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HLA-DRB1¹08, DRB1^,103/DRB3^,10101, and DRB3^,10202 Are Susceptibility Genes for Graves’ Disease in North American Caucasians, Whereas DRB1^,107 Is Protective^,1

The Research Institute for Children (Q.-Y.C., N.K.M.), Harahan, Louisiana 70123; Children’s Hospital (Q.-Y.C., N.K.M.); and the Department of Pediatrics, Louisiana State University Medical Center (Q.-Y.C., N.K.M.), New Orleans, Louisiana 70112; the Department of Pathology and Laboratory Medicine, University of Florida College of Medicine (W.H., J.-X.S., F.B.), Gainesville, Florida 32610; and the Division of Endocrinology, Department of Medicine, University of Toronto (R.V.), Toronto, Canada

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

	Abstract

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Graves’ disease is known to be HLA-D associated; however, the primary loci involved remain unclear. We examined HLA genotypes of DRB1 and DQB1 plus DRB3 subtypes using PCR-based sequence-specific priming in two groups of North American (Gainesville, FL; and Toronto, Canada) Caucasian patients with Graves’ disease. We stratified patients into those with either early age at onset (<20 yr; 13.1 ± 4.8 yr; n = 30) and later age at onset of disease (38.8 ± 9.7 yr; n = 62) and compared the results to 192 normal controls. As expected, we found that DRB1*03 was associated with Graves’ disease, but at a higher odds ratios for early-onset than later-onset patients (3.7 vs. 2.2). The frequency of DRB1*08 was also increased in both groups of patients, but significantly so only in patients with early-onset Graves’ (P = 0.001; ² = 10.8). DRB3 was highly associated with Graves’ in both groups of patients (P = 0.009; ² = 6.83 and P = 0.0015; ² = 10.1, respectively); however, the subtypes of DRB3 revealed differential susceptibilities. Whereas the frequencies of both DRB3*0101 and DRB3*0202 were increased over the entire cohort, that of DRB3*0301 was not. Significant P values were found for DRB3*0101 in patients with early-onset and for DRB3*0202 in patients with later onset of Graves’ disease. When the haplotypes of DRB1*03-DRB3 of all subtypes were removed for analysis (all DRB1*03 positive also had DRB3*0101), the frequency of DRB3*0202 remained significantly higher in the patients with later onset of Graves’ disease than in controls (P = 0.0043; ² = 8.13), but DRB3 was no longer positively associated with the early-onset group. In addition, we found that DRB1*07 was negatively associated with both groups of patients (P = 0.024; ² = 5.10 and P = 0.0085; ² = 6.93). These data suggest that DRB3*0202 is more likely to be the primary susceptible locus than DRB1*03 for patients with later onset of Graves’ disease.

	Introduction

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GRAVES’ disease is an autoimmune thyroid disease characterized by clinical hyperthyroidism with diffuse goiter, ophthalmopathy in many cases, and autoantibodies to the TSH receptor of thyrocytes, which results in excessive secretion of thyroid hormones. Along with environmental factors, genetic factors are attributable to Graves’ disease, as first degree relatives of patients with Graves’ disease have an increased prevalence of Graves’ disease and/or other related autoimmune thyroid diseases (1, 2, 3), and the concordance rate for identical twins for developing Graves’ disease approaches 60% (4).

Human leukocyte antigens (HLA) DRB1¹0301, DRB3¹0101, DQA1¹0501, and DQB1¹0201 have been reported to be associated with Graves’ disease in Caucasian patients (1, 5, 6, 7, 8). However, the primary locus (loci) has not been resolved, whereas HLA associations with Graves’ disease have not been fully addressed in terms of age at onset. Graves’ disease occurs in patients with a wide range of age at onset, but it occurs less common in young children or adolescents (9), although some ethnic groups have a relative high prevalence at these ages (10). Recent studies of HLA associations with Graves’ disease in Caucasians contained patients with a wide range of ages at onset (1, 5, 6, 7, 8). If HLA susceptibility differed in patients with different ages at onset of Graves’ disease, this could bias the analysis when the subject groups were composed of different ratios of patients with early vs. later onsets. This may have resulted in different conclusions for similar populations of North American Caucasian individuals with Graves’ disease with respect to HLA DQA1¹0501 (6, 7, 8).

Different allelic HLA associations have been reported for patients with early onset of Graves’ disease from those for patients with later onset of Graves’ disease in a Japanese study (11). In addition, a study of Caucasian patients suggested that the relative risk for DRB1¹0301 was higher for juvenile patients than for adult patients with Graves’ disease observed in other studies (12). Also, the DRB1¹0701, DQA1¹0201 haplotype has been shown to be protective for the juvenile form of Graves’ disease (12). Thus, clarification of the effect of age at onset on HLA susceptibility would help to identify the primary HLA loci associated with Graves’ disease.

We studied the genotypes of DRB1, DQB1, and DRB3 subtypes in two groups of North American Caucasian patients with either early onset or later onset of Graves’ disease. We found that the association of DR alleles with Graves’ disease differed in patients according to their ages at onset and showed that DRB1¹0701 is a protective allele for patients with either early or later onset of Graves’ disease, whereas DRB1¹03, DRB1¹08, and two subtypes of DRB3 appear to be susceptible genes.

	Subjects and Methods

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Subjects

Peripheral blood DNA samples were prepared from two groups of North American Caucasian patients (Gainesville, FL; and Toronto, Canada) with Graves’ disease and were studied by HLA gene typing for DR/DQ. One group was composed of 30 patients, 8 males and 22 females, with a mean age at onset of 13.1 ± 4.8 yr over an age range of 2–19 yr. The second group was composed of 62 patients, 10 males and 52 females, with a mean age at onset of 38.8 ± 9.7 yr over a range of 20–61 yr. The diagnosis of Graves’ disease was based on classical clinical presentations, typical histories and physical findings (diffusely enlarged goiter and degrees of exopthalmos), as well as definitive laboratory findings of hyperthyroidism. DNA samples were also prepared similarly from 192 control Caucasians residing in mid-north Florida. Their HLA profiles were similar to those reported for non-French Canadian Caucasians by others (13).

HLA typing

Molecular typing of HLA class II alleles was carried out according to the requirements of the American Society for Histocompatibility. Samples of genomic DNA were prepared from peripheral white blood cells by proteinase K digestion, followed by phenol-chloroform extraction as previously described (14). The primer pairs for HLA typing were designed according to published sequences. The major types of HLA DRB1, DQB1, and DRB3 and four subtypes of DRB3 were typed using the technique of sequence-specific priming (14). Briefly, PCR amplifications were performed on 50–100 ng genomic DNA in 25-µL reaction volumes containing 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 8.3), 1.5 mmol/L MgCl₂, and 60 mmol/L of each deoxy-NTPs. The PCR reaction was then subjected to 35 cycles of 30 s at 94 C for denaturing, 30 s at 65.5 C for annealing, and 30 s at 72 C for extension, using an automated thermal cycler (model 9600, Perkin Elmer Corp./Cetus, Emeryville, CA). The amplified genomic DNA products were separated in 2.5% agarose gel, stained with ethidium bromide, and visualized under UV illumination.

Statistical analyses

For the calculation of allelic frequencies, subjects with heterozygous alleles were counted twice for the presence of respective alleles 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. Thus, the frequencies for each of the alleles in a group may not add up to 100% as shown in the tables. ² tests with Yates’ correction were used, and P < 0.05 was considered statistically significant. The odds ratio (OR) was calculated using Haldane’s modification of Woolf’s methods.

	Results

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Association of HLA DR alleles with patients with Graves’ disease

The frequencies of patients with particular DR alleles were compared to those of normal controls using ² tests for significance. The allelic frequencies of HLA DRB1¹03 and DRB1¹08 were significantly higher in the pooled 92 patients with Graves’ disease, than in the 192 normal controls (Table 1). However, different patterns of association of HLA-DR alleles were shown for these two groups of patients when the frequencies of HLA alleles were analyzed based on their ages at onset. The frequency of DRB1¹03 was significantly increased in the total patient group, but higher frequencies were found in patients with early-onset disease (<20 yr) than in patients with later-onset disease (P = 0.0008; ² = 11.29 and P = 0.0131; ² = 6.16, respectively; Table 1). DRB1¹08 was significantly associated only with patients with early-onset Graves’ disease (P = 0.001; ² = 10.8), whereas DRB1¹07 was negatively associated in patients with both early (P = 0.023; ² = 5.1) and later onset of Graves’ disease (P = 0.0085; ² = 6.93).

DRB3 was significantly associated with patients with either early or later onset of Graves’ disease (P = 0.009; ² = 6.83 and P = 0.0015; ² = 10.1, respectively) as it was for the pooled group (P = 0.0001; ² = 7.85; Table 2). As expected, the frequency of the haplotype of DRB1¹03 and DRB3 was significantly higher in both age at onset groups than in normal controls (Table 2). As DRB3 is in strong linkage disequilibrium with HLA-DRB1¹03, the patients were stratified to assess any independent association of DRB3 with Graves’ disease. After subtraction of those patients with HLA-DRB1¹03, a significant association remained for patients who were DRB1¹03 negative but DRB3 positive in patients with later onset of Graves’ (P = 0.0154; ² = 5.87), but not in patients with early-onset disease. However, DRB1¹03 could not be otherwise analyzed independently of DRB3, as all subjects with DRB1¹03 also had DRB3.

We then examined the four subtypes of DRB3 for possible differential allelic associations and found that DRB3¹0101 was significantly higher in patients with early-onset disease (P = 0.0015; ² = 10.06) and DRB3¹0202 in patients with later-onset disease than in normal controls (P = 0.0117; ² = 6.35; Table 3). The total patient group had significantly higher frequencies for DRB3¹0101 and DRB3¹0202 subtypes than the normal controls (Table 3). To independently analyze the association of the four DRB3 subtypes with Graves’ disease, those subjects positive for DRB1¹03 were removed from the analyses. When this was done, DRB3¹0101 was no longer found in association with the early-onset disease; however, the frequency of DRB3¹0202 was still significantly higher in the later-onset patients than in controls [46% (18 of 39) vs. 23.2% (35 of 151); P = 0.0043; ² = 8.13].

The frequencies of DQB1 alleles were not significantly different for patients with Graves’ disease from those for normal controls (data not shown). The frequency of DQB1¹0201 was the highest of them (48.3% vs. 44.8% in controls). This was to be expected, as patients were a mixture of positively associated DRB1¹03 and negatively associated DRB1¹07 in the two common haplotypes. There were no significant differences in HLA allelic frequencies between the groups with early vs. later onset of Graves’ disease.

Distribution of allelic frequencies by decade of age at onset

The frequencies of DRB1¹03, DRB1¹08, and DRB3 increased inversely to the age at disease onset (Fig. 1). Compared to normal controls, significantly higher frequencies were observed in the group of 2- to 10-yr-old subjects for DRB1¹08 (P < 0.0001; ² = 18.66), in the group of 11- to 19-yr-old subjects for DRB1¹03 (P = 0.0001; ² = 16.45) and DRB3 (P = 0.0003; ² = 12.84), and in the group of 30- to 39-yr-old subjects for DRB3 (P = 0.0273; ² = 4.83).

View larger version (32K): [in this window] [in a new window]   Figure 1. Distribution of allelic frequencies of DRB1*03, *07, 08, and DRB3 in 92 patients with Graves’ disease according to age at onset and in 192 controls. The group with age at onset of 10–19 yr has the highest frequency for DRB1*03 and DRB3 of the groups. However, the frequencies of DRB1*03-, DRB3+ were higher in the older groups. DRB1*08 was most increased in the youngest affected children.

	Discussion

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DRB3 is known to be associated with Graves’ disease, as in our study here and as previously reported by others in patients with a variety of ages of disease onset (5, 22). However, DRB1¹03 and DRB3 are in such tight linkage disequilibrium (23) that it has been difficult to identify which is the primary locus. Lavard et al. (12) reported that the association of DRB3¹0101 with Graves’ disease in juvenile patients is secondary to that of DRB1¹0301. This is consistent with our results for the group with early onset of Graves’ disease, in which DRB3 was not independent of DRB1¹03. In contrast, DRB3, in particular the DRB3¹0202 subtype, is associated independent of DRB1¹03 with Graves’ disease in our study of patients with later onset of Graves’ disease, indicating that DRB3¹0202 could be a primary HLA-susceptible locus in patients with later onset of Graves’ disease.

We also observed that DRB1¹07 was protective and DRB1¹08 was an additional susceptibility gene in patients with Graves’ disease. DRB1¹07 has been reported previously to be negatively associated with juvenile Graves’ disease, as DRB1¹07 was absent in their patients studied (12). However, DRB1¹07 was present in our groups of patients with either early onset or later onset of Graves, but at low frequencies. DRB1¹07 is linked to both DQB1¹0201 and DQB1¹0303, but neither was associated with Graves’ disease in our study. The frequency of DRB1¹08 was significantly higher in the patients with early onset of the disease than in the controls. However, when the patients with early disease onset were further divided into two groups of onset of 2–10 and 11–19 yr, a significant association for DRB1¹08 was only observed in the group of 2- to 10-yr-old subjects, not in the group of 11- to 19-yr-old subjects. The younger group was not found in association with other susceptible alleles. These data suggest that patients with age at onset of Graves’ disease of less than 11 yr have distinct HLA associations from other groups of patients with Graves’ disease and possibly distinct environmental influences too.

Distinct HLA allelic associations according to age at onset have also been observed for other autoimmune diseases. For example, juvenile arthritis comprises different disease entities, each with distinct HLA associations (24). Similarly, type I diabetes mellitus has been observed with different HLA susceptibilities with respect to age at onset. DR4/DQ8 haplotype occurs more frequently in early-onset patients than in later-onset patients (25). The frequency of the DQA1/¹0301/DQA1¹0501 haplotype has been reported to be higher in Chinese patients with type I diabetes with early disease onset than in patients with later disease onset (26). Also, the frequencies of DR3 and DR3/DR4 haplotypes were increased inversely with the age at onset (27). Susceptibility to type I diabetes with respect to age at onset has been reported for HLA class I genes as well (28, 29). Our findings support the idea that patients with Graves’ disease have multiple distinct HLA susceptibilities with regard to HLA genotypes.

In conclusion, our results suggested that HLA DR allelic susceptibilities to Graves’ disease differ in patients according to their ages at onset. These observations may explain some of the variability in the findings by others reported in the literature.

	Footnotes

 
¹ This work was supported by Grant R01-HD-19469.

Received February 12, 1999.

Revised March 31, 1999.

Accepted June 1, 1999.

	References

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1. Volpe R. 1990 Immunology of human thyroid disease. In: Volpe R, ed. Autoimmunity in endocrine disease. Boca Raton: CRC Press; 73–98.
2. Farid NR, Bear JC. 1983 Autoimmune endocrine disorders and the major histocompatibility complex. In: Davies T, ed. Autoimmune Endocrine disease. New York: Wiley and Sons; 59.
3. Martin L, Fisher RA. 1945 The hereditary and familiar aspects of exophthalmic goiter and nodular goiter. Q J Med. 14:207–219.[Free Full Text]
4. Schleusener H, Bogner U, Peters H, et al. 1991 The relevance of genetic susceptibility in Graves’ disease and immune thyroiditis. Exp Clin Endocrinol. 97:127–132.[Medline]
5. Boehm BO, Kuhnl P, Manfras BJ, et al. 1992 HLA-DRB3 gene alleles in Caucasian patients with Graves’ disease. Clin Invest. 70:956–960.[Medline]
6. 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]
7. 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]
8. 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]
9. Lavard L, Perrild H, Brock Jacobsen B, et al. 1994 Incidence of juvenile thyrotoxicosis in Denmark, 1982–1988. A nation-wide study. Eur J Endocrinol. 130:565–568.[Abstract/Free Full Text]
10. Wong GW, Kwok MY, Ou Y. 1995 High incidence of juvenile Graves’ disease in Hong Kong. Clin Endocrinol (Oxf). 43:697–700.[Medline]
11. Onuma H, Ota M, Sugenoya A, Inoko H. 1994 Association of HLA-DPB1*0501 with early-onset Graves’ disease in Japanese. Hum Immunol. 39:195–201.[CrossRef][Medline]
12. 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 RB1*0701,DQA1*0201 haplotype. Tissue Antigens. 50:639–641.[Medline]
13. Gladman DD, Anhorn KAB. 1986 HLA and disease manifestation in rheumatoid arthritis: a Canadian experience. J Rheum. 13:274–276.[Medline]
14. Huang W, She JX, Muir A, Laskowska D, Zorovich B, Schatz D, Maclaren NK. 1994 High risk HLA-DR/DQ genotypes for IDDM confer susceptibility to autoantibodies but DQB1*0602 does not prevent them. J Autoimmun. 7:889–897.[CrossRef][Medline]
15. Stensky V, Kozma L, Balzas 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/Free Full Text]
16. Allanic H, Fauchet R, Lorcy Y, et al. 1980 HLA and Graves’s disease: an association with HLA-Dw3. J Clin Endocrinol Metab. 51:863–867.[Abstract/Free Full Text]
17. Farid NR, Stenszky V. 1988 Graves’ disease. In: Farid NR, ed. Immunogenetics of endocrine disorders. New York: Liss; 223–266.
18. Huang W, Connor E, Dela Rosa T, et al. 1995 Although DR3-DQB1*0201 may be associated with multiple component diseases of autoimmune polyglandular syndromes, the human leukocyte antigen DR4-DQB1*0302 haplotype is implicated only in ß cell autoimmunity. J Clin Endocrinol Metab. 81:2556–2563.
19. Farid NR, Stone E, Johnson G. 1980 Graves’ disease and HLA: clinical and epidemiologic associations. Clin Endocrinol (Oxf). 13:535–544.[Medline]
20. Yeo PP, Chan SH, Thai AC, et al. 1989 HLA Bw46 and DR9 associations in Graves’ disease of Chinese patients are age- and sex-related. Tissue Antigens. 34:179–184.[Medline]
21. Inoue D, Sato K, Enomoto T, et al. 1992 Correlation of HLA types and clinical findings in Japanese patients with hyperthyroid Graves’ disease: evidence indicating the existence of four subpopulations. Clin Endocrinol (Oxf). 36:75–82.[Medline]
22. Semana G, Allanic H, Quillivic F, et al. 1990 Implication of the HLA-DR3 gene in Graves’ disease: predominance of allele Dw24. Hum Immunol. 29:143–9.[CrossRef][Medline]
23. Fernandez-Vina MA, Moraes ME, Gao X, et al. 1991 Allele at four HLA class II loci determined by oligonucleotide hybridization and their associations in five ethnic groups. Immunogenetics. 34:299–312.[CrossRef][Medline]
24. Albert ED, Scholz S. 1998 Juvenile arthritis: genetic update. Bailliere Clin Rheumatol. 12:209–218.[Medline]
25. Lohmann T, Sessler J, Verlohren HJ, et al. 1997 Distinct genetic and immunological features in patients with onset of IDDM before and after age 40. Diabetes Care. 20:524–952.[Abstract]
26. Chang YW, Lam KS, Hawkins BR. 1998 Strong association between DQA1/DQB1 genotype and early-onset IDDM in Chinese: the association is with alleles rather than specific residues. Eur J Immunogenet. 25:273–280.[CrossRef][Medline]
27. Tait BD, Harrison LC, Drummond BP, Stewart V, Varney MD, Honeyman MC. 1995 HLA antigens and age at diagnosis of insulin-dependent diabetes mellitus. Hum Immunol. 42:116–122.[CrossRef][Medline]
28. Demaine AG, Hibberd ML, Mangles D, Millward BA. 1995 A new marker in the HLA class I region is associated with the age at onset of IDDM. Diabetologia. 38:623–628.[Medline]
29. Fujisawa T, Ikegami H, Kawaguchi Y, et al. 1995 Class I HLA is associated with age-at-onset of IDDM, while class II HLA confers susceptibility to IDDM. Diabetologia. 38:1493–1495.[CrossRef][Medline]

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, Q.-Y. Articles by Maclaren, N. K. Search for Related Content PubMed PubMed Citation Articles by Chen, Q.-Y. Articles by Maclaren, N. K.