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We found HLA-DR5 to be present among 53% of 40 patients with goitrous autoimmune (Hashimoto's ) thyroiditis compared to 26% of 80 controls. No deviations from those expected in the incidences of HLA-A, B, C antigens were seen. In contrast HLA-DR3 was increased among 50 patients with atrophic thyroiditis (65%) compared to controls (24%). These findings stress the immunogenetic heterogeneity between the goitrous and atrophic varieties of thyroiditis.

One-hundred-and-forty-seven patients with autoimmune thyroiditis were studied with respect to HLA antigens as they related to various clinical features. HLA--B8 was found to be significantly increased among 59 patients with atrophic thyroiditis (57% vs. 26% for controls) but was identical to controls in 88 patients with goitrous thyroiditis (26%). No relation was found in either group between B8 and thyroid autoantibody titer or, in the case of goitrous thyroiditis, the rate of progression of the disease. Thus a link seems to be established between Graves' disease and atrophic thyroiditis in that both are significantly associated with HLA-B8. This study stresses the need to take clinical features into consideration when examining for HLA/disease associations.

In order to further elucidate the genetics of Graves' disease, we studied two families with several affected members, as well as tested the degree to which HLA haplotypes were shared in affected sibpairs. Further, we sought to identify the disease related haplotypes by determining the haplotypes shared among affected parent-child combinations. In one family, two affected sibs differed at four possible parental HLA haplotypes; no evidence of recombination was observed which could account for the result. In the other family, five siblings were affected. Four out of the five affected sibs shared the maternal haplotype HLA-A11, Bw51, Cw5, Cw-, DRw5, Bfs, GLO1, whereas three shared the paternal haplotype HLA-A1, B8, Cw-, DRw3, BfS and GLO1. Looking at haplotype sharing, two pairs of sibs were found to be HLA identical, whereas the fifth sib shared one haplotype with one of these pairs but not with the other. Out of 14 (eight of our own and six from the literature) affected sibpairs examined, nine were found to be HLA identical and four shared one haplotype, suggesting that the contribution of both paternal haplotypes may be necessary for the susceptibility to the disease. Fourteen parent-child combinations were studied; in only three out of 13 in which the shared haplotype could be ascertained was the haplotype B8 positive; this distribution is similar to controls. However, of the remaining 10 combinations which did not share a B8 positive haplotype, five were B8 positive at one or the other of the non-shared haplotypes.

We studied the diallelic system HLA--Bw4/w6 in patients with Graves' disease and control subjects. Twenty-one out of the 22 patients with Graves' disease were found to be HLA--Bw6 positive and 16 of these were homozygous, contrasted with 28 and 9 out of 34 controls, respectively. HLA--Bw6 positivity results in a relative risk for Graves' disease of 3.27; homozygosity for that allele further increases the risk to 7.4. It is possible that the increased risk attached to HLA--Bw6 is secondary to the increase in HLA--B8 previously described in Graves' disease.

In view of the reported variation in the association between HLA antigens and Juvenile Diabetes Mellitus (J.D.M.) among different Caucasian populations, we have undertaken a study of these antigens among 44 Caucasian Newfoundlanders and 135 matched controls. We have also studied the allotypic markers for Immunoglobulin G (Gm) and variants of C3 among 36 of these patients. We found that both HLA--B8 and B15 were increased among the patient group, resulting in a relative risk of 3.9 and 4.4 respectively. While these values are the highest to be described for J.D.M. among Caucasians, and fell outside the 95% confidence intervals for the combined relative risk calculated from published series, it is still possible that they can be accounted for by sampling. The combination of the two antigens increased the relative risk for J.D.M. in an additive fashion. Additionally, we also found that the combination of HLA B8 and B18, but not B15 and B18, also appear to act in an additive manner. The incidence of Gm allotypes and variants of C3 were not different in the J.D.M. group from those observed among controls.

HLA/Bf haplotypes were examined in a large three-generation Newfoundland family with a high incidence of Graves' disease. In that family Graves' disease was inherited in association with the haplotype HLA Aw24, Bw39 in some instances and with HLA B8-containing haplotypes in other instances. As all seven members of the family who suffered from Graves' disease were homozygous for the Bf S allele, the study for Bf was uninformative. However, the examination of other HLA/Bf haplotypes disclosed some interesting associations. One-hundred-and-five out of 168 HLA-A, -B, -Bf haplotypes were Bf S. Although numerically deviant, no unusual HLA B/Bf associations were observed. Bf F entered the family only once. A new finding is the association between HLA B27 and Bf S1; the haplotype entered the family once and was passed on to eight family members over three generations. Bf S1 was previously reported in association with HLA B12 or W21. None of these family members had ankylosing spondylitis. The Bf allele F1 entered the family three times, always in association with HLA B18.

We examined HLA association with differentiated thyroid carcinoma in 45 patients from Newfoundland. No association was found. This finding contrasts with the description of an association of thyroid cancer with HLA-DR1 in Italy and Hungary (iodide deficient areas) and with DR7 in the American mid-west. We suggest that iodide deficiency predisposes DR1 + individuals to thyroid cancer and that this risk is negated by iodide sufficiency unless some other risk factor supervenes.

Serum levels of immunoglobulins (Ig) IgA, IgG and IgM were measured in 96 HLA—typed patients with Graves'disease and an equal number of sex and age matched controls. Patients showed significantly increased serum immunoglobulin levels compared to controls. HLA DR3-positive patients had larger elevations of IgG concentration than their HLA—DR3-negative counterparts. Variation in serum immunoglobulin levels was not associated with sex, treatment or ophthalmopathy. It is suggested that the hypergammaglobulinemia of Graves'disease is related to defective suppressor cells triggered by Ig or Ig-linked genes. HLA-related gene(s) must, in addition, be involved to account for hypergammaglobulinemia G in the HLA—DR3-positive subset of patients.

In order to further elucidate the genetics of Graves' disease, we studied two families with several affected members, as well as tested the degree to which HLA haplotypes were shared in affected sibpairs. Further, we sought to identify the disease related haplotypes by determining the haplotypes shared among affected parent-child combinations. In one family, two affected sibs differed at four possible parental HLA haplotypes; no evidence of recombination was observed which could account for the result. In the other family, five siblings were affected. Four out of the five affected sibs shared the maternal haplotype HLA-A11, Bw51, Cw5, Cw-, DRw5, Bfs, GLO1, whereas three shared the paternal haplotype HLA-A1, B8, Cw-, DRw3, BfS and GLO1. Looking at haplotype sharing, two pairs of sibs were found to be HLA identical, whereas the fifth sib shared one haplotype with one of these pairs but not with the other. Out of 14 (eight of our own and six from the literature) affected sibpairs examined, nine were found to be HLA identical and four shared one haplotype, suggesting that the contribution of both paternal haplotypes may be necessary for the susceptibility to the disease. Fourteen parent-child combinations were studied; in only three out of 13 in which the shared haplotype could be ascertained was the haplotype B8 positive; this distribution is similar to controls. However, of the remaining 10 combinations which did not share a B8 positive haplotype, five were B8 positive at one or the other of the non-shared haplotypes.

Association between Graves' disease and HLA—B8 has been previously documented, as have been associations between 1 gG heavy chain allotype markers (Gm). We found a significant increase in the phenotype fnb/fb (ie. positivity for fb) in patients with Graves' diesase compared to controls, raising the possibility of allotypic restriction of thyroid stimulating antibodies thought to be causally related to the disease. The influence of fb on the susceptibility to Graves' disease was found to be independent of HLA—B8 status suggesting that the immunological network operated by the Histocompatibility-linked genes is independent of that centered around IgG allotypes. It is postulated that, whereas the former genes determine the level of helper T lymphocyte function in the production of thyroid stimulating antibodies in Graves' disease, a person who also happens to carry the Gm marker fb would be assured of the production of IgG antibodies with thyroid stimulatory activity.

We have studied 25 patients with polyglandular autoimmune disease with respect to HLA antigens. Whereas the combination of insulin dependent diabetes with Graves’disease or atrophic thyroiditis was associated with an increase in HLA–B8, this was not found to be the case for patients with I.D.D.M. and goitrous thyroiditis. However 4/7 of these patients were DRw3 positive in contrast to previously established normal distribution of HLA–B8 in patients with goitrous thyroiditis alone. These data suggest that patients with polyglandular failure may be highly selected for HLA-B8/DRw3 positivity. We also report on two families with polyglandular autoimmune disease; the results suggest that these disorders are not necessarily transmitted with B8/DRw3 bearing haplotypes. In one family both the affected mother and non-affected father were B8 positive. The mother's B8, which was associated with DRw7, BfF and Rga did not appear to be involved in the transmission of disease susceptibility to two affected offspring. The search for complete haplotypic arrangement should be pursued to see whether this uncommon haplotype arrangement is peculiar to autoimmune diseases.

Forty-seven patients with Graves’ disease, 73 with thyroiditis and 128 controls drawn from the same geographical area of Newfoundland were HLA typed. The frequency of HLA-B8 was significantly increased in the Graves’ disease patients when compared to the control group giving a relative risk of 3.9. There were no significant HLA differences between the thyroiditis and control groups. Homozygosity for the HLA haplotype, which is common in this island population, was more common in Graves’ disease patients (12.8%) than in controls (5.5%) but did not reach statistical significance in this sample. Homozygosity was due in five of the six cases to either an A1;B8 haplotype or an A2;B8 haplotype. This contrasted with an apparently random assortment of haplotypes in the control and thyroiditis groups. Calculations suggest that homozygosity for a B8 haplotype confers an additional risk over heterozygosity for B8 of about 3.5 fold; however, homozygosity had no observable influence on the severity of the disease. These results strengthen the idea that B8, or an allele in linkage disequilibrium with it, determines in part the susceptibility of an individual to developing Graves’ disease.