation and functions of CD4+ T-cell subsets.
test (TDT) for multi-allele marker loci. Am J Hum Genet 1995;
Immunol Rev 1991; 123: 5–22. 59: 323–336.
14 HayGlass KT, Wang M, Gieni RS, Ellison C, Gartner J. In vivo
38 Merriman TR, Eaves IA, Twells RC, Merriman ME, Danoy PA,
direction of CD4 T cells to Th1 and Th2-like patterns of cyto- kine synthesis. Advances in Experiment Med and Biol 1996; 409:
Muxworthy CE. Transmission of haplotypes of microsatellite
markers rather than single marker alleles in the mapping of
15 Kapsenberg ML, Wierenga EA, Bos JD, Jansen HM. Functional
putative type 1 diabetes susceptibility gene (IDDM6). Hum Mol
subsets of allergen-reactive human CD4+ T cells. ImmunolGenet 1998; 7: 517–524. Today 1991; 12: 392–395.
39 Falk CT, Ashley A, Lamb N, Sherman SL. Identification of sus-
16 Kelso A, Troutt AB, Maraskovsky E et al. Heterogeneity in lym-
ceptibility loci contributing to a complex disease using conven-
phokine profiles of CD4+ and CD8+ T cells and clones acti-
tional segregation, linkage, and association methods. Genet Epi-
vated in vivo and in vitro. Immunolog Rev 1991; 123: 85–114. demiol 1995; 12: 601–606.
17 Lederer JA, Liou JS, Todd MD, Glimcher LH, Lichtman AH.
40 Bailly S, di Giovine FS, Duff GW. Polymorphic tandem repeat
Regulation of cytokine gene expression in T helper cell subsets.
region in interleukin-1 alpha intron 6. Hum Genet 1993; 91: J Immunol 1994; 152: 77–86.
18 Mosmann TR, Sad S. The expanding universe of T-cell subsets:
41 Kornman KS, di Giovine FS. Genetic variations in cytokine
Th1, Th2 and more. Immunol Today 1996; 17: 138–146.
expression: a risk factor for severity of adult periodontitis. Ann
19 Williams ME, Chang TL, Burke SK, Lichtman AH, Abbas AK. Periodontol 1998; 3: 327–338.
Activation of functionally distinct subsets of CD4+ T lympho-
42 Todd S, Naylor SL. Dinucleotide repeat polymorphism in the
cytes. Res Immunol 1991; 142: 23–28.
human interleukin 1, alpha gene (IL1A). Nucleic Acids Res 1991;
20 Mosmann TR. Cytokine secretion patterns and cross-regulation
19: 3756.
of T cell subsets. Immunol Res 1991; 10: 183–188.
43 Epplen C, Frank G, Gomolka M, Albert E, Nurnberg P, Epplen
21 Ha¨ssig A, Kremer H, Liang WX, Stampfli K. The role of the
JT. Dinucleotide repeat polymorphism in the human IL1A
Th-1 to Th-2 shift of the cytokine profiles of CD4 helper cells
gene. Hum Mol Genet 1994; 3: 1710.
in the pathogenesis of autoimmune and hypercatabolic dis-
44 Zuliani G, Hobbs HH. A high frequency of length polymor-
eases. Med Hypotheses 1998; 51: 59–63.
phisms in repeated sequences adjacent to Alu sequences. Am
22 Cunha-Neto E, Rizzo LV, Albuquerque F et al. Cytokine pro-
J Hum Genet 1990; 46: 963–969.
duction profile of heart-infiltrating T cells in Chagas’ disease
45 di Giovine FS, Takhsh E, Blakemore AI, Duff GW. Single base
cardiomyopathy. Brazilian J Med Biolog Res 1998; 31: 133–137.
polymorphism at -511 in the human interleukin-1 beta gene
23 Shearer GM, Clerici M. Cytokine profiles in HIV type 1 disease
(IL1 beta). Hum Mol Genet 1992; 1: 450.
and protection. Aids Res and Human Retroviruses 1998; 14 (Suppl
46 Guasch JF, Bertina RM, Reitsma PH. Five novel intragenic
dimorphisms in the human interleukin-1 genes combine to
24 Miossec P, van den Berg W. Th1/Th2 cytokine balance in
high informativity. Cytokine 1996; 8: 598–602.
arthritis. Arthritis and Rheumatism 1997; 40: 2105–2115.
47 Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J. A TaqI
Cytokine gene polymorphism in human disease J Bidwell et al
polymorphism in the human interleukin-1 beta (IL-1 beta) gene
berg JR. A greater variability in the 3Ј flanking region of the
correlates with IL-1 beta secretion in vitro. Eur J Clin Invest
IL-6 gene in patients with systemic lupus erythematosus (SLE).
1992; 22: 396–402. Autoimmunity 1996; 23: 199–209.
48 Tarlow JK, Blakemore AI, Lennard A et al. Polymorphism in
70 Tsukamoto K, Haruta K, Shiba T, Emi M. Isolation and map-
human IL-1 receptor antagonist gene intron 2 is caused by vari-
ping of a polymorphic CA repeat sequence at the human
able numbers of an 86-bp tandem repeat. Hum Genet 1993; 91:
interleukin 6 locus. J Hum Genet 1998; 43: 71–72.
71 Tsukamoto K, Ohta N, Shirai Y, Emi M. A highly polymorphic
49 Bergholdt R, Karlson AE, Johannesen J et al. Characterization of
CA repeat marker at the human interleukin 6 receptor (IL6R)
polymorphisms of an interleukin 1 receptor type 1 gene (IL1RI)
locus. J Hum Genet 1998; 43: 289–290.
promotor region (P2) and their relation to insulin-dependent
72 Fey MF, Tobler A. An interleukin-8 (IL-8) cDNA clone ident-
diabetes mellitus (IDDM). The Danish Study Group of Diabetes
ifies a frequent HindIII polymorphism. Hum Genet 1993; 91: 298.
in Childhood. Cytokine 1995; 7: 727–733.
73 Polymeropoulos MH, Xiao H, Rath DS, Merril CR. Dinucleo-
50 John S, Turner D, Donn R et al. Two novel biallelic polymor-
tide repeat polymorphism at the human interleukin 9 gene.
phisms in the IL-2 gene. Eur J Immunogenet 1998; 25: 419–420. Nucleic Acids Res 1991; 19: 688.
51 Epplen C, Frank G, Gomolka M, Nagy M, Nurnberg P, Epplen
74 Tounas N, Cominelli F. Identification and initial characteris-
JT. Dinucleotide repeat polymorphism in the IL2 and IL5RA
ation of two polymorphisms in the human IL-10 promoter. Eur-
genes. Hum Mol Genet 1994; 3: 679. opean Cytokine Network 1996; 7: 578 (Abstract).
52 Cottrell S, Bodmer WF, Markie D. TaqI RFLP for the IL2RA
75 Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ,
locus. Hum Mol Genet 1994; 3: 2085.
Hutchinson IV. An investigation of polymorphism in the
53 Brewster ES, Brennan MB, Vissing H. Dinucleotide repeat poly-
interleukin-10 gene promoter. Eur J Immunogenet 1997; 24: 1–8.
morphism in the IL-2R beta gene. Nucleic Acids Res 1991; 19:
76 Eskdale J, Kube D, Tesch H, Gallagher G. Mapping of the
human IL 10 gene and further characterization of the 5Ј flank-
54 Jaquet K, Kreipe H, Felgner J, Radzun HJ, Parwaresch MR. A
ing sequence. Immunogenetics 1997; 46: 120–128.
Bg1II RFLP demonstrated for the IL-3 gene in normal human
77 Eskdale J, Gallagher G. A polymorphic dinucleotide repeat in
blood cells and leukemias. Nucleic Acids Res 1989; 17: 3620.
the human IL-10 promoter. Immunogenetics 1995; 42: 444–445.
55 Jeong MC, Navani A, Oksenberg JR. Limited allelic polymor-
78 Eskdale J, Kube D, Gallagher G. A second polymorphic
phism in the human interleukin-3 gene. Molecular and Cellular
dinucleotide repeat in the 5Ј flanking region of the human IL
Probes 1998; 12: 49–53.
10 gene. Immunogenetics 1996; 45: 82–83.
56 Walley AJ, Cookson WO. Investigation of an interleukin-4 pro-
79 Bellingham J, Gregory-Evans K, Gregory-Evans CY. A poly-
moter polymorphism for associations with asthma and atopy.
morphic dinucleotide repeat in the 5Ј flanking region of the
J Med Genet 1996; 33: 689–692.
human interleukin 11 (IL11) gene. Immunogenetics 1998; 47:
57 Mout R, Willemze R, Landegent JE. Repeat polymorphisms in
the interleukin-4 gene (IL4). Nucleic Acids Res 1991; 19: 3763.
80 Higuchi T, Seki N, Kamizono S et al. Polymorphism of the 5Ј-
58 Deichmann K, Bardutzky J, Forster J, Heinzmann A, Kuehr J.
flanking region of the human tumor necrosis factor (TNF)-
Common polymorphisms in the coding part of the IL4-receptor
alpha gene in Japanese. Tissue Antigens 1998; 51: 605–612.
gene. Biochem Biophys Res Commun 1997; 231: 696–697.
81 Uglialoro AM, Turbay D, Pesavento PA et al. Identification of
59 Hershey G, Friedrich M, Esswein L, Thomas M, Chatila T. The
three new single nucleotide polymorphisms in the human
association of atopy with a gain-of-function mutator in the ␣
tumor necrosis factor-alpha gene promoter. Tissue Antigens
subunit of the interleukin 4 receptor. N Engl J Med 1997; 337:
1998; 52: 359–367.
82 Brinkman BM, Huizinga TW, Kurban SS et al. Tumour necrosis
60 Kollintza A, Worthington J, John S, Ollier WER, Hajeer AH. A
factor alpha gene polymorphisms in rheumatoid arthritis:
novel polymorphism in the IL-5R alpha gene promoter. Eur J
association with susceptibility to, or severity of, disease? Br JImmunogenet 1998; 25: 79 (Abstract). Rheumatol 1997; 36: 516–521.
61 Kollintza A, Worthington J, John S, Ollier WE, Hajeer AH. A
83 Wilson AG, de Vries N, Pociot F, di Giovine FS, van der Putte
new polymorphism in the promoter of the interleukin 5 recep- tor alpha subunit (IL-5RA) gene. Immunogenetics 1998; 48: 65–66.
LB, Duff GW. An allelic polymorphism within the human
62 Olomolaiye OO, Wood NAP, Bidwell JL. Identification of a
tumor necrosis factor alpha promoter region is strongly asso-
novel polymorphism in the human IL-6 promoter region.
ciated with HLA A1, B8, and DR3 alleles. J Exp Med 1993; 177: Immunology 1997; 92 (Suppl 1): 66 (Abstract 15.32).
63 Olomolaiye OO, Wood NAP, Bidwell JL. A novel NlaIII poly-
84 Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff
morphism in the human IL-6 promoter. Eur J Immunogenet
GW. Effects of a polymorphism in the human tumor necrosis
1998; 25: 267.
factor alpha promoter on transcriptional activation. Proc Natl
64 Fishman D, Faulds G, Jeffery R et al. The effect of novel poly-
Acad Sci USA 1997; 94: 3195–3199.
morphisms in the interleukin-6 (IL-6) gene on IL-6 transcrip-
85 D’Alfonso S, Richiardi PM. A polymorphic variation in a puta-
tion and plasma IL-6 levels, and an association with systemic-
tive regulation box of the TNFA promoter region. Immuno-
onset juvenile chronic arthritis. J Clin Invest 1998; 102: 1369– genetics 1994; 39: 150–154.
86 Nedospasov SA, Udalova IA, Kuprash DV, Turetskaya RL.
65 Bowcock AM, Ray A, Erlich H, Sehgal PB. Rapid detection and
DNA sequence polymorphism at the human tumor necrosis
sequencing of alleles in the 3Ј flanking region of the interleu-
factor (TNF) locus. Numerous TNF/lymphotoxin alleles
kin-6 gene. Nucleic Acids Res 1989; 17: 6855–6864.
tagged by two closely linked microsatellites in the upstream
66 Murray RE, McGuigan F, Grant SF, Reid DM, Ralston SH. Poly-
region of the lymphotoxin (TNF-beta) gene. J Immunol 1991;
morphisms of the interleukin-6 gene are associated with bone
147: 1053–1059.
mineral density. Bone 1997; 21: 89–92.
87 Udalova IA, Nedospasov SA, Webb GC, Chaplin DD, Turets-
67 Fugger L, Morling N, Bendtzen K et al. MspI polymorphism
kaya RL. Highly informative typing of the human TNF locus
in the human interleukin 6 (IL 6) gene. Nucleic Acids Res 1989;
using six adjacent polymorphic markers. Genomics 1993; 16: 17: 4419.
68 Blankenstein T, Volk HD, Techert-Jendrusch C, Qin ZH,
88 Messer G, Spangler U, Jung MC et al. Polymorphic structure
Richter G, Diamantstein T. Lack of correlation between Bg1II
of the tumor necrosis factor (TNF) locus: an NcoI polymor-
RFLP in the human interleukin 6 gene and rheumatoid
phism in the first intron of the human TNF-beta gene correlates
arthritis. Nucleic Acids Res 1989; 17: 8902.
with a variant amino acid in position 26 and a reduced level
69 Linker-Israeli M, Wallace DJ, Prehn JL, Nand R, Li L, Klinen-
of TNF-beta production. J Exp Med 1991; 173: 209–219. Cytokine gene polymorphism in human disease
89 Rink L, Kirchner H. Recent progress in the tumor necrosis fac-
acute myeloid leukaemia (AML) are rare. Leukemia 1996; 10:
tor-alpha field. Int Arch Allergy Immunol 1996; 111: 199–209.
90 Ferencik S, Lindemann M, Horsthemke B, Grosse-Wilde H. A
109 Eskdale J, Gallagher C, Verweij CL, Keijsers V, Westendorp
new restriction fragment length polymorphism of the human
RG, Huizinga TW. Interleukin 10 secretion in relation to
TNF-B gene detected by AspHI digest. Eur J Immunogenet 1992;
human IL-10 locus haplotypes. Proc Natl Acad Sci USA 1998;
19: 425–430. 95: 9465–9470.
91 Pitts SA, Olomolaiye OO, Elson CJ, Westacott CI, Bidwell JL.
110 Bailly S, di Giovine FS, Blakemore AI, Duff GW. Genetic poly-
An MspA1 I polymorphism in exon 1 of the human TNF recep-
morphism of human interleukin-1 alpha. Eur J Immunol 1993;
tor type I (p55) gene. Eur J Immunogenet 1998; 25: 269–270. 23: 1240–1245.
92 Pitts SA, Olomolaiye OO, Elson CJ, Westacott CI, Bidwell JL.
111 Danis VA, Millington M, Hyland VJ, Grennan D. Cytokine pro-
Identification of a rare BglII polymorphism in the promoter
duction by normal human monocytes: inter-subject variation
region of the human TNF receptor type I (p55) gene. Eur J
and relationship to an IL-1 receptor antagonist (IL-1Ra) gene
Immunogenet 1998; 25: 271–272.
polymorphism. Clin Exp Immunol 1995; 99: 303–310.
93 Kaufman BA, White PS, Steinbrueck T, Donis-Keller H, Brod-
112 Hurme M, Santtila S. IL-1 receptor antagonist (IL-1Ra) plasma
cur GM. Linkage mapping of the tumor necrosis factor receptor
levels are co-ordinately regulated by both IL-1Ra and IL-1beta
2 (TNFR2) gene to 1p36.2 using the single-strand conformation
genes. Eur J Immunol 1998; 28: 2598–2602.
polymorphism technique. Human Genetics 1994; 94: 418–422.
113 Pravica V, Asderakis C, Perry C, Hajeer A, Sinnott PJ, Hutchin-
94 Golovleva I, Kandefer-Szerszen M, Beckman L, Lundgren E.
son IV. In vitro production of IFN-␥ correlates with CA repeat
Polymorphism in the interferon-alpha gene family. Am J Hum
polymorphism in the human IFN-␥ gene. Eur J ImmunogenetGenet 1996; 59: 570–578.
1999; 26: 1–3.
95 Kwiatkowski DJ, Diaz MO. Dinucleotide repeat polymorphism
114 Awad MR, El Gamel A, Hasleton P, Turner DM, Sinnott PJ,
at the IFNA locus (9p22). Hum Mol Genet 1992; 1: 658.
Hutchinson IV. Genotypic variation in the transforming growth
96 Vielh E, Uze G, Lutfalla G, Bandu MT, Mogensen KE. HindIII
factor-beta1 gene: association with transforming growth factor-
RFLP at the human IFNAR locus. Nucleic Acids Res 1990; 18:
beta1 production, fibrotic lung disease, and graft fibrosis after
lung transplantation. Transplantation 1998; 66: 1014–1020.
97 Riggin CH, Jr., Pitha PM. Methylation and a polymorphic
115 Pociot F, Briant L, Jongeneel CV et al. Association of tumor
restriction site adjacent to human beta-interferon gene. DNA
necrosis factor (TNF) and class II major histocompatibility com-
1982; 1: 267–271.
plex alleles with the secretion of TNF-alpha and TNF-beta by
98 Gray PW, Goeddel DV. Human immune interferon (IFN-
human mononuclear cells: a possible link to insulin-dependent
gamma) gene sequence and structure. Basic Life Sciences 1983;
diabetes mellitus. Eur J Immunol 1993; 23: 224–231. 25: 35–61.
116 Derkx HH, Bruin KF, Jongeneel CV. Familial differences in
99 Ruiz-Linares A. Dinucleotide repeat polymorphism in the
endotoxin-induced TNF release in whole blood and peripheral
interferon-gamma (IFNG) gene. Hum Mol Genet 1993; 2: 1508.
blood mononuclear cells in vitro: relationship to TNF gene
100 Hauptschein R, Dalla-Favera R, Gaidano G. TaqI RFLP in the
polymorphism. J Endothelial Res 1995; 2: 19–25.
interferon gamma receptor 1 gene (IFNGR1) on human chro-
117 Turner DM, Grant SC, Lamb WR et al. A genetic marker of
mosome 6q. Nucleic Acids Res 1992; 20: 1158.
high TNF-alpha production in heart transplant recipients.
101 Hayward NK, Nancarrow DJ, Bell GI. A Taq I polymorphism
Transplantation 1995; 60: 1113–1117.
118 Grove J, Daly AK, Bassendine MF, Day CP. Association of a
for the human transforming growth factor alpha gene (TGFA).
tumor necrosis factor promoter polymorphism with suscepti-
Nucleic Acids Res 1987; 15: 5503.
bility to alcoholic steatohepatitis. Hepatology 1997; 26: 143–146.
102 Cambien F, Ricard S, Troesch A et al. Polymorphisms of the
119 Pociot FSDA, Compasso S, Scorza R, Richiardi PM. Functional
transforming growth factor-beta 1 gene in relation to myocar-
analysis of a new polymorphism in the human TNF alpha gene
dial infarction and blood pressure. The Etude Cas-Temoin de
promoter. Scand J Immunol 1995; 42: 501–504.
l’Infarctus du Myocarde (ECTIM) Study. Hypertension 1996; 28:
120 Huizinga TW, Westendorp RG, Bollen EL et al. TNF-alpha pro-
moter polymorphisms, production and susceptibility to mul-
103 Awad MR, El Gamel A, Hasleton P, Sinnott P, Hutchinson IV.
tiple sclerosis in different groups of patients. J Neuroimmunol
Polymorphism in transforming growth factor-beta 1 gene and
1997; 72: 149–153.
its correlation to TGF-beta 1 production, allograft fibrosis and
121 Kaijzel EL, van Krugten MV, Brinkman BM et al. Functional
fibrotic lung diseases. Eur J Immunogenet 1998; 25: 70 (Abstract).
analysis of a human tumor necrosis factor alpha (TNF-alpha)
104 Langdahl BL, Knudsen JY, Jensen HK, Gregersen N, Eriksen
promoter polymorphism related to joint damage in rheumatoid
EF. A sequence variation: 713–8delC in the transforming
arthritis. Molecular Med 1998; 4: 724–733.
growth factor-beta 1 gene has higher prevalence in osteopor-
122 Pociot F, Wilson AG, Nerup J, Duff GW. No independent
otic women than in normal women and is associated with very
association between a tumor necrosis factor-alpha promotor
low bone mass in osteoporotic women and increased bone
region polymorphism and insulin-dependent diabetes mellitus.
turnover in both osteoporotic and normal women. Bone 1997;
Eur J Immunol 1993; 23: 3050–3053. 20: 289–294.
123 Galbraith GM, Steed RB, Sanders JJ, Pandey JP. Tumor necrosis
105 Nishimura DY, Purchio AF, Murray JC. Linkage localization of
factor alpha production by oral leukocytes: influence of tumor
TGFB2 and the human homeobox gene HLX1 to chromosome
necrosis factor genotype. J Periodontol 1998; 69: 428–433.
1q. Genomics 1993; 15: 357–364.
124 Kralovics R, Sokol L, Prchal JT. Absence of polycythemia in a
106 Wagner HM, Gale RE, Freeburn RW, Devereux S, Linch DC.
child with a unique erythropoietin receptor mutation in a fam-
Analysis of mutations in the GM-CSF receptor alpha coding
ily with autosomal dominant primary polycythemia. J Clin
sequence in patients with acute myeloid leukaemia and haema-
Invest 1998; 102: 124–129.
tologically normal individuals by RT-PCR-SSCP. Leukemia
125 Epplen C, Rumpf H, Albert E, Haas P, Truckenbrodt H, Epplen
1994; 8: 1527–1532.
J. Immunoprinting excludes many potential susceptibility
107 Freeburn RW, Gale RE, Linch DC. Activating point mutations
genes as predisposing to early onset pauciarticular juvenile
in the betaC chain of the GM-CSF, IL-3 and IL-5 receptors are
chronic arthritis except HLA class II and TNF. Eur J Immuno-
not a major contributory factor in the pathogenesis of acute
genet 1995; 22: 311.
myeloid leukaemia. Br J Haematol 1998; 103: 66–71.
126 Epplen C, Jackel S, Santos EJ et al. Genetic predisposition to
108 Freeburn RW, Gale RE, Wagner HM, Linch DC. The beta sub-
multiple sclerosis as revealed by immunoprinting. Ann Neurol
unit common to the GM-CSF, IL-3 and IL-5 receptors is highly
1997; 41: 341–352.
polymorphic but pathogenic point mutations in patients with
127 Siegmund T, Usadel KH, Donner H, Braun J, Walfish PG, Bad-
Cytokine gene polymorphism in human disease J Bidwell et al
enhoop K. Interferon-gamma gene microsatellite polymor-
146 Mok CC, Lanchbury JS, Chan DW, Lau CS. Interleukin-10 pro-
phisms in patients with Graves’ disease. Thyroid 1998; 8:
moter polymorphisms in Southern Chinese patients with sys-
temic lupus erythematosus. Arthritis And Rheumatism 1998; 41:
128 Awata T, Matsumoto C, Urakami T, Hagura R, Amemiya S,
Kanazawa Y. Association of polymorphism in the interferon
147 Lazarus M, Hajeer AH, Turner D et al. Genetic variation in the
gamma gene with IDDM. Diabetologia 1994; 37: 1159–1162.
interleukin 10 gene promoter and systemic lupus ery-
129 Pociot F, Veijola R, Johannesen J et al. Analysis of an interferon-
thematosus. J Rheumatol 1997; 24: 2314–2317.
gamma gene (IFNG) polymorphism in Danish and Finnish
148 Stokkers PC, van Aken BE, Basoski N et al. Five genetic mark-
insulin-dependent diabetes mellitus (IDDM) patients and con-
ers in the interleukin 1 family in relation to inflammatory
trol subjects. Danish Study Group of Diabetes in Childhood.
bowel disease. Gut 1998; 43: 33–39. J Interferon Cytokine Res 1997; 17: 87–93.
149 Langabeer SE, Linch DC. IL-1 receptor antagonist gene poly-
130 Awad MR, Pravica V, El-Gamel A, Hasleton P, Sinnott PJ, Hut-
morphism in patients with secondary acute myeloid leu-
chinson IV. CA repeat allele in the first intron of the interferon
kaemia. Cytokines Cell Mol Ther 1998; 4: 7–9.
gamma (IFNg) gene is associated with the development of
150 Takamatsu M, Yamauchi M, Maezawa Y, Ohata M, Saitoh S,
fibrosis in lung transplants. Abstracts of the British Transplan-
Toda G. Correlation of a polymorphism in the interleukin-1
tation Society 1st Annual Congress 1998.
receptor antagonist gene with hepatic fibrosis in Japanese
131 Wansen K, Pastinen T, Kuokkanen S et al. Immune system
alcoholics. Alcoholism, Clin Exp Res 1998; 22: 141S–144S.
genes in multiple sclerosis: genetic association and linkage
151 Tarlow JK, Clay FE, Cork MJ et al. Severity of alopecia areata
analyses on TCR, IGH, IFN␥ and IL-1Ra/IL-1 loci. J Neuro-
is associated with a polymorphism in the interleukin-1 receptor
immunol 1997; 79: 29–36.
antagonist gene. J Invest Dermatol 1994; 103: 387–390.
132 He B, Xu C, Yang B, Landtblom AM, Fredrikson S, Hillert J.
152 Cork MJ, Tarlow JK, Clay FE et al. An allele of the interleukin-
Linkage and association analysis of genes encoding cytokines
1 receptor antagonist as a genetic severity factor in alopecia
and myelin proteins in multiple sclerosis. J Neuroimmunol 1998;
areata. J Invest Dermatol 1995; 104: 15S–16S. 86: 13–19.
153 Keen RW, Woodford-Richens KL, Lanchbury JS, Spector TD.
133 Asderakis A, Sankaran D, Pravica V et al. High producer inter-
Allelic variation at the interleukin-1 receptor antagonist gene
feron gamma (IFNg) and interleukin 10 (IL-10) genotype is
is associated with early postmenopausal bone loss at the spine.
associated with increased frequency of acute rejection episodes
Bone 1998; 23: 367–371.
in kidney transplant recipients. Abstracts of the British Trans-
154 Hurme M, Helminen M. Polymorphism of the IL-1 gene com-
plantation Society 1st Annual Congress 1998.
plex in Epstein–Barr virus seronegative and seropositive adult
134 Tanaka Y, Nakashima H, Hisano C et al. Association of the
blood donors. Scand J Immunol 1998; 48: 219–222.
interferon-gamma receptor variant (Val14Met) with systemic
155 Blakemore AI, Watson PF, Weetman AP, Duff GW. Association
lupus erythematosus. Immunogenetics 1999; 49: 266–271.
of Graves’ disease with an allele of the interleukin-1 receptor
135 Parkes M, Satsangi J, Jewell D. Contribution of the IL-2 and
antagonist gene. J Clin Endocrinol Metab 1995; 80: 111–115.
IL-10 genes to inflammatory bowel disease (IBD) susceptibility.
156 Mu¨hlberg T, Kirchberger M, Spitzweg C, Herrmann F, Heber-
Clin Exp Immunol 1998; 113: 28–32.
ling HJ, Heufelder AE. Lack of association of Graves’ disease
136 Eskdale J, Wordsworth P, Bowman S, Fiels M, Gallagher G.
with the A2 allele of the interleukin-1 receptor antagonist gene
Association between polymorphisms at the IL-10 locus and sys-
in a white European population. Eur J Endocrinol 1998; 138:
temic lupus erythematosus. Tissue Antigens 1997; 49: 635–639.
137 Mehrian R, Quismorio FP, Jr, Strassmann G et al. Synergistic
157 Cuddihy RM, Bahn RS. Lack of an association between alleles
effect between IL-10 and bcl-2 genotypes in determining sus-
of interleukin-1 alpha and interleukin-1 receptor antagonist
ceptibility to systemic lupus erythematosus. Arthr Rheum 1998;
genes and Graves’ disease in a North American Caucasian
41: 596–602.
population. J Clin Endocrinol Metab 1996; 81: 4476–4478.
138 Allen MH, Skov L, Barber R et al. Ultraviolet B induced sup-
158 Liu ZH, Cheng ZH, Yu YS, Tang Z, Li LS. Interleukin-1 recep-
pression of induction of contact sensitivity in human skin is
tor antagonist allele: is it a genetic link between Henoch-
not associated with tumour necrosis factor-alpha-308 or interleukin-10 genetic polymorphisms. Br J Dermatol 1998; 139:
Schonlein nephritis and IgA nephropathy? Kidney Int 1997; 51:
139 Middleton PG, Taylor PR, Jackson G, Proctor SJ, Dickinson
159 Pociot F, Ronningen KS, Bergholdt R et al. Genetic suscepti-
AM. Cytokine gene polymorphisms associating with severe
bility markers in Danish patients with type 1 (insulin-
acute graft-versus-host disease in HLA-identical sibling trans-
dependent) diabetes-evidence for polygenicity in man. Danish
plants. Blood 1998; 92: 3943–3948.
Study Group of Diabetes in Childhood. Autoimmunity 1994; 19:
140 Eskdale J, McNicholl J, Wordsworth P et al. Interleukin-10
microsatellite polymorphisms and IL-10 locus alleles in rheu-
160 Blakemore AI, Cox A, Gonzalez AM et al. Interleukin-1 recep-
matoid arthritis susceptibility. Lancet 1998; 352: 1282–1283.
tor antagonist allele (IL1RN*2) associated with nephropathy in
141 Zappala F, Grove J, Watt FE et al. No evidence for involvement
diabetes mellitus. Hum Genet 1996; 97: 369–374.
of the interleukin-10-592 promoter polymorphism in genetic
161 Hacker UT, Gomolka M, Keller E et al. Lack of association
susceptibility to primary biliary cirrhosis. J Hepatol 1998; 28:
between an interleukin-1 receptor antagonist gene polymor-
phism and ulcerative colitis. Gut 1997; 40: 623–627.
142 Hobbs K, Negri J, Klinnert M, Rosenwasser LJ, Borish L.
162 Hacker UT, Bidlingmaier C, Gomolka M et al. Inflammatory
Interleukin-10 and transforming growth factor-beta promoter
bowel disease: no association between allele combinations of
polymorphisms in allergies and asthma. Am J Resp Crit Care
the interleukin (IL) I beta and IL-I receptor antagonist gene
Med 1998; 158: 1958–1962.
polymorphisms. Eur J Clin Invest 1998; 28: 214–219.
143 Lim S, Crawley E, Woo P, Barnes PJ. Haplotype associated with
163 Mansfield JC, Holden H, Tarlow JK et al. Novel genetic associ-
low interleukin-10 production in patients with severe asthma
ation between ulcerative colitis and the anti- inflammatory
[letter]. Lancet 1998; 352: 113.
cytokine interleukin-1 receptor antagonist. Gastroenterology
144 Hajeer AH, Lazarus M, Turner D et al. IL-10 gene promoter
1994; 106: 637–642.
polymorphisms in rheumatoid arthritis. Scand J Rheumatol 1998;
164 Bioque G, Bouma G, Crusius JB et al. Evidence of genetic het-
27: 142–145.
erogeneity in IBD: 1. The interleukin-1 receptor antagonist in
145 Coakley G, Mok CC, Hajeer AH et al. Interleukin-10 promoter
the predisposition to suffer from ulcerative colitis. Eur J Gastro-
polymorphisms in rheumatoid arthritis and Felty’s syndrome. enterol Hepatol 1996; 8: 105–110. Br J Rheumatol 1998; 37: 988–991.
165 Louis E, Satsangi J, Roussomoustakaki M et al. Cytokine gene
Cytokine gene polymorphism in human disease
polymorphisms in inflammatory bowel disease. Gut 1996; 39:
185 Heresbach D, Alizadeh M, Dabadie A et al. Significance of
interleukin-1beta and interleukin-1 receptor antagonist genetic
166 Clay FE, Cork MJ, Tarlow JK et al. Interleukin 1 receptor antag-
polymorphism in inflammatory bowel diseases. Am J Gastroen-
onist gene polymorphism association with lichen sclerosus. terol 1997; 92: 1164–1169. Hum Genet 1994; 94: 407–410.
186 Lanng S, Thorsteinsson B, Pociot F et al. Diabetes mellitus in
167 Bellamy R, Kwiatkowski D, Hill AV. Absence of an association
cystic fibrosis: genetic and immunological markers. Acta
between intercellular adhesion molecule 1, complement recep-
Paediatr 1993; 82: 150–154.
tor 1 and interleukin 1 receptor antagonist gene polymor-
187 Loughrey BV, Maxwell AP, Fogarty DG et al. An interleukin
phisms and severe malaria in a West African population. Trans-
1B allele, which correlates with a high secretor phenotype, is
actions Of The Royal Society Of Tropical Medicine And Hygiene
associated with diabetic nephropathy. Cytokine 1998; 10: 984–988.
1998; 92: 312–316.
188 Majeed GS, Glew S, Bidwell J. An association between LSIL
168 Crusius JB, Pena AS, Van Oosten BW et al. Interleukin-1 recep-
and the high secretor phenotype of IL-1. Gynecol Oncol 1999;
tor antagonist gene polymorphism and multiple sclerosis. 73: 359–361. Lancet 1995; 346: 979.
189 Gore EA, Sanders JJ, Pandey JP, Palesch Y, Galbraith GM.
169 de la Concha EG, Arroyo R, Crusius JBA et al. Combined effect
Interleukin-1beta+3953 allele 2: association with disease status
of HLA-DRB1*1501 and interleukin-1 receptor antagonist gene
in adult periodontitis. J Clin Periodontol 1998; 25: 781–785.
allele 2 in susceptibility to relapsing/remitting multiple scler-
190 Katila H, Hanninen K, Hurme M. Polymorphisms of the
osis. J Neuroimmunol 1997; 80: 172–178.
interleukin-1 gene complex in schizophrenia. Mol Psychiatry
170 Huang WX, He B, Hillert J. An interleukin 1-receptor-antagon-
1999; 4: 179–181.
ist gene polymorphism is not associated with multiple scler-
191 Nimgaonkar VL, Yang ZW, Zhang XR, Brar JS, Chakravarti
osis. J Neuroimmunol 1996; 67: 143–144.
A, Ganguli R. Association study of schizophrenia and the IL-
171 Semana G, Yaouanq J, Alizadeh M, Clanet M, Edan G. Interleu-
2 receptor beta chain gene. Am J Med Genet 1995; 60: 448–451.
kin-1 receptor antagonist gene in multiple sclerosis. Lancet
192 Tatsumi M, Sasaki T, Sakai T et al. Genes for interleukin-2
1997; 349: 476.
receptor beta chain, interleukin-1 beta, and schizophrenia: no
172 Huang D, Pirskanen R, Hjelmstro¨m P, Lefvert AK. Polymor-
evidence for the association or linkage. Am J Med Genet 1997;
phisms in IL-1 beta and IL-1 receptor antagonist genes are asso-
74: 338–341.
ciated with myasthenia gravis. J Neuroimmunol 1998; 81: 76–81.
193 Clark PA, Lester T, Genet S et al. Screening for mutations caus-
173 Perrier S, Coussediere C, Dubost JJ, Albuisson E, Sauvezic B.
ing X-linked severe combined immunodeficiency in the IL-2R
IL-1 receptor antagonist (IL-1RA) gene polymorphism in Sjo¨g-
gamma chain gene by single-strand conformation polymor-
ren’s syndrome and rheumatoid arthritis. Clin Immunol Immun-
phism analysis. Hum Genet 1995; 96: 427–432. opath 1998; 87: 309–313.
194 Pepper AE, Buckley RH, Small TN, Puck JM. Two mutational
174 Francis SE, Camp NJ, Dewberry RM et al. Interleukin-1 recep-
hotspots in the interleukin-2 receptor gamma chain gene caus-
tor antagonist gene polymorphism and coronary heart disease.
ing human X-linked severe combined immunodeficiency. AmCirculation 1999; 99: 861–866. J Hum Genet 1995; 57: 564–571.
175 Blakemore AI, Tarlow JK, Cork MJ, Gordon C, Emery P, Duff
195 Puck JM, Pepper AE, Bedard PM, Laframboise R. Female germ
GW. Interleukin-1 receptor antagonist gene polymorphism as
line mosaicism as the origin of a unique IL-2 receptor gamma-
a disease severity factor in systemic lupus erythematosus.
chain mutation causing X-linked severe combined immuno-
Arthritis Rheum 1994; 37: 1380–1385.
deficiency. J Clin Invest 1995; 95: 895–899.
176 Suzuki H, Matsui Y, Kashiwagi H. Interleukin-1 receptor
196 O’Marcaigh AS, Puck JM, Pepper AE, De Santes K, Cowan MJ.
antagonist gene polymorphism in Japanese patients with sys-
Maternal mosaicism for a novel interleukin-2 receptor gamma-
temic lupus erythematosus. Arthritis Rheum 1997; 40: 389–390.
chain mutation causing X-linked severe combined immuno-
177 Danis VA, Millington M, Huang Q, Hyland V, Grennan D.
deficiency in a Navajo kindred. J Clin Immunol 1997; 17: 29–33.
Lack of association between an interleukin-1 receptor antagon-
197 Puck JM, Middelton L, Pepper AE. Carrier and prenatal diag-
ist gene polymorphism and systemic lupus erythematosus. DisMarkers 1995; 12: 135–139.
mutation detection methods and utilization. Hum Genet 1997;
178 Bouma G, Crusius JB, Garcι´a-Gonza´lez MA et al. Genetic mark-
99: 628–633.
ers in clinically well defined patients with ulcerative colitis
198 Puck JM, Pepper AE, Henthorn PS et al. Mutation analysis of
(UC). Clin Exp Immunol 1999; 115: 294–300.
IL2RG in human X-linked severe combined immunodeficiency.
179 Metcalfe KA, Hitman GA, Pociot F et al. An association
Blood 1997; 89: 1968–1977.
between type 1 diabetes and the interleukin-1 receptor type 1
199 Wengler GS, Giliano S, Fiorini M et al. Mutation analysis by a
gene. The DiMe Study Group. Childhood Diabetes in Finland.
non-radioactive single-strand conformation polymorphism
Hum Immunol 1996; 51: 41–48.
assay in nine families with X-linked severe combined immuno-
180 Gomolka M, Menninger H, Saal JE et al. Immunoprinting: vari-
deficiency (SCIDX1). Br J Haematol 1998; 101: 586–591.
ous genes are associated with increased risk to develop rheu-
200 Fugmann SD, Mu¨ller S, Friedrich W, Bartram CR, Schwarz K.
matoid arthritis in different groups of adult patients. J Mol Med
Mutations in the gene for the common gamma chain (gammac)
1995; 73: 19–29.
in X-linked severe combined immunodeficiency. Human Gen-
181 McDowell TL, Symons JA, Ploski R, Forre O, Duff GW. A gen-
etics 1998; 103: 730–731.
etic association between juvenile rheumatoid arthritis and a
201 Noguchi E, Shibasaki M, Arinami T et al. Association of asthma
novel interleukin-1 alpha polymorphism. Arthritis Rheum 1995;
and the interleukin-4 promoter gene in Japanese. Clin Exp38: 221–228. Allergy 1998; 28: 449–453.
182 Bailly S, Hayem G, Fay M, Kahn MF, Gougerot-Pocidalo MA.
202 Kawashima T, Noguchi E, Arinami T et al. Linkage and associ-
Absence of correlation between IL-1 alpha intron 6 polymor-
ation of an interleukin 4 gene polymorphism with atopic der-
phism and rheumatoid arthritis. Br J Rheumatol 1995; 34:
matitis in Japanese families. J Med Genet 1998; 35: 502–504.
203 Vandenbroeck K, Martino G, Marrosu M et al. Occurrence and
183 Kornman KS, Crane A, Wang HY et al. The interleukin-1 geno-
clinical relevance of an interleukin-4 gene polymorphism in
type as a severity factor in adult periodontal disease. J Clin
patients with multiple sclerosis. J Neuroimmunol 1997; 76: Periodontol 1997; 24: 72–77.
184 Bioque G, Crusius JB, Koutroubakis I et al. Allelic polymor-
204 Huang D, Xia S, Zhou Y, Pirskanen R, Liu L, Lefvert AK. No
phism in IL-1 beta and IL-1 receptor antagonist (IL-1Ra) genes
evidence for interleukin-4 gene conferring susceptibility to
in inflammatory bowel disease. Clin Exp Immunol 1995; 102:
myasthenia gravis. J Neuroimmunol 1998; 92: 208–211.
205 Mitsuyasu H, Izuhara K, Mao X-Q et al. I1e50Val variant of
Cytokine gene polymorphism in human disease J Bidwell et al
IL4R␣ upregulates IgE synthesis and associates with atopic
mutations in the extracellular domains of the 55 kDa TNF
asthma. Nature Genetics 1998; 19: 119–120.
receptor, TNFR1, define a family of dominantly inherited auto-
206 Izuhara K, Shirakawa T. Signal transduction via the interleu-
inflammatory syndromes. Cell 1999; 97: 133–144.
kin-4 receptor and its correlation with atopy. Int J Mol Med
226 Rau H, Donner H, Usadel K, Badenhoop K. Polymorphisms of
1999; 3: 3–10.
tumor necrosis factor receptor 2 are not associated with insulin-
207 Fugger L, Morling N, Bendtzen K et al. IL-6 gene polymor-
dependant diabetes mellitus or Grave’s disease. Tissue Antigens
phism in rheumatoid arthritis, pauciarticular juvenile rheuma-
1997; 49: 535–536.
toid arthritis, systemic lupus erythematosus, and in healthy
227 Hamann A, Mantzoros C, Vidal-Puig A, Flier JS. Genetic varia-
Danes. J Immunogenet 1989; 16: 461–465.
bility in the TNF-alpha promoter is not associated with type II
208 Scapoli L, Pezzetti F, Carinci F, Martinelli M, Carinci P, Tognon
diabetes mellitus (NIDDM). Biochem Biophys Res Comm 1995;
M. Lack of linkage disequilibrium between transforming
211: 833–839.
growth factor alpha Taq I polymorphism and cleft lip with or
228 Ho¨hler T, Kruger A, Gerken G et al. A tumor necrosis factor-
without cleft palate in families from Northeastern Italy. Am J
alpha (TNF-alpha) promoter polymorphism is associated with
Med Genet 1998; 75: 203–206.
chronic hepatitis B infection. Clin Exp Immunol 1998; 111:
209 Syrris P, Carter ND, Metcalfe JC et al. Transforming growth
factor-betal gene polymorphisms and coronary artery disease.
229 Ho¨hler T, Kruger A, Gerken G et al. Tumor necrosis factor
Clin Sci (Colch) 1998; 95: 659–667.
alpha promoter polymorphism at position −238 is associated
210 Pociot F, Hansen P, Karlsen A, Langdahl B, Johannnesen J,
with chronic active hepatitis C infection. J Med Virol 1998; 54:
Nerup J. Transforming growth factor-beta 1 gene mutations in
insulin-dependent diabetes mellitus (IDDM) and diabetic
230 Jacob N, Ruschendorf F, Schmitt-Egenolf M et al. Promoter
nephropathy. J Am Soc Nephrol 1998; 9: 2302–2307.
polymorphism at −238 of the tumor necrosis factor alpha gene
211 Yamada Y, Miyauchi A, Goto J et al. Association of a polymor-
is not associated with early onset psoriasis when tested by the
phism of the transforming growth factor-betal 1 gene with gen-
transmission disequilibrium test. J Invest Dermatol 1999; 112:
etic susceptibility to osteoporosis in postmenopausal Japanese
women. J Bone Miner Res 1998; 13: 1569–1576.
231 Day CP, Grove J, Daly AK, Stewart MW, Avery PJ, Walker M.
212 Li B, Khanna A, Sharma V, Singh T, Suthanthiran M, August
Tumour necrosis factor-alpha gene promoter polymorphism
P. TGF-betal DNA polymorphisms, protein levels and blood
and decreased insulin resistance. Diabetologia 1998; 41: 430–434.
pressure. Hypertension 1999; 33: 271–275.
232 Vinasco J, Beraun Y, Nieto A et al. Polymorphism at the TNF
213 Sandberg-Wollheim M, Ciusani E, Salmaggi A, Pociot F. An
loci in rheumatoid arthritis. Tissue Antigens 1997; 49: 74–78.
evaluation of tumour necrosis factor microsatellite alleles in
233 Conway DJ, Holland MJ, Bailey RL et al. Scarring trachoma is
genetic susceptibility to multiple sclerosis. Multiple Sclerosis:
associated with polymorphism in the tumor necrosis factor
Clin Lab Res 1995; 1: 181–185.
alpha (TNF-alpha) gene promoter and with elevated TNF-
214 Matthias C, Jahnke V, Fryer A, Strange R, Ollier W, Hajeer A.
alpha levels in tear fluid. Infect Immun 1997; 65: 1003–1006.
Influence of tumour necrosis factor microsatellite polymor-
234 Beraun Y, Nieto A, Collado MD, Gonzalez A, Martin J. Poly-
phisms on susceptibility to head and neck cancer. Acta Oto-
morphisms at tumor necrosis factor (TNF) loci are not associa-
laryngol (Stockh) 1998; 118: 284–288.
ted with Chagas’ disease. Tissue Antigens 1998; 52: 81–83.
215 Monos DS, Kamoun M, Udalova IA et al. Genetic polymor-
235 Fraile A, Nieto A, Beraun Y, Vinasco J, Mataran L, Martin J.
phism of the human tumor necrosis factor region in insulin-
Tumor necrosis factor gene polymorphisms in ankylosing
dependent diabetes mellitus. Linkage disequilibrium of TNFab
spondylitis. Tissue Antigens 1998; 51: 386–390.
microsatellite alleles with HLA haplotypes. Hum Immunol 1995;
236 Zhai R, Jetten M, Schins RP, Franssen H, Borm PJ. Polymor-
44: 70–79.
phisms in the promoter of the tumor necrosis factor-alpha gene
216 Hajeer AH, Worthington J, Silman AJ, Ollier WE. Association
in coal miners. Am J Ind Med 1998; 34: 318–324.
of tumor necrosis factor microsatellite polymorphisms with
237 Westendorp RG, Langermans JA, Huizinga TW et al. Genetic
HLA-DRBI *04-bearing haplotypes in rheumatoid arthritis
influence on cytokine production and fatal meningococcal dis-
patients. Arthritis Rheum 1996; 39: 1109–1114.
ease. Lancet 1997; 349: 170–173.
217 Ma JJ, Nishimura M, Minc H et al. Genetic contribution of the
238 Rudwaleit M, Tikly M, Khamashta M et al. Interethnic differ-
tumor necrosis factor region in Guillain-Barre syndrome. Ann
ences in the association of tumor necrosis factor promoter poly-
Neurol 1998; 44: 815–818.
morphisms with systemic lupus erythematosus. J Rheumatol
218 Gallagher G, Lindemann M, Oh H-H et al. Association of the
1996; 23: 1725–1728.
TNFa2 microsatellite allele with the presence of colorectal can-
239 D’Alfonso S, Colombo G, Della Bella S et al. Association
cer. Tissue Antigens 1998; 50: 47–51.
between polymorphisms in the TNF region and systemic lupus
219 Hjelmstrom P, Peacock CS, Giscombe R et al. Polymorphism in
erythematosus in the Italian population. Tissue Antigens 1996;
tumor necrosis factor genes associated with myasthenia gravis. 47: 551–555. J Neuroimmunol 1998; 88: 137–143.
240 Carey BS, Grabczynska SA, McGregor J, Hawk JLM, Vaughan
220 Polvi A, Maki M, Collin P, Partanen J. TNF microsatellite
RW. The association of DR4 with AP is not influenced by the
alleles a2 and b3 are not primarily associated with celiac dis-
−308 TNF alpha promoter polymorphism. Eur J Immunogenet
ease in the Finnish population. Tissue Antigens 1998; 51: 553–555.
1998; 25: 55 (Abstract).
221 Mulcahy B, Waldron-Lynch F, McDermott MF et al. Genetic
241 Verjans GM, Brinkman BM, Van Doornik CE, Kijlstra A,
variability in the tumor necrosis factor-lymphotoxin region
Verweij CL. Polymorphism of tumour necrosis factor-alpha
influences susceptibility to rheumatoid arthritis. Am J Hum
(TNF-alpha) at position −308 in relation to ankylosing spondy-
Genet 1996; 59: 676–683.
litis. Clin Exp Immunol 1994; 97: 45–47.
222 Asano H et al. Significance of tumor necrosis factor microsatel-
242 Manus RM, Wilson AG, Mansfield J, Weir DG, Duff GW, Kel-
lite polymorphism in renal transplantation. Tissue Antigens
leher D. TNF2, a polymorphism of the tumor necrosis-alpha
1997; 50: 484–488.
gene promoter, is a component of the celiac disease major his-
223 Turbay D, Lieberman J, Alper CA et al. Tumor necrosis factor
tocompatibility complex haplotype. Eur J Immunol 1996; 26:
constellation polymorphism and clozapine-induced agranulo-
cytosis in two different ethnic groups. Blood 1997; 89: 4167–4174.
243 McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkow-
224 Khoo SH, Pepper L, Snowden N et al. Tumour necrosis factor
ski D. Variation in the TNF-alpha promoter region associated
c2 microsatellite allele is associated with the rate of HIV disease
with susceptibility to cerebral malaria. Nature 1994; 371: 508–510.
progression. AIDS 1997; 11: 423–428.
244 Demeter J, Porzsolt F, Ramisch S, Schmidt D, Schmid M,
225 McDermot MF, Aksentijevich I, Galon J et al. Germline
Messer G. Polymorphism of the tumour necrosis factor-alpha
Cytokine gene polymorphism in human disease
and lymphotoxin-alpha genes in chronic lymphocytic leu-
of the regulatory region of tumour necrosis factor alpha gene
kaemia. Br J Haematol 1997; 97: 107–112.
in patients with systemic lupus erythematosus. Ann Acad Med
245 Wihlborg C, Sjoberg J, Intaglietta M, Axdorph U, Pisa EK, Pisa
Singapore 1996; 25: 90–93.
P. Tumour necrosis factor-alpha cytokine promoter gene poly-
265 Brown K, Luddington R, Baglin T. A common polymorphism
morphism in Hodgkin’s disease and chronic lymphocytic leu-
in the tumour necrosis factor-alpha gene associated with high
kaemia. Br J Haematol 1999; 104: 346–349.
TNF levels is not a risk factor for venous thromboembolism.
246 Herrmann SM, Ricard S, Nicaud V et al. Polymorphisms of the
Br J Haematol 1998; 101: 480–482.
tumour necrosis factor-alpha gene, coronary heart disease and
266 Turner D, Grant S, Yonan N et al. Cytokine gene polymorphism
obesity. Eur J Clin Invest 1998; 28: 59–66.
and heart transplant rejection. Transplantation 1997; 64: 776–779.
247 Wilson AG, Clay FE, Crane AM, Cork MJ, Duff GW. Compara-
267 Sankaran D, Ashraf S, Asderakis A et al. Tumour necrosis fac-
tive genetic association of human leukocyte antigen class II and
tor alpha (TNFa) and interleukin-10 (IL-10) gene polymor-
tumor necrosis factor-alpha with dermatitis herpetiformis.
phisms predict acute renal allograft rejection. Abstracts of theJ Invest Dermatol 1995; 104: 856–858. British Transplantation Society 1st Annual Congress 1998.
248 Mayer FR, Messer G, Knabe W et al. High response of TNF␣
268 Sankaran D, Ashraf S, Martin S et al. High interleukin-10 pro-
secretion in vivo in patients undergoing BMT may be associa-
ducer genotype is not protective against renal allograft rejec-
ted with the −308 TNFa gene enhancer polymorphism. Bone
tion in high TNF␣ producers. Eur J Immunogenet 1998; 25: 68 Marrow Transplant 1996; 17: (Suppl 1): 101.
249 Sato-Matsumura KC, Berger J, Hainfellner JA, Mazal P, Budka
269 Moffatt MF, Cookson WO. Tumour necrosis factor haplotypes
H. Development of HIV encephalitis in AIDS and TNF-alpha
and asthma. Hum Mol Genet 1997; 6: 551–554.
regulatory elements. J Neuroimmunol 1998; 91: 89–92.
270 Trabetti E, Patuzzo C, Malerba G et al. Association of a lympho-
250 Deng GY, Maclaren NK, Huang HS, Zhang LP, She JX. No
toxin alpha gene polymorphism and atopy in Italian families.
primary association between the 308 polymorphism in the
J Med Genet 1999; 36: 323–325.
tumor necrosis factor alpha promoter region and insulin-
271 Albuquerque RV, Hayden CM, Palmer LJ et al. Association of
dependent diabetes mellitus. Hum Immunol 1996; 45: 137–142.
polymorphisms within the tumour necrosis factor (TNF) genes
251 Roy S, McGuire W, Mascie-Taylor CG et al. Tumor necrosis
and childhood asthma. Clin Exp Allergy 1998; 28: 578–584.
factor promoter polymorphism and susceptibility to lepromat-
272 Park KS, Mok JW, Rho SA, Kim JC. Analysis of TNFB and
ous leprosy. J Infect Dis 1997; 176: 530–532.
TNFA Ncol RFLP in colorectal cancer. Mol Cells 1998; 8: 246–249.
252 Clay FE, Cork MJ, Wilson AG et al. Promoter region polymor-
273 Kubota T, McNamara DM, Wang JJ et al. Effects of tumor
phism in the human TNF-alpha gene is not associated with
necrosis factor gene polymorphisms on patients with conges-
lichen sclerosus. Exp Dermatol 1996; 5: 227–229.
tive heart failure. VEST Investigators for TNF Genotype Analy-
253 He B, Navikas V, Lundahl J, Soderstrom M, Hillert J. Tumor
sis. Vesnarinone Survival Trial. Circulation 1998; 97: 2499–2501.
necrosis factor alpha-308 alleles in multiple sclerosis and optic
274 Messer G, Kick G, Ranki A, Koskimies S, Reunala T, Meurer
neuritis. J Neuroimmunol 1995; 63: 143–147.
M. Polymorphism of the tumor necrosis factor genes in patients
254 Wingerchuck D, Liu Q, Sobell J, Sommer S, Weinshenker B. A
with dermatitis herpetiformis. Dermatology 1994; 189: (Suppl 1):
population-based case-control study of the tumor necrosis fac-
tor alpha-308 polymorphism in multiple sclerosis. Neurology
275 Demeter J, Porzsolt F, Ramisch S, Schmid M, Messer G. Poly-
1997; 49: 626.
morphism of the tumour necrosis factor-alpha and lympho-
255 Kanerva M, Vaheri A, Mustonen J, Partanen J. High-producer
toxin-alpha genes in hairy cell leukaemia. Br J Haematol 1997;
allele of tumour necrosis factor-alpha is part of the suscepti-
97: 132–134.
bility MHC haplotype in severe puumala virus-induced
276 Mycko M, Kowalski W, Kwinkowski M et al. Multiple sclerosis:
nephropathia epidemica. Scand J Infect Dis 1998; 30: 532–534.
the frequency of allelic forms of tumor necrosis factor and lym-
256 Bernal W, Moloney M, Underhill J, Donaldson PT. Association
photoxin-alpha. J Neuroimmunol 1998; 84: 198–206.
of tumor necrosis factor polymorphism with primary scleros-
277 Warzocha K, Ribeiro P, Bienvu J et al. Genetic polymorphisms
ing cholangitis. J Hepatol 1999; 30: 237–241.
in the tumor necrosis factor locus influence non-Hodgkin’s
257 Wilson AG, Gordon C, di Giovine FS et al. A genetic association
between systemic lupus erythematosus and tumor necrosis fac-
lymphoma outcome. Blood 1998; 91: 3574–3581.
tor alpha. Eur J Immunol 1994; 24: 191–195.
278 Cabrera M, Shaw MA, Sharples C et al. Polymorphism in tumor
258 Danis VA, Millington M, Hyland V, Lawford R, Huang Q,
necrosis factor genes associated with mucocutaneous leishman-
Grennan D. Increased frequency of the uncommon allele of a
iasis. J Exp Med 1995; 182: 1259–1264.
tumour necrosis factor alpha gene polymorphism in rheuma-
279 Mullighan CG, Fanning GC, Chapel HM, Welsh KI. TNF and
toid arthritis and systemic lupus erythematosus. Dis Markers
lymphotoxin-alpha polymorphisms associated with common
1995; 12: 127–133.
variable immunodeficiency: role in the pathogenesis of granu-
259 Wattavidanage J, Carter R, Perera KL et al. TNFalpha*2 marks
lomatous disease. J Immunol 1997; 159: 6236–6241.
high risk of severe disease during Plasmodium falciparum
280 Verjans GM, van der Linden SM, van Eys GJ, de Waal LP,
malaria and other infections in Sri Lankans. Clin Exp Immunol
Kijlstra A. Restriction fragment length polymorphism of the
1999; 115: 350–355.
tumor necrosis factor region in patients with ankylosing spon-
260 Stuber F, Udalova IA, Book M et al. −308 tumor necrosis factor
dylitis. Arthritis Rheum 1991; 34: 486–489.
(TNF) polymorphism is not associated with survival in severe
281 Chung JH, Cho BY, Lee HK, Kim TG, Han H, Koh CS. The
sepsis and is unrelated to lipopolysaccharide inducibility of the
tumor necrosis factor beta* 1 allele is linked significantly to
human TNF promoter. J Inflamm 1995; 46: 42–50.
HLA-DR8 in Koreans with atrophic autoimmune thyroiditis
261 Kim HY, Lee SH, Yang HI et al. TNFB gene polymorphism in
who are positive for thyrotropin receptor blocking antibody.
patients with systemic lupus erythematosus in Korean. KoreanJ Korean Med Sci 1994; 9: 155–161. J Intern Med 1995; 10: 130–136.
282 Shimura T, Hagihara M, Takebe K et al. 10.5-kb homozygote
262 Kim TG, Kim HY, Lee SH et al. Systemic lupus erythematosus
of tumor necrosis factor-beta gene is associated with a better
with nephritis is strongly associated with the TNFB*2 homozy-
prognosis in gastric cancer patients. Cancer 1995; 75: 1450–1453.
gote in the Korean population. Hum Immunol 1996; 46: 10–17.
283 Badenhoop K, Schwarz G, Schleusener H et al. Tumor necrosis
263 Sullivan K, Wooten C, Schmeekpeper B, Goldman D, Petri M.
factor beta gene polymorphisms in Graves’ disease. J Clin
A promoter polymorphism of tumor necrosis factor alpha
Endocrinol Metab 1992; 74: 287–291.
associated with systemic lupus erythematosus in African-
284 Badenhoop K, Schwarz G, Walfish PG, Drummond V, Usadel
Americans. Arthr Rheum 1997; 40: 2207–2211.
KH, Bottazzo GF. Susceptibility to thyroid autoimmune dis-
264 Fong KY, Howe HS, Tin SK, Boey ML, Feng PH. Polymorphism
ease: molecular analysis of HLA-D region genes identifies new
Cytokine gene polymorphism in human disease J Bidwell et al
markers for goitrous Hashimoto’s thyroiditis. J Clin Endocrinol
(TNF alpha) region in primary biliary cirrhosis and in healthy
Metab 1990; 71: 1131–1137.
Danes. Scand J Immunol 1989; 30: 185–189.
285 Braun J, Marz W, Winkelmann BR, Donner H, Usadel K, Bad-
304 Messer G, Spengler U, Jung MC et al. Allelic variation in the
enhoop K. Tumour necrosis factor beta alleles and hyperinsuli-
TNF-beta gene does not explain the low TNF-beta response in
naemia in coronary artery disease. Eur J Clin Invest 1998; 28:
patients with primary biliary cirrhosis. Scand J Immunol 1991;
34: 735–740.
286 Badenhoop K, Schwarz G, Bingley P et al. TNF-alpha gene
305 Fugger L, Morling N, Ryder LP et al. NcoI restriction fragment
polymorphisms: association with type 1 (insulin-dependent)
length polymorphism (RFLP) of the tumor necrosis factor (TNF
diabetes mellitus. J Immunogenet 1989; 16: 455–460.
alpha) region in four autoimmune diseases. Tissue Antigens
287 Badenhoop K, Schwartz G, Trowsdale J et al. TNF-alpha gene
1989; 34: 17–22.
polymorphisms in type 1 (insulin-dependent) diabetes mel-
306 Atsumi T. Tumor necrosis factor alpha in systemic lupus ery-
litus. Diabetologia 1989; 32: 445–448.
thematosus: evaluation by restriction fragment length poly-
288 Badenhoop K. Immunogenetic markers for autoimmune dis-
morphism and production by peripheral blood mononuclear
eases of the endocrine system. Klin Wochenschr 1990; 68 (Suppl
cells. Hokkaido Igaku Zasshi 1992; 67: 408–419.
307 Bettinotti MP, Hartung K, Deicher H et al. Polymorphism of the
289 Jenkins D, Penny MA, Mijovic CH, Jacobs KH, Fletcher J, Bar-
tumor necrosis factor beta gene in systemic lupus erythematosus:
nett AH. Tumour necrosis factor-beta polymorphism is
TNFB-MHC haplotypes. Immunogenetics 1993; 37: 449–454.
unlikely to determine susceptibility to type 1 (insulin-
308 Campbell DA, Nelson S, Madhok R, Field M, Gallagher G. TNF
dependent) diabetes mellitus. Diabetologia 1991; 34: 576–578.
Nco-I RFLP is not an independent risk factor in rheumatoid
290 Pociot F, Molvig J, Wogensen L et al. A tumour necrosis factor
arthritis. Eur J Immunogenet 1994; 21: 461–467.
beta gene polymorphism in relation to monokine secretion and
309 Vandevyver C, Raus P, Stinissen P, Philippaerts L, Cassiman
insulindependent diabetes mellitus. Scand J Immunol 1991; 33:
JJ, Raus J. Polymorphism of the tumour necrosis factor beta
gene in multiple sclerosis and rheumatoid arthritis. Eur J Immu-
291 Yamagata K, Hanafusa T, Nakajima H et al. HLA-DQA1*1 con-
nogenet 1994; 21: 377–382.
tributes to resistance and A1*3 confers susceptibility to type 1
310 Laitinen T, Lokki ML, Tulppala M, Ylikorkala O, Koskimies S.
(insulin-dependent) diabetes mellitus in Japanese subjects.
Tumour necrosis factor B gene polymorphism in relation to
Diabetologia 1991; 34: 133–136.
complotype in couples with spontaneous abortions and in con-
292 Ilonen J, Merivuori H, Reijonen H et al. Tumour necrosis factor-
trol families. Scand J Immunol 1992; 35: 131–135.
beta gene RFLP alleles in Finnish IDDM haplotypes. The Child-
311 Mizuki N, Inoko H, Sugimura K et al. RFLP analysis in the
hood Diabetes in Finland (DiMe) Study Group. Scand J Immunol
TNF-beta gene and the susceptibility to alloreactive NK cells in
1992; 36: 779–783.
Behcet’s disease. Invest Ophthalmol Vis Sci 1992; 33: 3084–3090.
293 Feugeas JP, Dosquet C, Wautier JL, Montchamp-Moreau C,
312 Roth MP, Nogueira L, Coppin H, Clanet M, Clayton J, Cam-
Krishnamoorthy R, Caillens H. Dysregulation of in vitro TNF-
bon-Thomsen A. Tumor necrosis factor polymorphism in mul-
beta production in insulin-dependent diabetes mellitus. C R
tiple sclerosis: no additional association independent of HLA. Acad Sci III 1993; 316: 1255–1259. J Neuroimmunol 1994; 51: 93–99.
294 Vendrell J, Ercilla G, Gutierrez C et al. A tumor necrosis factor
313 Petrovsky N, Harrison LC. Diurnal rhythmicity of human cyto-
beta-gene polymorphism associated with islet cell antibodies
kine production — A dynamic disequilibrium in T helper cell
in newly diagnosed type I diabetic patients. Diabetes Care 1994;
type 1/T helper cell type 2 balance? J Immunol 1997; 158: 17: 944–945.
295 Whichelow CE, Hitman GA, Raafat I, Bottazzo GF, Sachs JA.
314 Petrovsky N, Harrison LC. HLA-class 11-associated polymor-
The effect of TNF*B gene polymorphism on TNF-alpha and
phism of interferon-gamma production. Implications for HAL-
-beta secretion levels in patients with insulin-dependent dia-
disease association. Hum Immunol 1997; 53: 12–16.
betes mellitus and healthy controls. Eur J Immunogenet 1996;
315 Mineta M, Tanimura M, Tana T, Yssel H, Kashiwagi S, Sasa-
23: 425–435.
zuki T. Contribution of HLA class I and class II alleles to the
296 Medcraft J, Hitman GA, Sachs JA, Whichelow CE, Raafat I,
regulation of antibody production to hepatitis B surface anti-
Moore RH. Autoimmune renal disease and tumour necrosis
gen in humans. Int Immunol 1996; 8: 525–531.
factor beta gene polymorphism. Clin Nephrol 1993; 40: 63–68.
316 Candore G, Cigna D, Todaro M et al. T-cell activation in HLA-
297 Xia B, Bouma G, Grusius JB, Meuwissen SG, Pena AS. Distri-
B8, DR3-positive individuals. Early antigen expression defect
bution of an Ncol polymorphism in the lymphotoxin alpha
in vitro. Hum Immunol 1995; 42: 289–294.
gene in Dutch patients with inflamatory bowel diseases. Chin
317 Caruso C, Candore G, Modica MA et al. Major histocompat-
Med J (Engl) 1995; 108: 739–742.
ibility complex regulation of cytokine production. J Interferon
298 Shimura T, Haihara M, Takebe K et al. The study of tumor
Cytokine Res 1996; 16: 983–988.
necrosis factor beta gene polymorphism in lung cancer
318 Lio D, Candore G, Romano GC et al. Modification of cytokine
patients. Cancer 1994; 73: 1184–1188.
secretion patterns in subjects bearing the HLA-B8,DR3 pheno-
299 Hagihara M, Shimura T, Sato K, Genga K, Suzuki M, Tsuji K.
type: implications for autoimmunity. Cytokines Cell Mol Ther
HLA and tumor necrosis factor beta gene polymorphisms in
1997; 3: 217–224.
Okinawa lung cancer patients: comparative study with main-
319 Stassi G, Todaro M, De Maria R et al. Defective expression of
land Japan lung cancer patients. Hum Immunol 1995; 43: 95–100.
CD95 (FAS/APO-1) molecule suggests apoptosis impairment
300 Fugger L, Morling N, Sandberg-Wollheim M, Ryder LP,
of T and B cells in HLA-B8,DR3-positive individuals. Hum
Svejgaard A. Tumor necrosis factor alpha gene polymorphism
Immunol 1997; 55: 39–45.
in multiple sclerosis and optic neuritis. J Neuroimmunol 1990;
320 Caruso C, Bongiardina C, Candore G et al. HLA-B8,DR3 haplo-
27: 85–88.
type affects lymphocyte blood levels. Immunol Invest 1997; 26:
301 Zelano G, Lino MM, Evoli A et al. Tumour necrosis factor beta
gene polymorphisms in myasthenia gravis. Eur J Immunogenet
321 Fleury S, Thibodeau J, Croteau G et al. HLA-DR polymorphism
1998; 25: 403–408.
affects the interaction with DR4. J Exp Med 1995; 182: 733–741.
302 Vendrell J, Gutierrez C, Pastor R, Richart C. A tumor necrosis
322 Lio D, Candore G, Cigna D et al. In vitro T-cell activation in
factor-beta polymorphism associated with hypertriglyceride-
elderly individuals: failure in CD69 and CD71 expression. Mech
mia in non-insulin-dependent diabetes mellitus. MetabolismAgeing Dev 1996; 89: 51–58.
1995; 44: 691–694.
323 Pawelec G, Effros RB, Caruso C, Remarque E, Banett Y, Solana
303 Fugger L, Morling N, Ryder LP et al. NcoI restriction fragment
R. T-cells and ageing (update 1999). Front Biosci 1999; 4:
length polymorphism (RFLP) of the tumour necrosis factor
Patient Information (please complete in ink) Name: Mr/Mrs/Ms___________________________________________ Address: __________________________________________________________ Home Phone: _____________________ Work Phone: _____________________ Cell Phone: ____________________ Occupation: _____________________________ Employer: _____________________________________________ Who can we thank
HEALTH INFORMATION & HISTORY Patient’s Name __________________________________________________ Date_ ______________________________ Address____________________________________City_ _________________ State__________ Zip__________________Occupation_ _______________________________SSN_#_ _______________ Date_of_Birth_ ______________________Height_______ Weight________ Single______ _Ma