Genetic Variation Within the HLA-DRA1 Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes
| Autor: | Frank Bearoff, Patrick W Marsh, Elizabeth P. Blankenhorn, Åke Lernmark, Ozkan Aydemir, Janelle A. Noble, Jeffrey A. Bailey, John P. Mordes, Agnes Andersson Svärd |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Linkage disequilibrium Diabetes risk endocrine system diseases Genotype Endocrinology Diabetes and Metabolism HLA-DR3 030209 endocrinology & metabolism Single-nucleotide polymorphism HLA-DR alpha-Chains Human leukocyte antigen Biology Polymorphism Single Nucleotide 03 medical and health sciences 0302 clinical medicine HLA-DR3 Antigen Gene Frequency immune system diseases Internal Medicine Humans Genetic Predisposition to Disease Alleles Genetics Genetic heterogeneity Haplotype Homozygote Genetic Variation Genetics/Genomes/Proteomics/Metabolomics Introns 030104 developmental biology Diabetes Mellitus Type 1 Case-Control Studies Expression quantitative trait loci Female |
| Zdroj: | Diabetes |
| Popis: | Type 1 diabetes (T1D) involves the interaction of multiple gene variants, environmental factors, and immunoregulatory dysfunction. Major T1D genetic risk loci encode HLA-DR and -DQ. Genetic heterogeneity and linkage disequilibrium in the highly polymorphic HLA region confound attempts to identify additional T1D susceptibility loci. To minimize HLA heterogeneity, T1D patients (N = 365) and control subjects (N = 668) homozygous for the HLA-DR3 high-risk haplotype were selected from multiple large T1D studies and examined to identify new T1D susceptibility loci using molecular inversion probe sequencing technology. We report that risk for T1D in HLA-DR3 homozygotes is increased significantly by a previously unreported haplotype of three single nucleotide polymorphisms (SNPs) within the first intron of HLA-DRA1. The homozygous risk haplotype has an odds ratio of 4.65 relative to the protective homozygous haplotype in our sample. Individually, these SNPs reportedly function as “expression quantitative trait loci,” modulating HLA-DR and -DQ expression. From our analysis of available data, we conclude that the tri-SNP haplotype within HLA-DRA1 may modulate class II expression, suggesting that increased T1D risk could be attributable to regulated expression of class II genes. These findings could help clarify the role of HLA in T1D susceptibility and improve diabetes risk assessment, particularly in high-risk HLA-DR3 homozygous individuals. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|