0021-972X/92/7402-0287$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright 0 1992 by The Endocrine Society

Tumor Necrosis Factor Graves’ Disease*

Vol. 74, No. 2 Printed in U.S.A.

,8 Gene Polymorphisms

K. BADENHOOP, G. SCHWARZ, H. SCHLEUSENER, H. PETERS, G. F. BOTTAZZO, AND K. H. USADEL

A. P. WEETMAN,

in

S. RECKS,

II. Medizinische Klinik, Klinikum Mannheim der Universitat (K.B., S.R., K.H.U.), Heidelberg, Germany; Department of Diabetes and Immunogenetics, St. Bartholomew’s Hospital, (G.S.), and Department of Immunology, University College and Middlesex School of Medicine, (G.F.B.), London, England; Addenbrooke’s Hospital, Department of Medicine, University of Cambridge, (A.P. W.), Cambridge, United Kingdom; and Endocrine Department, Medical Clinic, (H.S., H.P.), Klinikum Steglitz der Freien Universitat Berlin, Germany

ABSTRACT. The physical mapping of tumor necrosis factor (Y (TNF (Y) and lymphotoxin (TNF @) genes to the short arm of chromosome 6 in man between the loci for histocompatibility leucocyte antigens (HLA)-B and the complement system focused attention to this genetic region that controls immune responses in many ways. It also holds susceptibility genes for a variety of autoimmune disorders that are linked to specific alleles of loci in the HLA D subregion. We have recently identified a TNF restriction fragment length polymorphism with the enzyme NcoI (K. Badenhoop, G. Schwarz, J. Trowsdale, et al. Diabetologia. 1989;32:445-8). The less frequent fragment of 5.5 kilobase (kb) is in strong linkage disequilibrium with the HLA haplotype AlB8DR3. Since Graves’ disease is linked to AlBSDR3, we analyzed TNF gene polymorphisms in a large group of Graves’ disease patients and normal controls derived from four Centers. We show here a significant association of TNFp polymorphisms

with Graves’ disease. The patients have less homozygotes for the 10.5 kb band (60 of 174,34%) and more heterozygotes 10.5/ 5.5 kb (96 of 174, 55%), than 173 controls (49% homozygotes 10.5 kb and 42% heterozygotes; x2 = 7.45, P < 0.03). When DR3+ patients and controls were analyzed separately, heterozygotes were still significantly increased in DR3+ Graves’ disease patients (54 of 77, 70%) compared to DR3+ controls (21 of 45, 47%; x2 = 6.6, P < 0.04). Furthermore, TNF fragment heterozygotes were found predominantly in patients, who had TSH-receptor antibodies (29/45,64%, P < 0.007), implying that these patients might represent an immunogenetic subset of the disease. Although TNF/3 polymorphisms are linked to AlB8DR3, these results suggest that they represent an additional susceptibility marker in Graves’ disease. (J Clin Endocrinol Metab 74: 287-291,1992)

G

ENETIC susceptibility to Graves’ disease has been associated with the histocompatibility leucocyte antigen (HLA) region on the short arm of chromosome 6. Earlier studies on Caucasoid patients showed HLA B8, and later HLA DR3 to be the immunogenetic markers with the strongest association (1, 2). Since a variety of studies have shown different associations and the strength of the DR3 association has varied, other genes in the vicinity of the HLA system are candidates to confer susceptibility. The major histocompatibility complex consists of several gene clusters: class I, class II, and class III. The latter harbors the tumor necrosis factor (Y (TNF (Y) and lymphotoxin (TNF /3) genes that map between HLA B and the complement genes (3, 4). TNF Received February 14,1991. Address all correspondence and requests for reprints to: Dr. Klaus Badenhoop, University Hospital, Center of Internal Medicine, Department of Endocrinology, Theodor Stern Kai 7, D 6000 Frankfurt am Main 70, Germany. * K.B. is supported by the Deutsche Forschungsgemeinschaft (Ba 976/2-l).

(Y and TNF p are closely related cytokines that share 30% amino acid residues and use the same cell surface receptor (5). Both molecules play a major role in the cytokine network (5). In peripheral mononuclear cells both seem to be independently regulated (6). Although produced by different cells (TNF LY by macrophages/ monocytes, and TNF @ predominantly by T-lymphocytes) their intrinsic cytolytic properties are similar. The fact that TNF is so closely linked to HLA raises the possibility that it might be involved in the susceptibility to disease. Since TNF in conjunction with y-interferon induces MHC class II and enhances class I expression on thyroid cells, it might be also functionally involved in the pathogenesis of autoimmune thyroid disease (7). We have, therefore, tested the possibility to identify an association between TNF and HLA DR by studying a large group of Graves’ disease patients and normal controls from four Centers with restriction fragment length polymorphism (RFLP) using TNF gene probes 03).

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288

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Subjects

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M .1992 Voll4.No2

and Methods

Patients and controls One hundred and seventy-four patients with Graves’ disease were studied: 107 patients were from two Centers in London (51 patients from the Middlesex Hospital and 56 from the Hammersmith Hospital), 54 from Berlin, and 13 from Mannheim. The diagnosis of Graves’ disease was based on established criteria which include: clinical and chemical hyperthyroidism, combined with diffuse enlargement of the thyroid. Ninety-six patients had endocrine ophthalmopathy (defined by WHO grade II or greater). TSH-receptor-antibodies (TRAb) were measured in a prospective fashion using a well defined TSH-binding-inhibiting assay (9). Sixty-seven patients were tested for the initial presence or subsequent development of these antibodies as well as for HLA-serology and TNF-fragments by RFLP. Of those, 45 (67%) were found to be positive at the onset or during the course of the disease. Thirty patients had antibodies as well as endocrine ophthalmopathy. One hundred and seventy-three healthy control subjects were from London (48), Berlin (47), and Mannheim (78). Careful family history taking excluded thyroid autoimmune diseases in controls and their relatives. HLA-specificities did not differ among the three control subgroups. HLA-serology Complete HLA serology was performed according to Ninth International Histocompatibility Workshop definitions for A, B, C, DR, DQ, and DRw 52/53 (10, 11). The analysis was performed on the phenotype AlB8DR3 since we could not assign haplotypes without family analysis. The distribution of HLA specificities was homogeneous within the three patient groups and in the controls, respectively.

Results HLA-serology Among all HLA DR specificities tested, only DR3 was significantly increased (Table 1): 77 patients out of 174 (44%) were DR3+ compared to 45 of 173 controls (26%), P < 0.006, relative risk (RR) = 2.26. DR3 was increased in all centers. DR3 was found in 47 of 96 (49%) patients with ophthalmopathy (P < 0.003, compared to controls) and in 21 of 45 TRAb+ Graves’ disease patients (P < 0.05). This confirms the association of Graves’ disease with DR3 and reveals an association of TRAb+ patients with the DR3 specificity, but there was no difference in the distribution of DR3 in patients with or without ophthalmopathy or TRAb. The phenotype AlB8DR3 was found in 42 (24%) of all Graves’ disease patients, in 22 (23%) of those with ophthalmopathy, in 17 (38%) TRAb+ patients, but only in 21 (12%) controls. HLA B8 was less frequent than DR3 in all groups. Interestingly, TRAb+ patients also showed an increase of the DR5 specificity 16 (36%) compared to 21 (12%) of controls (P < 0.005). The DR7 specificity was decreased in Graves’ disease patients, reaching significance in those with ophthalmopathy (P < 0.02). No other DR, A, B, nor C specificities were increased or decreased (data not shown). No particular heterozygosity was increased for HLA ABC or DR specificities (data not shown). TABLE trols

1. HLA-DR

Graves’ all n = 114

RFLP studies RFLP studies were performed according to standard procedures (12). DNA was prepared from peripheral blood, digested with NcoI (Boehringer Mannheim GmbH, Mannheim, Germany), electrophoresed on a 0.8% agarose gel, transferred onto Hybond N membranes (Amersham, UK), prehybridized and hybridized with a hexamer-labeled genomic probe for TNF (Y (13) and TNF /3 (kindly provided by Elisabeth We& Munich). Before rehybridization with the second probe, filters were dehybridized. Filters were washed down to 0.2 x SSC, 0.1% sodium dodecyl sulfate and exposed on Hyperfilm (Amersham). The TNF LYprobe used was a 2.9 kilobase (kb) EcoRI insert that had been subcloned in pAT153. This probe contains several introns and 4 exons of the human TNF (Ygene (13). The TNF j3 probe was a 2.4 kb EcoRI insert (14). Gene frequencies of the polymorphic fragments were determined by direct gene counting. Two by two tables and three by two tables were analyzed by x2 or Fisher’s exact test, where appropriate, with allowance for the number of comparisons made for TNF polymorphisms. P-values for DR-associations were corrected for the number of DR-specificities (10).

DRl DR2 DR3 DR4 DR.5 DR6 DR7 DR8 DR9 DRlO AlB8 -DR3 B8

38 39 77 50 40 25 32 7

(22%) (22%) (44%) (29%) (23%) (14%) (18%) (4%)

42 (24%)’ 49 (28%)

specificitiesin Graves’diseasepatients and conGraves’ ophthalmopathy n = 96 23 27 47 29 25 13 13 6

TBIAb+ (n = 67 tested) n = 45

Controls n = 1,3

(24%) (28%) (49%)b (30%) (26%) (14%) (14%)e (6%)

8 (18%) 8 (18%) 21 (47%)’ 7 (16%) 16 (36%)d 9 (20%) 10 (22%) 1(2%)

35 45 45 35 21 35 55 14 1 3

22 (23%)# 27 (28%)

17 (38%)h 17 (38%)

21 (12%)’ 29 (17%)

All P-values ’ I’ < 0.006, b P < 0.003,

as compared to controls. x2 = 11.9, RR = 2.26. x2 = 13.4, RR = 2.45. 'P c 0.05, x2 = 6.27, RR = 2.49. d P < 0.005, x2 = 12.28, RR = 3.99. 'PC 0.02, x2 = 9.9, RR = 0.33. f x2 = 7.62, P C 0.006 (nx.). 8 x2 = 4.57, PC 0.04 (n.c.). h x2 = 14.58, P < 0.0002 (n.c.) ’ Phenotype AlB8DR3.

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(20%) (26%) (26%) (20%) (12%) (20%) (32%) (8%) (0.5%) (2%)

TNFB

GENE

POLYMORPHISMS

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60 out of 174 patients (34%) were homozygous for the TNFP*2 allele, 96 (55%) heterozygous, and 18 (10%) homozygous for the TNFP*l allele (x2 = 7.45, P < 0.03, Table 2).

123456789

TNF /3 RFLP in DR3+ subjects

10Skb

5Skb 5.0kb

FIG. 1. Autoradiograph of a Southern blot: AM digested DNA hybridized with a TNF@ probe. Lane 1 displays a 10.5-kb homozygote (TNF@*2 allele); lanes 2-8, 10.5/5.5-5kb heterozygotes (TNF@*2pl alleles); and lane 9, a 5.5-5-kb homozygote (TNFP*l allele).

TNF- RFLP Hybridization of NcoI digested genomic DNA with a TNF (Yprobe reveals 10.5 and 5.5 kb bands. These bands behave in a diallelic fashion: one can be homozygous for either fragment or heterozygous for both. Rehybridization with a TNF p probe reveals three bands: 10.5, 5.5, and 5.0 kb (Fig. 1). The 5.5 and 5.0 kb fragments always occur together, indicating that the NcoI polymorphism is situated in the TNF p gene. Also, sequencing studies by Messer et al. (14) have demonstrated the localization of the NcoI restriction site in the TNF p intron. The 5.5 kb NcoI fragment of the TNF p gene has been proposed by Messer et al. (14) to be denominated as the TNFP*l allele, the 10.5 kb NcoI fragment as the TNFP*2 allele, respectively, a nomenclature that we apply throughout this manuscript. Eighty-four of 173 controls (49%) were homozygous for the TNFP*2 allele, 72 (42%) were heterozygous, and 17 (10%) were homozygous for TNFP*l. In comparison, TABLE

2. TNF polymorphisms TNFB*2 homozygous

Graves’ 60 (34%) Controls 84 (49%) x2 = 7.45; P = 0.024.

in Graves’ disease TNFB*2/*1 heterozygous

TNFB*l bomozygous

Total

96 (55%) 72 (42%)

18 (10%) 17 (10%)

174 173

In order to test whether TNFP polymorphisms are related to DR3 or AlB8DR3, we analyzed DR3+ and DR3- patients and controls and those with the phenotype AlB8DR3. The presence of DR3 and Al, B8, DR3 was tested in comparison to the distribution of TNFP alleles (x2-test for 3 x 2 tables, Table 3). Nine out of 77 DR3+ patients (12%) were homozygous TNFP*2,54 (70%) heterozygous, and 14 (18%) homozygous TNFP*l. This distribution was different in DR3+ controls: 9 of 45 (20%) were homozygous TNFP*2, 21 (47%) heterozygous, and 15 (33%) homozygous TNFP*l, (x2 = 6.6, P < 0.04, Table 3). The phenotype DR3 combined with TNF/3 heterozygosity provides the highest relative risk (odds ratio = 3.6) comparing DR3+ TNFP heterozygous Graves’ disease patients with DR3- TNFP nonheterozygous controls (x2 = 16.46, P < 5 X 10V4, Table 3). There was neither a difference between AlB8DR3 patients and controls nor between DR3- patients and controls regarding TNF p polymorphisms: 31 (74%) AlB8DR3 patients were TNFP*1/*2 heterozygous [ 15 (71%) controls] and 11 (26%) were homozygous for the less frequent TNFP*l allele [6 (29%) AlB8DR3 controls] (Table 3). Fifty-one (53%) DR3- patients were homozygous for TNFP*2 [75 (59%) DR3- controls], 42 (43%) were heterozygous TNFP*1/*2 [51 (40%) controls] and 4 (4%) were homozygous for TNFP*l [2 (2%) DR3controls] (Table 3). TABLE

3. TNF polymorphisms TNFB:2 homozygous

in DR3+ patients and controls TNFB*2/*1 heterozygous

TNFB*l homozygous

Total

Graves’ 9 (12%) 54 (70%)d 14 (18%) 77 DR3 +“.* 11 (26%) 42 AlB8DR3 0 31 (74%) 51 (53%) 42 (43%) 4 (4%) 97 DR3* Controls 21 (47%) 15 (33%) 45 DR3+“.’ 9 (20%) AlBSDR3 0 15 (71%) 6 (29%) 21 75 (59%)d 51 (40%) 2 (2%)d 128 DR3-’ n$ = 6.6, P < 0.04, (DR3+ Graves’ patients compared to DR3+ controls). * x2 = 34.61, P < 10e6 (DR3+ Graves’ patients compared to DR3patients). c~2 = 44.79, P < 10m6(DR3+ controls compared to DR3- controls). d x2 = 16.46, P < 4.9 X 10m4,odds ratio (=relative risk) 3.6 (DR3+ TNFB heterozygous patients compared with DR3- and TNFB nonheterozygous controls).

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290

BADENHOOP

TNF /3 RFLP in Graves’ disease patients ophthalmopathy

with endocrine

Ninety-six patients had endocrine ophthalmopathy (WHO grade II or greater). Forty-eight (50%) patients were heterozygous for TNF fi fragments, 30 (31%) homozygous for the TNFP*2 allele, and 8 (8%) homozygous for TNF/3*1. Patients without endocrine ophthalmopathy did not differ for TNF /3 fragments from patients with eye disease (data not shown). TNF p fragments

in Graves’ disease patients

with TRAb

Sixty-seven of all patients could be tested prospectively for the development of TRAb at the beginning or during the course of the disease, of whom 45 (67%) were positive. Twenty-nine (64%) were heterozygous for TNF @fragments, 10 (22%) homozygous for the TNF/3*2 allele, and 6 (13%) homozygous for the TNFP*l allele, P < 0.007, x2 = 10.18 in comparison to controls (Table 4). TRAb- patients did not differ from controls, although the number is small: 10 (45%) TRAbpatients were TNFP*2 homozygous, 11 (50%) heterozygous TNFP*l/ *2, and 1 (5%) homozygous TNFP*l (Table 4). Nor did TRAP- patients differ from TRAP+ patients significantly (P = 0.11). Discussion Immunogenetic factors that predispose to Graves’ disease have been shown to be complex for HLA-linked and non-HLA-linked gene regions (15-19). Therefore, the genetic susceptibility is likely to be conferred by more than one gene. We assessed genetic variability of TNF in Graves’ disease. Previous analysis of family haplotypes showed strong linkage of the 5.5 kb TNF fragment (TNF/3*1 allele) with the extended haplotype AlB8DR3, although homozygous cell lines showed exceptions with the 10.5 kb fragment (TNFP*2 allele) (20). Our analysis of a large group of patients and controls demonstrates an association of TNF fragment heterozygosity with Graves’ disease, that is particularly increased in DR3+ patients. DR3+ TNFP heterozygotes have the highest relative risk as indicated by the odds ratio compared with DR3- TNFp nonheterozygous controls. This confirms an additional risk for DR3+ patients TABLE 4. TNFB polymorphisms

TRAb + Graves”!* TRAb - Graves’* Controls”

TNFB*2 10 (22%) 10 (45%) 84 (49%)

in TRAb+

Graves’ patients

TNFB*2/*1 29 (64%) 11 (50%) 72 (42%)

TNFB*l 6 (13%) 1 (5%) 17 (10%)

Total 45 22 173

’ x2 = 10.18; P < 0.007. TRAb+ patients compared with controls. *x2 = 4.28; P = 0.11. TRAb+ patients compared with TRAbpatients.

ET AL.

JCE & M. 1992 Vo114.No2

conferred by TNFP heterozygosity. It is interesting that this is different than previous analysis in type 1 diabetes, where heterozygosity results from the linkage of DR3 to TNFP*l and DR4DQw8 to TNFP*2 (20). However, patients and controls matched for the phenotype AlB8DR3 do not differ for heterozygosity of TNFP alleles, indicating that this phenotype which is increased in Graves’ disease patients includes the TNF@ marker. Also, TRAb+ Graves’ disease patients display a stronger association with TNF fragment heterozygosity, implying that they may represent an immunogenetic subset of the disease. Heterozygosity could also be explained by close linkage to another predisposing gene in the vicinity on the short arm of chromosome 6, possibly between the complement genes and HLA B (21). However, TNFp polymorphism results from two alleles that are difficult to compare with more polymorphic genes of the major histocompatibility complex (22). Since restriction fragments as detected by Southern blot hybridization reflect mostly variation in introns, the origin of the TNF fragments is of interest. According to published nucleotide sequence information, NcoI sites are found in both TNFA and TNFp genes separated by 5.4 kb (23). The polymorphic NcoI site resides in the TNF@ gene as can be demonstrated by rehybridization with the TNFP probe, where the 5.5/5.0 kb bands always occur together, and by direct sequencing (14). Since the polymorphic NcoI site is in an intron of TNFP, it is not present in the processed messenger RNA. However, homozygotes for either TNF fragment differ in TNF p production of in vitro stimulated peripheral mononuclear blood cells (14). TNFP alleles might, therefore, mark a particular immunological responder status that is found in B8/DR3 individuals with an altered immune response to mitogens and suppressor T-cells (24, 25), and may contribute in a predisposing manner to the development of autoimmune diseases like Graves’ disease. Furthermore, TNFP*l alleles as defined by the 5.5-kb NcoI fragment possess a triplet variation coding for asparagine at amino acid position 26, whereas 10.5 kb fragment alleles have threonine at this position (14). TNF RFLP might therefore represent functionally relevant gene variations confined sofar to TNF ,& whereas TNF (Yproduction of stimulated macrophages does not seem to correlate with this TNF RFLP pattern (26). In another, yet destructive autoimmune disease, type 1 diabetes mellitus, TNF a! is expressed during the development of the disease in nonobese mice exclusively in intraislet infiltrates, where a proportion of CD4+ Tlymphocytes produce TNF (Y(27), (and presumably TNF @,although this was not studied). Whether early expression of TNF @ is also involved in a stimulating autoimmune disorder like Graves’ disease remains to be shown.

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TNF@

GENE

POLYMORPHISMS

These results suggest TNF gene polymorphisms represent an additional risk factor in HLA-linked genetic susceptibility to Graves’ disease. It remains to be established whether Graves’ disease patients differ from controls for TNF 6 inducibility and whether such variation in local production affects the target organ, i.e. the thyroid. Acknowledgments We are indebted to Elisabeth WeiR and Gerald Messer, Institute of Immunology, University of Munich, for the TNF fl probe and for letting us know their results prior to publication. Boehringer Mannheim kindly provided us with laboratory reagents.

References 1. Farid NR, Stenszky V. Graves’ disease. In: Farid NR, ed. Immunogenetics of endocrine disorders. New York: Alan R. Liss, Inc; 1988223-66. 2. Schleusener H, Peters H, Bogner U, et al. Immunogenetics in Graves’ disease: An overview. Acta Endocrinol (Copenh). 1989;121(Suppl2):123-9. 3. Snies T. Morton CC. Nedosnasov SA. Fiers W. Pious D. Strominger h. Genes for the tumor necrosis factor alpha and beta are linked to the human major histocompatibility complex. Proc Nat1 Acad Sci USA. 1986;83:8699-8702. 4. Ragoussis J, Bloemer K, Weiss EH, Ziegler A. Localization of the genes for tumor necrosis factor and lymphotoxin between the HLA class I and II regions by field inversion gel electrophoresis. Immunogenetics. 198&27:66-Q. 5. Beutler B, Cerami A. The biology of cachectin/TNF-a primary mediator of the host response. Ann Rev Immunol. 1989;7:625-55. 6. Cuturi MC, Murphy M, Costa-Giomi MP, Weinmann R, Perussia B, Trinchieri G. Independent regulation of tumor necrosis factor and lymphotoxin production by human peripheral blood lymphocytes. J Exp Med. 1987;165:1581-94. 7. Buscema M, Todd I, Deuss U, et al. Influence of tumor necrosis factor-a on the modulation by interferon-gamma of HLA class II molecules in human thyroid cells and its effect on interferongamma binding. J Clin Endocrinol Metab. 1989;69:433-9. 8. Badenhoop K, Schwarz G, Trowsdale J, et al. TNF-a gene polymorphisms in Type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1989;32:445-8. 9. Schleusener H, Kotulla P, Finke R, et al. Relationship between thyroid status and Graves’ disease-specific immunoglobulins. J Clin Endocrinol Metab. 1978:47:379-84. 10. Terasaki PI, Parks MS. M&droplet lymphocyte cytotoxicity test. In: Ray JG, ed. Manual of tissue typing techniques. Bethesda, MD, NIH; 1980:91-103. 11. van Rood JJ, van Leeuwen A, Ploem JS. Simultaneous detection of two cell populations by two-colour fluorescence and applications to the recognition of B cell determinants. Nature. 1976;262:795-7.

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12. Marcadet A, O’Connell P, Cohen D. Standardized Southern blot workshop technique. In: DuPont B, ed. Immunobiology of HLA. ~011: Histocompatibility testing 1987. New York: Springer-Verlag; 1989:553-60. 13. Shirai T, Yamguchi H, Ito H, Todd CW, Wallace RB. Cloning and expression in Escherichia coli of the gene for human tumour necrosis factor. Nature. 1985;313:803-6. 14. Messer G, Spengler U, Jung MC, et al. Polymorphic structure of the TNF locus: A NcoI polymorphism in the first intron of the human TNF-fl gene correlates with a variant amino acid in position 26 and a reduced level of TNF-B production. J Exp Med. 1991;173:209-19. 15. Weetman AP, So AK, Warner CA, Foroni L, Fells P, Shine B. Immunogenetics of Graves’ ophthalmopathy. Clin Endocrinol (Oxf). 1988;28:619-28. 16. Fletcher J, Franklyn JA, McLachlan SM, Young E, Sheppard MC. HLA class II DNA genotypes in Graves’ disease: Clues to inheritance of the HLA-linked component of susceptibility. Clin Endocrinol (Oxf). 1988;29:539-47. 17. Weetman AP, Zhang L, Webb S, Shine B. Analysis of HLA-DQB and HLA-DPB alleles in Graves’ disease by oligonucleotide probing of enzymatically amplified DNA. Clin Endocrinol (Oxf). 1990;33;65-71. 18. Pavami H. Joe S. Farid NR. et al. Relative nredisuositional effects (RPEs) ofmarker alleles with disease: HLA’-DR alleles and Graves disease. Am J Hum Genet. 1989;45:541-6. 19. Demaine AG, Ratanachaiyavong S, Pope R, Ewins D, Millward BA. McGreaor AM. Thvrozlobulin antibodies in Graves’ disease are associated with T-cell receptor beta chain and major histocompatibility complex loci. Clin Exp Immunol. 1989;77:21-4. 20. Badenhoop K, Schwarz G, Bingley P, et al. TNF-alpha gene polymorphisms: Association with type I (insulin-dependent) diabetes mellitus. J Immunogenet. 1989;16:455-60. 21. Sargent CA, Dunham I, Campbell RD. Identification of multiple HTF-island associated genes in the human major histocompatibility complex class III region. EMBO J. 1989;8:2305-12. 22. Svejgaard A, Platz P, Ryder LP. HLA and disease 1982-a survey. Immunol Rev. 1983;70:193-218. 23. Nedwin GE, Navlor SL. Sakaguchi AY, et al. Human lvmphotoxin and tumor necrosis factor genes: Structure, homology and chromosomal localization. Nucleic Acids Res. 1985:13:6361-73. 24. Hashimoto S, McCombs CC, Michalski JP. Mechanism of a lymphocyte abnormality associated with HLA- B8/DR3 in clinically healthy individuals. Clin Exp Immunol. 198376317-23. 25. Ambinder JM, Chiorazzi N, Gibofsky A, Fotino M, Kunkel HG. Special characteristics of cellular immune function in normal individuals of the HLA-DR3 type. Clin Immunol Immunopathol. 1982;23:269-74. 26. Jacob CO, Fronek Z, Lewis GD, Koo M, Hansen JA, Mcdevitt HO. Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor (Y: Relevance to genetic predisposition to systemic lupus erythematosus. Proc Nat1 Acad Sci USA. 1990;87:1233-7. 27. Held W, MacDonald HR, Weissman IL, Hess MW, Mueller C. Genes encoding tumor necrosis factor 01 and granzyme A are expressed during development of autoimmune diabetes. Proc Nat1 Acad Sci USA. 1990;87:2239-43. ”

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Tumor necrosis factor beta gene polymorphisms in Graves' disease.

The physical mapping of tumor necrosis factor alpha (TNF alpha) and lymphotoxin (TNF beta) genes to the short arm of chromosome 6 in man between the l...
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