The association of specific HLA class I and II alleles with type 1 diabetes among Filipinos.

The genetic predisposition to type 1 diabetes among Filipinos was examined by PCR/SSOP HLA class I and II typing of 90 patients and 94 general population controls. The HLA-DRB1, DQB1, and the A, B, and C loci were typed using the reverse SSO probe line-blot method while the DPB1 and DPA1 loci were typed using the SSO probe dot blot method. The Filipino population has a distinctive frequency distribution of HLA class II alleles as well as linkage disequilibrium patterns: a DR-DQ haplotype, unique to Filipinos, contains a DRB1 allele (0405) positively associated with type 1 diabetes in other populations and DQA1 and DQB1 alleles (0101-0503) that are negatively associated in other populations. Specific DR-DQ haplotypes or alleles could be identified as susceptible, neutral or protective based on the distribution among Filipino patients and controls. The DR9 and DR3 haplotypes showed the most dramatic increase among patients (0.156 vs 0.063) and (0.172 vs 0.042), respectively. Among Filipinos, the DR3/9 genotype confers approximately the same risk as the well-known high-risk DR3/4 genotype, similar to that for DR3/3 and DR9/9. The common DR2 haplotype in the Philippines (DRB11502-DQB10502) was only slightly decreased in type 1 diabetic patients (0.200 in patients vs 0.270 in controls). Another DR2 haplotype, DRB11502-DQB10501, was significantly decreased among patients. In addition, haplotypes containing DQB106 alleles, such as the DRB10803-DQB10601 (OR = 0.1), are strongly protective. The DR4 allele group was also increased in Filipino patients compared to controls. In this population there is, as in other populations, a hierarchy of type 1 diabetes associations among the many different DR4 haplotypes (n = 15). The high-risk haplotypes in this population are the very rare DRB10405-DQB10302 and DQB10405-DQB10201, followed by the more common DRB10405-DQB10401 and DRB10405-DQB10402. The DRB10403-DQB10302 is protective. The DRB10405-DQB105031 haplotype, which is unique to Filipinos, appears to be "neutral". HLA-DPB10202 was significantly increased among patients (0.056 vs 0.011; with OR = 5.3); this increase does not appear to simply reflect linkage disequilibrium with high risk DR-DQ haplotypes. The observed distribution of HLA class II alleles among Filipino patients and controls strongly supports the notion that specific combinations of alleles at the DRB1, DQB1, DQA1, and DPB1 loci are critical in determining the risk for type 1 diabetes. Specific HLA class I alleles also show significant associations with type 1 diabetes in this population. HLA-A2402 and 2403 were increased among patients; however, 2407 was decreased. Inaddition, A 1101 was significantly decreased among patients (OR = 0.51). Moreover, these HLA-A associations do not appear attributable to linkage disequilibrium with the DR-DQ region. The allele B5801 was increased in patients while B1301 was decreased; both of these associations, however, reflected linkage disequilibrium with high-risk and with protective DR-DQ haplotypes, respectively. The HLA-C0102 and 0302 alleles were increased (0.089 vs 0.037 and 0.122 vs 0.064) while C1502 and 0702 (0.028 vs 0.080 and 0.217 vs 0.330) were decreased. The observed associations of C0102 and C1502 do not simply reflect linkage disequilibrium with high-risk DR-DQ haplotypes. Thus, specific HLA class I-A and C alleles were associated with type 1 diabetes in the Filipinos and may, in combination with high risk DR-DQ haplotypes, significantly modify disease risk.