MULTIVARIATE-ANALYSIS OF HLA LOCI IN CONJUNCTION WITH A THYROTROPIN RECEPTOR CODON-52 POLYMORPHISM IN CONFERRING RISK OF GRAVES-DISEASE

Recent reports have suggested that the HLA alleles DRB30101 or DQA1*0 501 confer greater susceptibility to Graves' disease than does the DR3 allele. We have reported previously that a non-HLA-linked allele, a p olymorphism in codon 52 of the human thyrotropin receptor gene, is hig hly associated with Graves' disease in females. To determine which of these four susceptibility alleles confers greater independent risk for the development of Graves' disease, we analyzed the alleles in 134 No rth American Caucasian females who have Graves' disease (ut = 69) or a re normal controls (n = 65) in a logistic regression model. While we f ound each of these alleles to be associated with Graves' disease when analyzed independently (corrected p < 0.01 for each of 4 alleles teste d), only DR3 (p = 0.0001) and the thyrotropin receptor polymorphism (p = 0.0060) maintained a statistically significant independent associat ion when assessed in conjunction with each of the other alleles in a l ogistic model. We conclude that DR3 confers the greatest susceptibilit y to Graves' disease (odds ratio = 7.6) of the alleles within the HLA locus, and that any association between DRB30101 or DQA1*0501 and Gra ves' disease may be a result of the tight linkage disequilibrium betwe en these alleles and DR3. In addition, we found the non-HLA-linked thy rotropin receptor codon 52 polymorphism to confer significant independ ent risk of Graves' disease (odds ratio = 9.0). Further, because 6 of 6 individuals who possessed both DR3 and the thyrotropin receptor poly morphism had Graves' disease, while no individual in the normal contro l group possessed both alleles, study of a larger population to assess the potential synergism between these 2 alleles is warranted.