Newly discovered Genetic Variation within the HLA-DRA Gene Modulates Susceptibility to Type 1 Diabetes in Persons Homozygous for HLA-DR3

Janelle A. Noble, PhD¹, Özkan Aydemir, PhD², Jeffrey Bailey, MD², Åke Lernmark, PhD³, Patrick Marsh², Agnes Andersson Svärd³, Frank Bearoff, PhD⁴, Elizabeth P. Blankenhorn, PhD⁴, and John P. Mordes, MD^1,2

¹Children’s Hospital Oakland Research Institute, Oakland, CA; ²Department of Medicine, Divisions of Transfusion Medicine and Endocrinology, University of Massachusetts Medical School, Worcester, MA; ³Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital; ⁴Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA

Type 1 diabetes (T1D) is a polygenic autoimmune disorder involving the interaction of multiple gene variantsADDIN REFMGR.CITE    , environmental factorsADDIN REFMGR.CITE    , and immunoregulatory dysfunctionADDIN REFMGR.CITE    . The major genetic loci for T1D susceptibility are those encoding the Human Leukocyte Antigens HLA-DR and DQADDIN REFMGR.CITE    . Many non-HLA loci are also associated with the disease, but their individual contributions to risk are smallADDIN REFMGR.CITE    .

Genetic heterogeneity in the highly polymorphic HLA region and extensive linkage disequilibrium can confound attempts to identify other T1D susceptibility loci. Our objective was to study such loci in a way that minimizes HLA heterogeneity. Therefore, we examined a cohort of more than 1000 T1D patients and controls, who were homozygous for the HLA risk haplotype known as DR3, to identify new genes and loci that contribute to susceptibility to T1D. To do so efficiently, we used molecular inversion probe (MIP) sequencing technology. We report that risk for T1D in HLA-DR3 homozygotes is modulated significantly by a previously undiscovered haplotype of three single nucleotide polymorphisms (SNPs) within the first intron of HLA-DRA. This haplotype, when heterozygous, has an odds ratio of 2.54 (1.87-3.47, 95% CI; p-value of 3.1x10^-9) and an odds ratio of 4.65 (3.08-7.09, CI 95%; p-value 1.7x10^-13) when homozygous.

Individually, each of the three SNPs has previously been reported to function as “expression quantitative trait locus” (eQTL), modulating expression of numerous HLA genes including HLA-DR and DQ. Our review of available data suggests that the three-SNP T1D risk haplotype within HLA-DRA also modulates class II expression, and thus could modify the risk of T1D by regulating expression levels of class II genes even within the high-risk HLA-DR3 haplotype. This three-SNP haplotype could be useful in predicting diabetes in high-risk cohorts, particularly among DR3 homozygous individuals.