LINKAGE DISEQUILIBRIUM BETWEEN THE HUMAN-LEUKOCYTE ANTIGEN CLASS-II REGION OF THE MAJOR HISTOCOMPATIBILITY COMPLEX AND GRAVES-DISEASE - REPLICATION USING A POPULATION CASE-CONTROL AND FAMILY-BASED STUDY

Early case control studies found association of the DRB1 allele, DR3, with Graves' disease (GD). Recent reports, claim the DQA1 allele, DQA1 0501, to be the primary susceptibility determinant within the human l eukocyte antigen (HLA) class II region. We typed 228 GD patients, 364 controls, and 98 families (parents, GD, and unaffected sibling) at the DRB1, DQB1, and DQA1 loci. The case control study showed an increased frequency in GD, compared to controls, of DRB10304 (47% vs. 24%; pc < 1.4 x 10(-5)), DQB102 (58% vs. 46%; pc < 0.035), DQB1*0301/4(42% vs . 28%; pc ( 3.5 x 10(-8)) and DQA10501(67%, vs. 39%;pe < 7 x 10(-6)). The DRB10304-DQB1*02-DQA1*0501 haplotype was increased in GD (47%) v s. controls (24%; pc < 1.8 x 10(-5); odds ratio = 2.72). No independen t association of these alleles was observed. Preferential transmission of DRB10304-DQB1*02-DQA1*0501; from parents heterozygous for the hap lotype to GD siblings (72%) was seen in the families chi(2) = 11.95; 1 d.f.; P = 0.0005). Lack of preferential transmission to unaffected si blings (53%; chi(2) = 0.19; 1 d.f.;P = NS) excluded segregation distor tion. These results show that linkage disequilibrium between GD and th e HLA class II region is due to the extended haplotype DRB10304-DQB1* '02-DQA10501.