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 leukocyte 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 DRB1*0304 (47% vs. 24%; pc < 1.4 x 10(-5)), DQB1*02 (58% vs. 46%; pc < 0.035), DQB1*0301/4 (42% vs. 28%; pc < 3.5 x 10(-3)) and DQA1*0501 (67%, vs. 39%; pc < 7 x 10(-6)). The DRB1*0304-DQB1*02-DQA1*0501 haplotype was increased in GD (47%) vs. controls (24%; pc < 1.8 x 10(-5); odds ratio = 2.72). No independent association of these alleles was observed. Preferential transmission of DRB1*0304-DQB1*02-DQA1*0501 from parents heterozygous for the haplotype to GD siblings (72%) was seen in the families (chi2 = 11.95; 1 d.f.; P = 0.0005). Lack of preferential transmission to unaffected siblings (53%; chi2 = 0.19; 1 d.f.; P = NS) excluded segregation distortion. These results show that linkage disequilibrium between GD and the HLA class II region is due to the extended haplotype DRB1*0304-DQB1*02-DQA1*0501.
Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, United Kingdom.
J M
JM
Heward
A
A
Allahabadia
J
J
Daykin
J
J
Carr-Smith
A
A
Daly
M
M
Armitage
P M
PM
Dodson
M C
MC
Sheppard
A H
AH
Barnett
J A
JA
Franklyn
S C
SC
Gough
D000483:Alleles; D016022:Case-Control Studies; D005220:Fathers; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D006111:Graves Disease / Q000235:genetics* / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D008297:Male; D009035:Mothers; D012016:Reference Values
D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II