The rare HLA-DQA1*03-DQB1*02 haplotype confers susceptibility to type 1 diabetes in whites and is preferentially associated with early clinical disease onset in male subjects.
The heterozygous combination of DQA1*03-DQB1*0302 (DQ8) and DQA1*05-DQB1*0201 (DQ2) confers the highest known HLA-DQ-linked risk for type 1 diabetes, suggesting a role for transcomplementation. The trans-heterodimer encoded by DQA1*03 and DQB1*02 is also rarely observed in cis in whites. Islet antibody-positive diabetic patients (P; n = 2,238) and control subjects (C; n = 2,223) of white descent were genotyped by a HLA-DQA1-DQB1 dot-blot method. The presence of the DQA1*03-DQB1*02 haplotype was observed in 22 patients (1%) versus 6 controls (0.3%) (odds ratio [OR] = 3.7, p = 0.005). It was more prevalent in whites of Northern African descent, but both in European (n = 3,813) and in Northern African whites (n = 648), the DQA1*03-DQB1*02 haplotype tended to be associated with diabetes (respectively, P 0.3% vs. C 0.03%, OR = 12.2, p = 0.005; and P 2.1% vs. C 0.6%, OR = 3.8, p = 0.03). DRB1 typing revealed that DQA1*03-DQB1*02 is usually associated with the DRB1*0405 risk allele in European patients and with DRB1*0405, DRB1*07 and DRB1*09 in Northern African whites. Like in DQ2/DQ8-positive patients, the presence of DQA1*03-DQB1*02 is preferentially associated with younger age at clinical onset than in other genotypes, but unlike in subjects carrying DQ2/DQ8, earlier clinical manifestation was mostly restricted to male subjects, often carrying DR3 and/or DQB1*02 on the other chromosome. These results are compatible with an effect of cis-encoded heterodimers or with previously suggested interactions of X-linked genetic factors with (DR3-)DQB1*02 haplotypes.
Diabetes Research Center, Molecular Diagnosis, Vrije Universteit Brussel, B-1070 Brussels, Belgium.
Jan E
JE
van Autreve
Ilse
I
Weets
Béatrice
B
Gulbis
Françoise
F
Vertongen
Frans K
FK
Gorus
Bart J
BJ
van der Auwera
D000293:Adolescent; D000328:Adult; D000352:Africa, Northern / Q000208:ethnology; D017668:Age of Onset; D001323:Autoantibodies / Q000097:blood; D001530:Belgium; D015992:Body Mass Index; D002096:C-Peptide / Q000097:blood; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics* / Q000652:urine; D005060:Europe / Q000208:ethnology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006442:Glycated Hemoglobin / Q000032:analysis; 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 / Q000235:genetics*; D006801:Humans; D007223:Infant; D007659:Ketones / Q000652:urine; D008297:Male; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012737:Sex Factors; D044465:White People / Q000235:genetics*
D001323:Autoantibodies; D002096:C-Peptide; D004247:DNA; D006442:Glycated Hemoglobin; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D007659:Ketones; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen