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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 4 1545-1549
Copyright © 2000 by The Endocrine Society

Original Studies

The Human Leukocyte Antigen HLA DRB3*0202/DQA1*0501 Haplotype Is Associated with Graves’ Disease in African Americans

Qiao-Yi Chen, David Nadell, Xian-Yang Zhang, Anjli Kukreja, Yao-Jin Huang, Jonathan Wise, Frank Svec, Robert Richards, Karen E. Friday, Alfonso Vargas, Ricardo Gomez, Stuart Chalew, Michael S. Lan, Yaron Tomer and Noel K. Maclaren1

The Research Institute for Children (Q.-Y.C., D.N., X.-Y.Z., A.K., Y.-J.H., A.V., R.G., S.C., M.L., N.K.M.), Children’s Hospital, Harahan, Louisiana 70123; Departments of Pediatrics (Q.-Y.C., A.K., A.V., R.G., S.C., M.S.L., N.K.M.) and Medicine (F.S.), LSUMS, New Orleans, Louisiana 70112; Institute for the Treatment of Diabetes and Metabolism (J.W.), Methodist Hospital, New Orleans, Louisiana 70127; Department of Medicine (R.R., K.E.F.), Tulane University Medical Center, New Orleans, Louisiana 70112; and Division of Endocrinology and Metabolism (Y.T.), Mount Sinai School of Medicine, New York, New York 10029

Address correspondence and requests for reprints to: Noel K. Maclaren, M.D., Director, Research Institute for Children, 520 Elmwood Park Boulevard, Suite 160, Harahan, Louisiana 70123. E-mail: nkmaclaren{at}aol.com


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Information on genetic susceptibility to Graves’ disease in African Americans is limited. We studied DRB1, DQB1, DRB3 subtypes, DQA1*0501, DQA1*0201, and CTLA-4 polymorphisms in 49 African American patients with adult onset Graves’ disease and 47 racially-matched controls using PCR-based sequence-specific priming methods. There were no significant differences in DRB1 or DQB1 allelic frequencies or CTLA-4 polymorphisms between patients and controls. However, we found that the frequency of DRB3 was significantly increased in the patients (75.5% vs. 57.4%, P = 0.006, X2 = 3.52), especially for the DRB3*0202 subtype (53.1% vs. 23.4, P = 0.003, X2 = 8.91). In this one respect, the finding was in concordance with our previous observations in Caucasian patients with adult-onset Graves’ disease. In addition, whereas the frequency of DQA1*0501 was increased (P = 0.018, X2 = 5.63) in our patients, the haplotype of DRB3/DQA1*0501, or DRB3*0202/DQA1*0501 was found to be more strongly associated (P = 0.008, X2 = 7.0; P = 0.0008, X2 = 11.34, respectively). These data suggest that DRB3*0202, particularly when found with DQA1*0501 in a haplotype is a susceptible gene(s) for Graves’ disease in adult African Americans. Considering these data with those in Caucasian patients, our results would suggest that the primary Graves susceptible locus is likely DRB3 and not DRB1.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GRAVES’ DISEASE is a common autoimmune thyroid disease characterized by the presence of autoantibodies to the TSH receptors, which results in increased levels of T3 and T4, and manifested by clinical features related to hyperthyroidism, as well as a specific opthalmopathy of unknown etiology. It has been demonstrated that Graves’ disease is sometimes familial, and is associated with certain human leukocyte antigens (HLA) in various ethnic groups. DRB1*0301, DRB3*0101, and DQA1*0501 are all associated with Graves’ disease in Caucasians (1, 2, 3, 4, 5), but the primary locus (loci) has not been resolved. We recently reported that Caucasian patients with Graves’ disease had distinct HLA associations, with respect to their ages at onset (6). DRB1*03 was generally associated with Graves’ disease but at a significant frequency for patients with Graves’ disease of juvenile onset, compared with patients with adult onset. These findings were similar to a previous report (5). In addition, DRB3*0101 was associated with patients with juvenile onset of Graves’ disease, whereas DRB3*0202 was associated with patients with adult-onset of the disease. DRB1*07 was protective at all ages (6).

Though Graves’ disease is also common in African Americans, few studies have addressed the associations between HLA class II genes and Graves’ disease in this ethnic group. In two recent studies, one group found DQ3 to be associated with Graves’ disease (7), whereas another group found no significant associations between Graves’ disease and the HLA class II genes they tested, which included the major alleles of the DRB1, DQA1, and DQB1 loci (8). It has not yet been reported that African American patients with Graves’ disease have distinct HLA genotypes, with respect to their ages at onset, nor that the disease is associated with DRB3 or CTLA-4, both of which have been reported to be associated with Graves’ disease in Caucasians (2, 4, 9, 10, 11, 12, 13). We therefore studied a group of African American patients, with mostly adult onset Graves’ disease, and racially matched controls, seeking HLA and CTLA-4 associations. We studied the major alleles of DRB1, DQB1, DQA1, the four subtypes of DRB3, presence of DRB4, and CTLA-4 gene polymorphisms. We report here that DRB3 and DQA1*0501 are positively associated with Graves’ disease in this group of patients, with highest odds ratio (OR) for the HLA-haplotype of DRB3/DQA1*0501, especially when the haplotype is DRB3*0202/DQA1*0501.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The subjects comprised 39 [34 female (F), 6 male (M)] African American patients with Graves’ disease and 47 racially matched controls (33 F, 14 M) from the metropolitan area of New Orleans, Louisiana. An additional 10 (8 F, 2 M) African American patients with Graves’ disease were from the Mount Sinai Medical Center in New York. The diagnosis of Graves’ disease was established according to a classical clinical presentation, typical histories, and physical findings (diffusely enlarged goiter and degrees of proptosis and/or exopthalmos), as well as definitive laboratory findings of hyperthyroidism and antibodies to TSH receptors by a radioimmunoprecipitation assay (Kronus Co, CA). The HLA allelic frequencies were similar for patients from New Orleans and New York (data not shown). Thus, the two groups were pooled for this study, albeit they were also analyzed separately. The mean age at onset for the 49 patients was 49 ± 12 yr, with a range of 17–73 yr. The 47 controls were from healthy laboratory staff, hospital volunteers, and 9 patient controls with multinodular goiter with no exopthalmos, no family history of Graves’ disease, and no antibodies to TSH receptors. The mean age for the 47 controls was 47.2 ± 12.3 yr. The HLA frequencies in these controls were similar to those of African Americans with type II diabetes whom we studied (data not shown). Patients and controls were studied after written informed consent was obtained, as approved by the respective Institute Review Boards.

HLA DR, DQ typing

Molecular typing of HLA DR and DQ was carried out according to the requirements of The American Society for Histocompatibility. Samples of genomic DNA were prepared from peripheral blood mononuclear cells by proteinase K digestion, followed by phenolchloroform extraction, as previously described (14). The primer pairs for HLA typing were designed according to published sequences (14, 15). The major types of HLA-DRB1, DQB1, DRB3, DRB4, and four subtypes of DRB3 were typed using the technique of sequence-specific priming (6, 14). Briefly, PCR amplifications were performed on 50–100-ng genomic DNA in 25-µL reaction vols containing 50 mmol/L KCL, 10 mmol/L Tris-HCL (pH 8.3), 1.5 mmol/L MgCl2, 60 mmol/L each deoxynucleotide triphosphates. The PCR reactions were then subjected to 35 cycles of 30 sec at 94 C for denaturing, 30 sec at 65.5 C for annealing, and 30 sec at 72 C for extension, using an automated thermal cycler (9600; Perkin-Elmer Cetus, California). The amplified genomic DNA products were separated in 2.5% agarose gel, stained with ethidium bromide, and visualized under ultraviolet illumination.

CTLA-4 polymorphisms

The polymorphism of CTLA-4 at the amino acid position 17 in exon 1 was examined by restriction enzyme (BbvI) digestion of the PCR products produced using the primer pair 5'-gct cta ctt cct gaa gac ct-3 and 5'-agt ctc act cac ctt tgc ag-3'. PCR reactions were performed as for HLA typing, except that the annealing temperature was 62 C. Some 20 µL of the amplified product was digested with 5 U BbvI (Pharmegen) at a final vol of 30 µL at 37 C for 2 h. The digested DNA was then separated with 2.5% agarose gel and visualized as for HLA typing. The presence of G allele at the nucleotide of 49 gives rise to a cleavage site for restriction enzyme BbvI.

Statistical analyses

For the calculation of allelic frequencies of patients, compared with controls, subjects with heterozygous alleles were counted for the presence of each allele of interest, whereas subjects with homozygous alleles were counted only once. The numbers of the subjects with a specific allele were then divided by the total numbers of the subjects in the group and multiplied by 100 to express frequencies as percentages. Chi-square tests with Yates’ correction were used, and P-values of less than 0.05 were considered to be statistically significant. The OR were calculated using Haldane’s modification of Woolf’s method.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Allelic distribution of DRB1 and DQA1, DQB1 genes

The frequencies of DR and DQ alleles were compared between the 49 patients and the 47 controls (Tables 1Go and 2Go). DRB1*03, which is associated with Graves’ disease in Caucasians, was similar between the disease and the control groups. However, the patients with Graves’ disease had a higher frequency of DRB1*11 (DR5) than controls, although the difference was not significant after Yates correction. Similarly, there were no significant differences for the frequency of DQB1 alleles between the patients and controls, whereas the frequency of DQB1*0302 was nonsignificantly decreased after Yates’ correction. DQB1*07, which is reported to be negatively associated with Graves’ disease in Caucasians, was not significantly different between the patients and the controls in this study. However, the frequency of DQA1*0501 was significantly higher in the Graves’ patients than in the controls [49% (24 of 49) vs. 25.5% (12 of 47), P = 0.018, X2 = 5.63].


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  		Table 1. Distribution of representative alleles of HLA DRB1 in 49 African American patients with Graves’ disease and 47 racially matched controls

 

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  		Table 2. Distribution of representative alleles of HLA DQA1 and DQB1 in 49 African American patients with Graves’ disease and 47 racially matched controls

 
DRB3, DRB4, and the four subtypes of DRB3

The frequency of DRB3 was increased significantly in patients with Graves’ disease, over that in controls [75.5% (37 of 49) vs. 57.4% (27 of 47), P = 0.006, X2 = 3.52]. There was no difference for the frequency of DRB4 (in linkage with DRB1*07) between the disease and the controls (data not shown). For the four subtypes of DRB3, the frequency of DRB3*0202 alone was increased significantly in the patients, whereas the remaining three subtypes had frequencies similar to controls (Table 3Go).


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  		Table 3. Allelic distribution of DRB3, and the four subtypes of DRB3, and the haplotype of DQA1*0501-DRB3 or DRB3*0202 in 49 African American patients with Graves’ disease and 47 racially matched controls

 
Haplotypes of DRB3 and DQA1*0501

The allelic frequencies in the patients and controls were also analyzed for the haplotype of DRB3/DQA1*0501 (Table 3Go). The frequency of the haplotype of DRB3/DQA1*0501 was significantly higher in the patients than in the controls [46.9% (23 of 49) vs. 21.3% (10 of 47), P = 0.008, X2 = 7.0]. Further, the most significant association was found for the haplotype of DRB3*0202/DQA1*0501 [40.8% (20 of 49 vs. 10.6% (5 of 47), P = 0.0008, X2 = 11.34].

Polymorphism of CTLA-4

The nucleotide A/G polymorphisms at the amino acid position of 17 located at the exon 1 of CTLA-4 gene were used to calculate the difference between the Graves group and the controls. No differences were found in the distributions of the A or G alleles, nor did the AA, AG, or GG genotypes differ between patient and the controls (Table 4Go). Similar results were observed when we excluded the 10 subjects from the New York area and compared the allelic frequencies of the tested HLA DR, DQ, or CTLA4 polymorphisms of the remaining 39 subjects with Graves’ disease from New Orleans with those of 47 controls (data not shown).


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  		Table 4. Distribution of threonine (A) or alanine (G) at amino acid position 17 of CTLA-4 in 49 African American patients with Graves’ disease and 47 racially matched controls

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Any association between HLA class II gene and Graves’ disease in African Americans in the literature had not been established. DQ3 was reported to be associated with Graves’ disease in African American patients from metropolitan Washington DC and Delaware (7). We observed that the frequency of any DQB1 allele including DQB1*0301 was not significantly increased in this study, whereas DQB1*0302 was nonsignificantly decreased. Our findings, in this respect, are in concordance with the results of a previous study of African American patients from the Chicago area (8). DR3 has been associated with Graves’ disease in Caucasians (1), as well as in African Blacks of Zulu descent (16). However, DR3 was not found to be associated with Graves’ disease in African American patients, as reported in previous studies (7, 8, 17), nor in our current study reported here. Taken together, these data suggest that neither DQB1*0301 allele nor DR3 specificity are susceptible to African American patients with Graves’ disease. The discordance of the results between Caucasians and African Americans in the United States may, however, be attributable to the ethnic diversity of HLA genotypes, or the complex interaction of HLA molecules with environmental factors, to initiate the pathogenic process of the disease. Further, our previous study in Caucasian patients with Graves’ disease suggested that patients with different ages at onset could have distinct differences in their HLA associations. The use of adult patients with Graves’ disease in this study would decrease the potential HLA heterogeneity brought about by age.

To our knowledge, this is the first report to test the association between DRB3 and Graves’ disease in African American patients. DRB3 and one of the subtype DRB3*0101 were reported to be associated with Graves’ disease in Caucasians (2, 4). However, studies also suggested that the association between DRB3 with Graves’ disease in Caucasians could be secondary to its linkage disequilibrium with other susceptible genes, such as DRB1*0301 (3, 5, 18). This is also in concordance with our previous study on Caucasian patients with juvenile onset, but not adult onset, Graves’ disease (6). Therefore, the association of DRB3*0101 (if any) with Graves’ disease could be attributable to its linkage disequilibrium with DRB1*0301 (DR3). However, we found DRB3*0202 to be positively associated with adult onset Graves’ disease in Caucasians, whereas DRB1*03 without DRB3*0202 was not (6). This is similar to the results found in the current group of African American patients with adult onset of Graves’ disease. These data indicate that DRB3*0202 could be a common susceptible allele for adult onset Graves’ disease in these two ethnic groups. Alternatively, the presence of susceptible HLA genes in the current group of African American patients could be attributable to its genetic admixture with Caucasian Americans. The frequency of DRB1*11, in fact, in this group of patients is similar to our previously reported data for Caucasian patients (6). Our patients, however, had reduced frequencies of the DRB1*04/DQB1*0302 haplotype, as expected (given that it is a characteristic haplotype of Caucasians).

Accumulated evidence indicates that African Americans share some genes, including HLA from American Caucasians. For example, DQA1 allelic frequencies are similar between Caucasian and African Americans living in Florida (19). The frequencies of HLA DRB1 in African Americans are intermediate between those of the two founding populations, native Africans and Europeans (20). However, HLA allelic frequencies and haplotype distributions through genetic admixture may vary between groups of African Americans residing in separate areas of the United States (20, 21). Future studies should involve larger numbers of patients and controls than we have here, to avoid potential racial admixture errors.

The frequency of DQA1*0501 was increased significantly in the patients with adult onset of Graves’ disease reported here, but this was not the case for a group of African American patients with Graves’ disease reported in another study (8). It is noted that the frequency of DQA1*0501 in African American control subjects varies, dependent on their residing areas (8, 22). Accordingly, the inconsistent association between DQA1*0501 and Graves’ disease could again be attributable to different genetic admixtures within the studied subjects. However, controversial results for DQA1*0501 have also been reported for Caucasians patients with Graves’ disease (23, 24, 25). Apart from racial heterogeneities of the studied subjects, factors like linkage disequilibria, ages at onset, and gender could have also contributed to the inconsistency of the results. For example, the association of DQA1*0501 with Graves’ disease in juvenile Caucasian patients was found to be attributable to its linkage disequilbrium with DRB1*0301 (5), although DQA1*0501 was still found in association with Graves’ disease reported in an earlier study, despite the exclusion of subjects with DR3 from analysis (3). It is noted that no study in the literature has been carried out to analyze for association of DQA1*0501 with adult onset Graves’ disease after stratification for DR3. Similarly, the increased frequency of the haplotype of DRB3/DQA1*0501, especially the haplotype DRB3*0202/DQA1*0501 found in the present study, is expected on the basis of a linkage disequilbrium between DRB3 and DQA1*0501. It is possible, however, that the combination of the susceptible HLA alleles DRB3*0202 and DQA1*0501 could confer additional risks for Graves’ disease.

The codon 17 polymorphism of CTLA-4 gene conferred no susceptibility to Graves’ disease in this group of African Americans. However, CTLA-4 gene has been fairly consistently reported to be associated with Graves’ disease in Caucasian patients (9, 10, 11, 12, 13). Again, the factors discussed above may play roles leading to our results, which seemingly contradict those in Caucasian patients. The CTLA-4 molecule plays an important role in T cell regulation, being expressed in activated T cells, leading to their eventual apoptosis and arrest of the response. Thus, further studies should be carried out in association with Graves’ disease in African Americans, using a larger numbers of subjects, before concluding that the CTLA-4 gene is not involved.

In conclusion, when we combine this data with that in Caucasian patients, our results suggest that the primary disease susceptible locus in Graves’ disease is DRB3 and its *0202 subtype, and/or DQA1*0501 but not DRB1. HLA class II genes may play roles in the pathogenesis of Graves’ disease, especially in young Caucasian patients, whereas the environment replete with high iodine consumption or putative thyroidal viruses may be more important to the Graves’ disease seen in African American adults than in Caucasians. If the primary association between Graves’ disease and DRB3 (*0202) is confirmed by others, then studies of binding affinities of TSHR peptides to DRB3 molecules would seem to be indicated.


   Acknowledgments
 
We thank our many colleagues and patients for assisting us with these studies.


   Footnotes
 
1 Present address: Department of Pediatrics, Weill College of Medicine, Cornell University, 525 East 68th Street, New York, New York 10021. Back

Received September 3, 1999.

Revised November 8, 1999.

Accepted December 14, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Volpe R. 1990 Immunology of human thyroid disease. In: VolpÈ R, ed. Autoimmune diseases of the endocrine system. Boca Raton: CRC Press; 732–739.
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  3. Yanagawa T, Mangklabruks A, Chang YB, 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]
  4. Chen M, Maerz W, Manfras BJ, Kuehnl P, Usadel KH, Boehm BO. 1993 Rapid and simple subtyping of the HLA-DRB3 gene in Graves’ disease by using temperature-gradient gel electrophoresis. Hum Immunol. 36:199–203.[CrossRef][Medline]
  5. Lavard L, Madsen HO, Perrild H, Jacobsen BB, Svejgaard A. 1997 HLA class II associations in juvenile Graves’ disease: indication of a strong protective role of the DRB1*0701,DQA1*0201 haplotype. Tissue Antigens. 50:639–641.[Medline]
  6. Chen QY, Huang W, She JX, Baxter F, Volpe R, Maclaren NK HLA-DRB1*08, DRB1*03/DRB3*0101 and DRB3*0202 are susceptibility genes for Graves’ disease in N. American Caucasians, while DRB1*07 is protective. J Clin Endocrinol Metab. In press.
  7. Ofosu MH, Dunston G, Henry L, et al. 1996 HLA-DQ3 is associated with Graves’ disease in African-Americans. Immunol Invest. 25:103–110.[Medline]
  8. Yanagawa T, DeGroot LJ. 1996 HLA class II associations in African-American female patients with Graves’ disease. Thyroid. 6:37–39.[Medline]
  9. Yanagawa T, Hidaka Y, Guimaraes V, Soliman M, DeGroot LJ. 1995 CTLA-4 gene polymorphism associated with Graves’ disease in a Caucasian population. J Clin Endocrinol Metab. 80:41–45.[Abstract]
  10. Kotsa K, Watson PF, Weetman AP. 1997 A CTLA-4 gene polymorphism is associated with both Graves disease and autoimmune hypothyroidism. Clin Endocrinol (Oxf). 46:551–554.[CrossRef][Medline]
  11. Donner H, Rau H, Walfish PG, et al. 1997 CTLA4 alanine-17 confers genetic susceptibility to Graves’ disease and to type 1 diabetes mellitus. J Clin Endocrinol Metab. 82:143–146.[Abstract/Free Full Text]
  12. Vaidya B, Imrie H, Perros P, et al. 1999 The cytotoxic T lymphocyte antigen-4 is a major Graves’ disease locus. Hum Mol Genet. 8:1195–1199.[Abstract/Free Full Text]
  13. Heward JM, Allahabadia A, Carr-Smith J, et al. 1998 No evidence for allelic association of a human CTLA-4 promoter polymorphism with autoimmune thyroid disease in either population-based case-control or family-based studies. Clin Endocrinol (Oxf). 49:331–334.[CrossRef][Medline]
  14. Huang W, Connor E, Rosa TD, et al. 1996 Although DR3-DQB1*0201 may be associated with multiple component diseases of the autoimmune polyglandular syndromes, the human leukocyte antigen DR4-DQB1*0302 haplotype is implicated only in beta-cell autoimmunity. J Clin Endocrinol Metab. 81:2559–2563.[Abstract]
  15. Olerup O, Aldener A, Fogdell A. 1993 HLA-DQB1 and -DQA1 typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours. Tissue Antigens. 41:119–134.[Medline]
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  18. Cuddihy RM, Schaid DS, Bahn RS. 1996 Multivariate analysis of HLA loci in conjunction with a thyrotropin receptor codon 52 polymorphism in conferring risk of Graves’ disease. Thyroid. 6:261–265.[Medline]
  19. Crouse CA, Feuer WJ, Nippes DC, et al. 1994 Analysis of HLA DQ alpha allele and genotype frequencies in populations from Florida. J Forensic Sci. 39:731–742.[Medline]
  20. Just JJ, King MC, Thomson G, Klitz W. 1997 African-American HLA class II allele and haplotype diversity. Tissue Antigens. 49:547–555.[Medline]
  21. Imanishi T, Azaka T, Kimura A, Tokunaga K, Gojobori T. 1992 Allele and haplotype frequencies for HLA and complement loci in various ethnic groups. In: Tsuji K, Aizawa M, Sasazuki T, eds. HLA 1991. Oxford: Oxford University Press; 1065–1220.
  22. Reed AM, Stirling JD. 1995 Association of the HLA-DQA1*0501 allele in multiple racial groups with juvenile dermatomyositis. Hum Immunol. 44:131–135.[Medline]
  23. Yanagawa T, Mangklabruks A, DeGroot LJ. 1994 Strong association between HLA-DQA1*0501 and Graves’ disease in a male Caucasian population. J Clin Endocrinol Metab. 79:227–229.[Abstract]
  24. Barlow AB, 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]
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