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Original Research
Type 2 Diabetes Associated Genetic Variants Regulate Chromatin Accessibility in Human Islets
Shubham Khetan, Romy Kursawe, Ahrim Youn, Nathan Lawlor, Alexandria Jillette, Eladio J. Marquez, Duygu Ucar, Michael L. Stitzel
Diabetes 2018 Aug; db180393. https://doi.org/10.2337/db18-0393
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Abstract

Type 2 Diabetes (T2D) is a complex disorder in which both genetic and environmental risk factors contribute to islet dysfunction and failure. Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs), most of which are noncoding, in >200 loci to islet dysfunction and T2D. Identification of the putative causal variants, their target genes, and whether they lead to gain- or loss-of-function remains challenging. Here, we profiled chromatin accessibility in pancreatic islet samples from 19 genotyped individuals and identified 2949 SNPs associated with in vivo cis-regulatory element (RE) use (i.e., chromatin accessibility quantitative trait loci (caQTL)). Among the caQTLs tested (n=13) using luciferase reporter assays in MIN6 beta cells, more than half exhibited effects on enhancer activity that were consistent with in vivo chromatin accessibility changes. Importantly, islet caQTL analysis nominated putative causal SNPs in 13 T2D-associated GWAS loci, linking 7 and 6 T2D risk alleles, respectively, to gain or loss of in vivo chromatin accessibility. By investigating the effect of genetic variants on chromatin accessibility in islets, this study is an important step forward in translating T2D-associated GWAS SNP into functional molecular consequences.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-0393.

  • Received April 5, 2018.
  • Accepted August 22, 2018.
  • © 2018 by the American Diabetes Association.
http://www.diabetesjournals.org/content/license

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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Type 2 Diabetes Associated Genetic Variants Regulate Chromatin Accessibility in Human Islets
Shubham Khetan, Romy Kursawe, Ahrim Youn, Nathan Lawlor, Alexandria Jillette, Eladio J. Marquez, Duygu Ucar, Michael L. Stitzel
Diabetes Aug 2018, db180393; DOI: 10.2337/db18-0393

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Type 2 Diabetes Associated Genetic Variants Regulate Chromatin Accessibility in Human Islets
Shubham Khetan, Romy Kursawe, Ahrim Youn, Nathan Lawlor, Alexandria Jillette, Eladio J. Marquez, Duygu Ucar, Michael L. Stitzel
Diabetes Aug 2018, db180393; DOI: 10.2337/db18-0393
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