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Linkage Disequilibrium between the Human Leukocyte Antigen Class II Region of the Major Histocompatibility Complex and Graves’ Disease: Replication Using a Population Case Control and Family-Based Study¹

Department of Medicine, University of Birmingham, Queen Elizabeth Hospital (J.M.H., A.A., J.D., J.C.-S., A.D., M.C.S., A.H.B., J.A.F., S.C.L.G.), Birmingham, United Kingdom; Royal Bournemouth Hospital (M.A.), Bournemouth, United Kingdom; and Birmingham Heartlands Hospital (P.M.D., A.H.B., S.C.L.G.), Birmingham, United Kingdom B9 5SS

Address all correspondence and requests for reprints to: Dr. Stephen C. L. Gough, Department of Medicine, University of Birmingham, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham, United Kingdom B9 5SS. E-mail: s.c.gough{at}bham.ac.uk

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Early case control studies found association of the DRB1 allele, DR3, with Graves’ disease (GD). Recent reports, claim the DQA1 allele, DQA1*0501, to be the primary susceptibility determinant within the human leukocyte antigen (HLA) class II region. We typed 228 GD patients, 364 controls, and 98 families (parents, GD, and unaffected sibling) at the DRB1, DQB1, and DQA1 loci. The case control study showed an increased frequency in GD, compared to controls, of DRB1*0304 (47% vs. 24%; pc < 1.4 x 10^-5), DQB1*02 (58% vs. 46%; pc < 0.035), DQB1*0301/4 (42% vs. 28%; pc < 3.5 x 10^-3) and DQA1*0501 (67%, vs. 39%; pc < 7 x 10^-6). The DRB1*0304-DQB1*02-DQA1*0501 haplotype was increased in GD (47%) vs. controls (24%; pc < 1.8 x 10^-5; odds ratio = 2.72). No independent association of these alleles was observed. Preferential transmission of DRB1*0304-DQB1*02-DQA1*0501 from parents heterozygous for the haplotype to GD siblings (72%) was seen in the families (² = 11.95; 1 d.f.; P = 0.0005). Lack of preferential transmission to unaffected siblings (53%; ² = 0.19; 1 d.f.; P = NS) excluded segregation distortion. These results show that linkage disequilibrium between GD and the HLA class II region is due to the extended haplotype DRB1*0304-DQB1*02-DQA1*0501.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
GRAVES’ disease (GD) is an autoimmune disease of the thyroid gland characterized by hyperthyroidism, diffuse goiter, and positive thyroid autoantibodies. Although the etiology is unknown, the disease process appears to be influenced by protective and permissive environments in genetically susceptible individuals (1). After genome-wide searches in type 1 diabetes and the identification of multiple susceptibility loci, it is likely that most autoimmune diseases will exhibit a polygenic mode of inheritance (2). Preliminary evidence for linkage on chromosome 14q31 (GD1) (3) and case control studies of the cytotoxic T lymphocyte-associated-4 (CTLA-4) gene (4, 5) in GD are in support of this. The concordance rate in GD in monozygotic twins is similar to that in type 1 diabetes (3, 4), and epidemiological data have shown that both diseases cluster within the same families and individuals (5). As the human leukocyte antigen (HLA) class II region is the major susceptibility locus for type 1 diabetes, accounting for 40% of familial clustering in the UK (s = 3, the ratio of the expected proportion of affected sibling pairs sharing zero alleles identical by descent, 0.25, and the observed proportion) (2), it seems likely that it will play a similar role in GD. This region is an obvious candidate for a role in the genetic susceptibility to GD, as there is aberrant expression of the major histocompatibility complex (MHC) class II antigens on follicular cells (the target cell in the autoimmune process) and on activated lymphocytes in patients with disease.

Although classical linkage analysis has been successfully used to find major genes, its ability to detect genes of modest effect has been limited (9). This may explain why linkage analysis of the HLA region in GD in family-based studies (10, 11, 12) has failed to replicate case control data (13, 14, 15, 16, 17, 18).

We have, therefore, examined the MHC HLA class II region in patients with GD using the alternative approach of linkage disequilibrium analysis in two independent United Kingdom datasets. The Transmission Disequilibrium Test (TDT) (19) was used in a family-based study to replicate the findings of a population-based case control study.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Caucasian patients (with both parents and both grandparents of British or Irish origin) with GD were recruited from three large thyroid clinics in Birmingham and Bournemouth, UK. Graves’ patients were defined by the presence of biochemical hyperthyroidism together with 2 of the following criteria: diffuse goiter; a significant titer of microsomal, thyroglobulin, or TSH receptor autoantibodies; and the presence of dysthyroid eye disease. Taking all index cases together, 87% had diffuse goiter, and 95% had positive thyroid autoantibodies. Thyroid eye disease was present in 22.7% of the index cases classified using the NOSPEC classification, with eye disease defined as positive features in any of classes 2–6 (20). Eyelid signs alone were not considered indicative of thyroid eye disease. Microsomal and thyroglobulin antibodies were measured by gelatin particle agglutination (SERODIA-AMC and SERODIA-ATG, Fujirebio, Inc., Tokyo, Japan), and a titer of 1:100 was considered significant for both assays. TSH receptor autoantibody status was determined by a radioactive inhibition method (RSR Ltd., Cardiff, UK). A value of 10 U/L or more was deemed significant after comparison with 50 controls obtained from the local blood transfusion service. Ethnically matched controls with no history of autoimmune disease were bled at various sites, including the Blood Transfusion Service, Birmingham Heartlands Hospital, and the Queen Elizabeth Hospital. Simplex families were also recruited, where in most instances blood samples were obtained from the index case, both parents, and any unaffected siblings. All siblings were tested for thyroid function and autoantibody status, and any showing evidence of subclinical autoimmune thyroid disease were removed from the study before genotyping was performed. In total, DNA was obtained from 228 Graves’ index cases, 58 males (25%) and 170 females (75%), and 364 controls, 77 males (22%) and 287 females (78%), for the population association study and from 98 simplex families.

The study was approved by the respective local ethics committees, and all subjects gave informed, written consent.

Genotyping of datasets

DNA was prepared from 10 mL whole blood using the Nucleon Bacc II kit from Nucleon Biosciences (UK). The HLA-DRB1, DQB1, and DQA1 regions were amplified using the phototyping method of the PCR, as previously published (21). Primers were obtained from Oswel (UK) and R&D Systems (UK). Results were visualized on a 1% ethidium bromide-stained agarose gel under ultraviolet light.

Statistical analysis

Analysis of the case control data was performed using the ² test with 95% confidence limits (CL). All P values were corrected for the number of comparisons made, and P < 0.05 was considered significant. Odds ratios (ORs) were calculated by the method of Woolf with Haldane’s modification for small numbers (22).

The TDT (19) was used to assess linkage disequilibrium between the HLA susceptibility haplotype and disease in the family dataset. A significant excess of transmission frequency of the associated haplotype DRB1¹0304-DQB1¹02-DQA1¹0501 from parents heterozygous for that haplotype to affected offspring was taken as evidence of linkage disequilibrium. Comparisons of transmissions to unaffected offspring using the 2 x 2 test of heterogeneity were performed to exclude segregation distortion.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Population-based case control study

Two hundred and twenty-eight Graves’ patients and 364 healthy control subjects were available to be genotyped at the DRB1, DQB1, and DQA1 loci. All patients and control subjects were successfully genotyped at all 3 loci.

The distribution of DRB1 alleles among patients and control subjects is summarized in Table 1. A significant increase in the frequency of the DRB1¹0304 allele was seen in patients compared to control subjects (47% vs. 24%, respectively; OR = 2.72; pc < 1.4 x 10^-5).

Transmission of the haplotype DRB1¹0304-DQB1¹02-DQA1¹0501 from heterozygous parents to affected and unaffected siblings was analyzed using a standard TDT, McNemar’s test (19). Of the 98 families available for study, 54 were informative for this haplotype. A significant increase in transmission (T) compared to nontransmission (NT) of the DRB1¹0304-DQB1¹02-DQA1¹0501 haplotype was seen in affected offspring [44 T (72%) vs. 17 NT (28%); ² = 11.95; 1 d.f.; P = 0.0005; Table 5]. There was no preferential transmission of this haplotype to unaffected offspring (53%). The 2 x 2 test of heterogeneity comparing transmission of the DRB1¹0304-DQB1¹02-DQA1¹0501 haplotype to affected and unaffected offspring (² 4.1; 1 d.f.; P = 0.04) confirms that the significant excess of transmissions to affected offspring was not the result of segregation distortion.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
HLA class II associations with GD have been reported in many case control studies, particularly associations of DR3 and DQA1¹0501 (13, 14, 15, 16, 17, 18). However, these results have been inconsistent, and linkage between GD and HLA remained to be confirmed in family-based studies (10, 11, 12). Studies reporting evidence against linkage support the suggestion that the HLA region is exerting a modest effect on the expression of the disease which can not easily be detected by classical linkage analysis. In the current study, we confirmed associations of the disease with the alleles DR3 (DRB1¹0304) and DQA1¹0501, with the latter conferring the highest risk of disease (OR = 3.16; 95% CL = 2.23–4.46). These results are in agreement with those seen in previous case control studies (15, 17, 23, 24, 25, 26, 27). Lack of an independent association of DQA1¹0501 with disease, despite the increased OR, may be the result of the allele being in linkage disequilibrium with an unknown non-HLA gene that has a stronger association with disease. However, a more likely explanation is linkage disequilibrium between DQA1¹0501 and DR5 (DRB1¹11 and DRB1¹12). All 42 Graves’ patients with DRB1¹11 also carried the DQA1¹0501 allele, suggesting that the increase in DQA1¹0501 in DRB1¹0304-negative patients is due to linkage disequilibrium with DRB1¹11. We also found weak association of the DQB alleles, DQB1¹02 and DQB1¹0301/4, with disease, implying that association with disease was secondary to that conferred by DRB1 and DQA1 alleles. All of the 107 Graves’ patients that were DRB1¹0304-DQA1¹0501 positive carried the DQB1¹02 allele, suggesting that the increase in DQB1¹02 is due to linkage disequilibrium with DRB1¹0304-DQA1¹0501.

Due to the increased frequencies of the alleles DRB1¹0304, DQB1¹02, and DQA1¹0501, the strong linkage disequilibrium between them, and their lack of independent association with disease, we investigated the frequency of the haplotype DRB1¹0304-DQB1¹02-DQA1¹0501 in our cohort of Graves’ patients and control subjects. An increase in the frequency of this haplotype was seen in patients compared to control subjects and was consistent with the allele frequency data (OR = 2.72; confidence limits = 1.91–3.87; pc = 1.8 x 10^-5). This result suggests that this haplotype is conferring genetic susceptibility to Graves’ disease in our population.

Although the case control approach has been frequently used to test candidate genes (28), it is widely accepted that differences in allele frequencies between a diseased population and normal control subjects may arise for reasons other than linkage disequilibrium between alleles of the marker and alleles of the disease locus. False positives can occur as the result of random chance events, a common occurrence in small datasets, or to population stratification (29). To minimize random chance events, it is important to use adequately sized datasets; to eliminate population stratification, it is crucial for susceptibility genes to be examined in family-based studies.

Classical linkage analysis has identified major genes in complex diseases, although its ability to detect genes of modest effect has proved limited (9). The TDT is a more powerful approach for detecting susceptibility loci that may be missed by classical linkage analysis (9). The detection of such susceptibility loci is important because, although likely to have small effects, the magnitude of their attributable risk may be large, as they are frequent in the general population. Moreover, by using single affected individuals and parents, the TDT does not require families with multiple affected siblings. This approach is particularly valuable, therefore, in diseases of late onset, such as autoimmune thyroid disease.

In the present study we used the TDT, which has been considered to be a test of linkage in the presence of linkage disequilibrium (19). In an independent family dataset, we examined the frequency of transmission of DRB1¹0304-DQB1¹02-DQA1¹0501 from parents heterozygous for the haplotype. We found a significant preferential transmission of the DRB1¹0304-DQB1¹02-DQA1¹0501 haplotype to affected Graves’ index cases (72%), providing evidence of linkage disequilibrium.

To overcome the confounding problem of subclinical or undiagnosed autoimmune thyroid disease in unaffected siblings, all had thyroid function and thyroid antibody status measured. Eight of 100 unaffected siblings (8%) were found to have evidence of subclinical autoimmune hypothyroidism, including a raised TSH receptor level and positive thyroid antibodies, and were excluded from our analysis. The transmission of the disease haplotype DRB1¹0304-DQB1¹02-DQA1¹0501 to unaffected siblings (25 transmissions, 53%) was reassuring and demonstrated that well characterized unaffected siblings can be used as controls for TDT analysis in GD. Inclusion of siblings with subclinical undiagnosed autoimmune thyroid disease as unaffected subjects, however, had no significant effect on the family results (data not shown). The 2 x 2 test of heterogeneity, performed between affected and unaffected offspring, ruled out segregation distortion as an alternative explanation to linkage disequilibrium of DRB1¹0304-DQB1¹02-DQA1¹0501 with GD.

In conclusion, we have shown for the first time in a family-based study that the MHC HLA class II region on chromosome 6p is in linkage disequilibrium with GD in Caucasians in the United Kingdom. The TDT in the family study provides strong confirmatory evidence for linkage disequilibrium between the haplotype DRB1¹0304-DQB1¹02-DQA1¹0501 and disease found in the case control study. No independent association of DQA1¹0501 was seen over and above linkage disequilibrium with DR alleles, suggesting that genetic susceptibility to GD cannot be attributed to any one allele.

	Acknowledgments

 
We thank John Todd for his critical appraisal of the manuscript, and our colleagues for help in recruiting patients.

	Footnotes

 
¹ This work was supported by a project grant from the Wellcome Trust (Grant M/95/3717), Eli Lilly UK, and the Trustees of the former United Birmingham Hospitals.

² Smith and Nephew Medical Research Fellow.

Received March 13, 1998.

Revised April 21, 1998.

Accepted June 15, 1998.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Stenszky V, Kozma L, Balaczs C, Rochlitz S, Bear JC, Farid NR. 1985 The genetics of Graves’ disease: HLA and disease susceptibility. J Clin Endocrinol Metab. 61:735–740.[Abstract]
2. Todd JA. 1995 Genetic analysis of type I diabetes using whole genome approaches. Proc Natl Acad Sci USA. 92:8560–8565.[Abstract/Free Full Text]
3. Tomer Y, Barbesino G, Keddache M, Greenberg DA, Davies TF. 1997 Mapping of a major susceptibility locus for Graves’ disease (GD-1) to chromosome 14q31. J Clin Endocrinol Metab. 82:1645–1648.[Abstract/Free Full Text]
4. Donner H, Rau H, Walfish PG, et al. 1997 CTLA4 alanine-17 confers genetic susceptibility to Graves’ disease and to type I diabetes mellitus. J Clin Endocrinol Metab. 82:143–146.[Abstract/Free Full Text]
5. Kotsa K, Watson PF, Weetman AP. 1997 A CTLA4 gene polymorphism is associated with both Graves’ disease and autoimmune hypothyroidism. Clin Endocrinol (Oxf). 46:551–554.
6. Olmos P, A’Hern R, Heaton DA, et al. 1988 The significance of the concordance rate for type I (insulin-dependent) diabetes in identical twins. Diabetologia. 31:747–750.[CrossRef][Medline]
7. Kyvik KO, Green A, Beck-Nielsen H. 1995 Concordance rates of insulin dependent diabetes mellitus: a population based study of young Danish twins. Br Med J. 311:913–917.[Abstract/Free Full Text]
8. Payami H, Joe S, Thomson G. 1989 Autoimmune thyroid disease in type I diabetic families. Genet Epidemiol. 7:83–85.
9. Risch N, Merikangas K. 1996 The future of genetic studies of complex diseases. Science. 273:1516–1517.[Abstract/Free Full Text]
10. Roman SH, Greenberg D, Rubinstein P, Wallenstein S, Davies TF. 1992 Genetics of autoimmune thyroid disease: lack of evidence for linkage to HLA within families. J Clin Endocrinol Metab. 74:496–503.[Abstract]
11. Shield DC, Ratanachaiyavong S, McGregor AM, Collins A, Morton NE. 1994 Combined segregation and linkage analysis of Graves’ disease with a thyroid autoantibody diathesis. Am J Hum Genet. 55:540–554.[Medline]
12. Ratanachaiyavong S, McGregor AM. 1994 HLA-DPB1 polymorphisms on the MHC-extended haplotypes of families of patients with Graves’ disease: two distinct HLA-DR17 haplotypes. Eur J Clin Invest. 24:309–315.[Medline]
13. Farid NR, Stone E, Johnson G. 1980 Graves’ disease and HLA: clinical and epidemiological associations. Clin Endocrinol (Oxf). 13:535–544.[Medline]
14. Boehm M, Kuhnl P, Manfras BJ, et al. 1992 HLA-DRB3 alleles in Caucasian patients with Graves’ disease. Mol Med. 70:956–960.
15. Yanagawa T, Mangklabruks A, Chang Y-B, et al. 1993 Human histocompatibility leukocyte antigen-DQA1*0501 allele associated with genetic susceptibility to Graves’ disease in a Caucasian population. J Clin Endocrinol Metab. 76:1569–1574.[Abstract]
16. Badenhoop K, Walfish PG, Rau H, et al. 1995 Susceptibility and resistance alleles of human leukocyte antigen (HLA) DQA1 and HLA DQB1 are shared in endocrine autoimmune disease. J Clin Endocrinol Metab. 80:2112–2117.[Abstract]
17. Barlow ABT, Wheatcroft N, Watson P, Weetman AP. 1996 Association of HLA-DQA1*0501 with Graves’ disease in English Caucasian men and women. Clin Endocrinol (Oxf). 44:73–77.[CrossRef][Medline]
18. Cuddihy RM, Bahn RS. 1996 Lack of an independent association between the human leukocyte antigen allele DQA1*0501 and Graves’ disease. J Clin Endocrinol Metab. 81:847–849.[Abstract]
19. Spielman RS, McGinnis RE, Ewens WJ. 1993 Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 52:506–516.[Medline]
20. Wiersinga WM, Prummel MF, Mourits MPh, et al. 1991 Classification of the eye changes of Graves’ disease. Thyroid. 4:357–360.
21. Bunce M, O’Neill CM, Barnardo MCMN, et al. 1995 Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 and DQB1 by PCR with 144 primer mixes utilizing sequence-specific primers (PCR-SSP). Tissue Antigens. 46:355–367.[Medline]
22. Mathews JD. 1984 Statistical aspects of immunogenetic association with disease. In: Simons MJ, Tait BD, eds. Detection of immune-associated genetic markers of human disease. London: Churchill Livingstone; 106–136.
23. Manglabruks A, Cox N, DeGroot LJ. 1991 Genetic factors in autoimmune thyroid disease analyzed by restriction fragment length polymorphisms of candidate genes. J Clin Endocrinol Metab. 73:326–324.[Abstract]
24. Payami H, Joe S, Farid NR, et al. 1989 Relative predispositional effects (RPEs) of marker alleles with disease: HLA-DR alleles and Graves’ disease. Am J Hum Genet. 45:541–546.[Medline]
25. Allanic H, Fauchet R, Lorcy Y, et al. 1980 HLA and Graves’ disease: an association with HLA-DRw3. J Clin Endocrinol Metab. 51:863–867.[Abstract]
26. Badenhoop K, Schwarz G, Schleusener H, et al. 1992 Tumour necrosis factor beta gene polymorphisms in Graves’ disease. J Clin Endocrinol Metab. 74:287–291.[Abstract]
27. Schleusener H, Schernthaner G, Mayr, WR, et al. 1983 HLA-DR3 and HLA-DR5 associated thyrotoxicosis–two different types of toxic diffuse goiter. J Clin Endocrinol Metab. 56:781–785.[Abstract]
28. Heward J, Gough SCL. 1997 Genetic susceptibility to the development of autoimmune disease. Clin Sci. 93:479–491.[Medline]
29. Gough SCL, Saker PJ, Pritchard, LE, et al. 1995 Mutation of the glucagon receptor gene and diabetes mellitus in the UK: association or founder effect? Hum Mol Genet. 4:1609–1612.[Abstract/Free Full Text]

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