Systematic Evaluation of Genes and Genetic Variants Associated with Type 1 Diabetes Susceptibility

The Journal of Immunology : Official Journal of the American Association of Immunologists
Ramesh RamG Morahan

Abstract

Genome-wide association studies have found >60 loci that confer genetic susceptibility to type 1 diabetes (T1D). Many of these are defined only by anonymous single nucleotide polymorphisms: the underlying causative genes, as well as the molecular bases by which they mediate susceptibility, are not known. Identification of how these variants affect the complex mechanisms contributing to the loss of tolerance is a challenge. In this study, we performed systematic analyses to characterize these variants. First, all known genes in strong linkage disequilibrium (r(2) > 0.8) with the reported single nucleotide polymorphisms for each locus were tested for commonly occurring nonsynonymous variations. We found only a total of 22 candidate genes at 16 T1D loci with common nonsynonymous alleles. Next, we performed functional studies to examine the effect of non-HLA T1D risk alleles on regulating expression levels of genes in four different cell types: EBV-transformed B cell lines (resting and 6 h PMA stimulated) and purified CD4(+) and CD8(+) T cells. We mapped cis-acting expression quantitative trait loci and found 24 non-HLA loci that affected the expression of 31 transcripts significantly in at least one cell type. Additionally, we obs...Continue Reading

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Citations

Mar 3, 2018·Journal of Diabetes Investigation·Fangying XieRonald Cw Ma
Sep 20, 2019·Nature Reviews. Endocrinology·Jorma IlonenRiitta Veijola
Jan 16, 2018·Clinical & Translational Immunology·Flemming Pociot
Oct 12, 2018·Archives of Endocrinology and Metabolism·Karla Simone Costa de SouzaAdriana Augusto de Rezende
Aug 22, 2018·The Journal of Immunology : Official Journal of the American Association of Immunologists·Maximiliano PresaDavid V Serreze
Nov 7, 2019·Current Diabetes Reports·Marina BakayHakon Hakonarson
Apr 16, 2020·Trends in Genetics : TIG·Youqiong YeLeng Han
Jul 1, 2020·Molecular Metabolism·Marc DiedisheimNicolas Venteclef

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