Two HLA DRB 1 alleles confer independent genetic susceptibility to Graves disease: Relevance of cross-population studies

Recent studies of Graves disease (GD) employing genome scanning techniques excluded the major histocompatibility complex as a contributor to disease l iability. These findings contradict earlier population association studies. Our own earlier studies have also emphasized that genetic variation inhuma n populations may give novel clues to disease liability and manifestations. To this end, we studied HLA class II alleles in 47 Latvian GD patients and 111 matched healthy controls. As expected, we found that DRB1*03 and DQA1* 0501 (OR = 3.6, P = 0.029 and OR 2.35, P = 0.0373, respectively) were assoc iated with GD. Unforeseen, DRB1*04 was found to be significantly increased in the patients compared to controls (OR 3.267, corrected P = 0.0319). The two DRB1 alleles conferred two non-overlapping and independent susceptibili ties to GD, in that only three patients were positive for both alleles, and the removal of each allele in turn resulted in only the other DRB1 allele showing significant association with the disease. There was no heterogeneit y between the two patient; groups (DRB1*03 positive and DRB1*04 positive) i n clinical characteristics or disease manifestations. The phenotype DRB1*03 and/or DRB1*04 was found in 34/47 patients compared to 27/111 controls yie lding an OR of 7.395 (P corrected = 0.000019). We examined the structural b asis of DRB1 susceptibility to GD in light of this and previous studies, sh owing that DRB1*03, 04, and 08 were positively associated with the disease, whereas DRB1*07 was negatively associated. Differences in-protein sequence s were noted at residues 54, 57, 59, and 66; positions 54, 57, and 66 are o n the same face of the alpha helix. The canonical arginine 54 is replaced b y glutamine in DRB1*07. At position 66, asparagine in DRR1*03 and tyrosine in DRB1*04 are replaced by phenylalanine in DRB1*07. Residue 59, likely inv olved in pocket formation in the antigen binding groove, is modified by rep lacement of tyrosine:in DRB1*03, 08, and 04 and by leucine in DRB1*07. The predicted differences in the shape and charges of the proximal reaches of t he antigen binding groove between DRB1*07, and 03, 04, and 08, could determ ine whether or not a peptide from an auto-antigen would be bound or not. Ge netic variation among human populations may yield important clues to specif ic disease liability (C) 2001 Wiley-Liss, Inc.