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Association of HLA-DPB1*0301 with IDDM in Mexican-Americans
H A Erlich1, J I Rotter, J D Chang
1Department of Human Genetics, Roche Molecular Systems, Alameda, CA 94501, USA.
Abstract:
Susceptibility to IDDM has been associated with specific alleles at the HLA class II loci in a variety of human populations. Previous studies among Mexican-Americans, a group ancestrally derived from Native Americans and Hispanic whites, showed that the DR4 haplotypes (DRB1*0405-DQB1*0302 and DRB1*0402-DQB1*0302) and the DR3 haplotype (DRB1*0301-DQB1*0201) were increased among patients and suggested a role for both DR and DQ alleles in susceptibility and resistance. Based on the analysis of 42 Mexican-American IDDM families and ethnically matched control subjects by polymerase chain reaction/sequence-specific oligonucleotide probe typing, we report an association of IDDM with the DPB1 allele, *0301 (relative risk = 6.6; P = 0.0012) in this population. The analysis of linkage disequilibrium patterns in this population indicates that the observed increased frequency in DPB1*0301 among patients cannot be attributed simply to linkage disequilibrium with high-risk DR-DQ haplotypes. These data suggest that in addition to alleles at the DRB1 and DQB1 loci, polymorphism at the DPB1 locus may also influence IDDM risk.
Insights
Type 1 diabetes susceptibility is linked to HLA class II genes. In Mexican-Americans, a specific HLA-DPB1 allele (*0301) is newly associated with increased risk, independent of HLA-DR and HLA-DQ alleles.
Area of Science:
- Immunogenetics
- Human Population Genetics
- Endocrinology
Background:
- Specific alleles at the Human Leukocyte Antigen (HLA) class II loci are linked to susceptibility to Insulin-Dependent Diabetes Mellitus (IDDM).
- Previous research in Mexican-Americans identified increased frequencies of HLA-DR4 and HLA-DR3 haplotypes in IDDM patients, suggesting roles for HLA-DR and HLA-DQ alleles.
- The ancestral origins of Mexican-Americans, comprising Native Americans and Hispanic whites, provide a unique population for genetic association studies.
Purpose of the Study:
- To investigate the association of HLA class II alleles with susceptibility to IDDM in the Mexican-American population.
- To determine if the HLA-DPB1 locus contributes to IDDM risk independently of HLA-DRB1 and HLA-DQB1 loci.
- To analyze linkage disequilibrium patterns to understand the genetic basis of IDDM susceptibility in this ethnic group.
Main Methods:
- Analysis of 42 Mexican-American IDDM families and ethnically matched control subjects.
- Utilized polymerase chain reaction/sequence-specific oligonucleotide probe typing for HLA allele identification.
- Examined linkage disequilibrium patterns between HLA loci.
Main Results:
- A significant association was found between the HLA-DPB1*0301 allele and increased IDDM susceptibility (relative risk = 6.6; P = 0.0012).
- The increased frequency of HLA-DPB1*0301 in IDDM patients was not solely due to linkage disequilibrium with high-risk HLA-DR-DQ haplotypes.
- These findings suggest an independent contribution of the DPB1 locus to IDDM risk.
Conclusions:
- Polymorphism at the HLA-DPB1 locus, specifically the *0301 allele, plays a significant role in IDDM susceptibility in Mexican-Americans.
- The genetic contribution to IDDM risk in this population involves multiple HLA class II loci, including DPB1, DRB1, and DQB1.
- These results expand our understanding of the complex genetic architecture underlying autoimmune diseases like Type 1 diabetes.