Transracial evidence for the influence of the homologous HLA DR-DQ haplotype on transmission of HLA DR4 haplotypes to diabetic children.
The HLA-DQB1*0302 allele on DR4 haplotypes is a marker for type 1 diabetes susceptibility and it is an especially high-risk allele in DR3/4 because of its preferential distribution in Caucasian DR3/4 patients. In Asians, not only DQB1*0302 but also DQB1*0401 on DR4 haplotypes are associated with type 1 diabetes. We investigated whether the contribution of these DQ molecules was also genotype-dependent in Asians. Although the prevalence of the DR4-DQB1*0302 haplotype did not differ in patients vs. controls, the DR3/4-DQB1*0302 genotype had a RR of 12 (P<10(-4)). Moreover, a significant association of DQB1*0302 with the DR3/4 genotype was found (RR=3, P<10(-2)). In contrast, the distribution of DQB1*0401 alleles of DR4/X (X: other than 3, 4) is different from that of DR3/4 and DR4/4. Especially a significant association of DQB1*0401 with DR4/X (X: other than 1, 3, 4) was found (RR=3, P<10(-3)). The frequency of transmission of the DR4-DQB1*0302 haplotypes to diabetic offspring with DR3 was 80%, while to those without DR3 was 40%. In contrast, the transmission of the DR4-DQB1*0401 to those with DR3 was 60%, while to those without DR3 was 80%. High-risk DR4 subtypes were predominant in DR4/X (RR=7, P<10(-3)), whereas protective DR4 subtypes were observed mainly in the DR3/4 (RR=3, P<0.05). The association with diabetes and transmission to a diabetic offspring of DR4 haplotypes varies depending on the haplotype borne on the homologous chromosome. This might contribute not only to the synergistic effect of DR3/4, but also to the susceptibility influence of HLA DQB1*0401 alleles confined to DR4/X.
Park
Y S
YS
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado, USA.
She
J X
JX
Noble
J A
JA
Erlich
H A
HA
Eisenbarth
G S
GS
D044466:Asian People / Q000235:genetics*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D015804:HLA-DR4 Antigen / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D012689:Sequence Homology, Nucleic Acid; D044465:White People / Q000235:genetics
D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D015804:HLA-DR4 Antigen