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Type 2 Diabetes-Associated Genetic Variants Regulate Chromatin Accessibility in Human Islets
Shubham Khetan1,2, Romy Kursawe1, Ahrim Youn1
1The Jackson Laboratory for Genomic Medicine, Farmington, CT.
Diabetes
|September 6, 2018
Summary
Researchers identified genetic variants affecting chromatin accessibility in pancreatic islets, linking them to type 2 diabetes risk. This study helps understand how genetic variations influence islet function in type 2 diabetes.
Area of Science:
- Genomics
- Endocrinology
- Molecular Biology
Background:
- Type 2 diabetes (T2D) arises from genetic and environmental factors impacting pancreatic islet cells.
- Genome-wide association studies (GWAS) have identified over 200 genetic loci associated with T2D, but causal variants and their functions remain unclear.
- Noncoding single nucleotide polymorphisms (SNPs) are frequently implicated in T2D risk, necessitating functional validation.
Purpose of the Study:
- To investigate the functional impact of genetic variants on chromatin accessibility in human pancreatic islets.
- To identify causal variants within T2D-associated GWAS loci that influence gene regulation in islets.
- To link specific genetic risk alleles to gain or loss of function in islet regulatory elements.
Main Methods:
- Profiling of chromatin accessibility in pancreatic islet samples from 19 genotyped individuals.
- Identification of chromatin accessibility quantitative trait loci (caQTLs) associated with genetic variation.
- Luciferase reporter assays in MIN6 β-cells to validate enhancer activity of candidate caQTLs.
- Analysis of T2D-associated GWAS loci to nominate putative causal SNPs affecting islet chromatin accessibility.
Main Results:
- Identified 2,949 SNPs associated with in vivo cis-regulatory element use (caQTLs) in pancreatic islets.
- Over half of the tested caQTLs (7 out of 13) showed enhancer activity consistent with in vivo chromatin accessibility changes.
- Nominated putative causal SNPs in 13 T2D-associated GWAS loci.
- Linked 7 T2D risk alleles to gain and 6 to loss of in vivo chromatin accessibility in islets.
Conclusions:
- This study provides functional insights into T2D-associated genetic variants by examining their effects on islet chromatin accessibility.
- The findings advance the understanding of how genetic variations contribute to islet dysfunction in type 2 diabetes.
- This approach is crucial for translating GWAS discoveries into molecular mechanisms underlying T2D pathogenesis.
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