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Genetic Variation Within the HLA-DRA1 Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes

Aydemir, Özkan ; Noble, Janelle A ; Bailey, Jeffrey A ; Lernmark, Åke LU ; Marsh, Patrick ; Andersson Svärd, Agnes LU ; Bearoff, Frank ; Blankenhorn, Elizabeth P and Mordes, John P (2019) In Diabetes 68(7). p.1523-1527
Abstract

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... (More)

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.

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author
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
68
issue
7
pages
5 pages
publisher
American Diabetes Association Inc.
external identifiers
  • pmid:30962219
  • scopus:85068537598
ISSN
1939-327X
DOI
10.2337/db18-1128
language
English
LU publication?
yes
additional info
© 2019 by the American Diabetes Association.
id
07d614ee-9e12-4d7a-8c27-8ad22469703f
date added to LUP
2019-06-25 13:11:10
date last changed
2019-09-25 03:00:22
@article{07d614ee-9e12-4d7a-8c27-8ad22469703f,
  abstract     = {<p>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.</p>},
  author       = {Aydemir, Özkan and Noble, Janelle A and Bailey, Jeffrey A and Lernmark, Åke and Marsh, Patrick and Andersson Svärd, Agnes and Bearoff, Frank and Blankenhorn, Elizabeth P and Mordes, John P},
  issn         = {1939-327X},
  language     = {eng},
  number       = {7},
  pages        = {1523--1527},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Genetic Variation Within the HLA-DRA1 Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes},
  url          = {http://dx.doi.org/10.2337/db18-1128},
  doi          = {10.2337/db18-1128},
  volume       = {68},
  year         = {2019},
}