Staff Scientist
National Institute of Diabetes and Digestive and Kidney Diseases
Project Title: “Modelling the function of type 2 diabetes loci in Pima Indians using iPSCs-derived pancreatic-islet like cells.”
The Pima Indian population has been living in the Sonoran Desert in Southern Arizona for the past couple of millennia. A longitudinal study in this population identified high prevalence of type 2 diabetes (T2D) and has prompted genetic studies to identify susceptibility genes for T2D, which included large scale whole exome sequencing, limited whole genome sequencing and genome-wide association studies (GWAS). Several novel genetic signals for T2D were identified subsequently. The strongest GWAS signals for T2D in Pima Indian population mapped to intron 15 of the gene KCNQ1.
Identifying the effector gene and the causal SNPs responsible for the GWAS signal at the KCNQ1 locus would help to understand the mechanistic details of the T2D pathology and has potential for drug development. Work in Dr. Nair’s laboratory has identified a region within intron 15 of KCNQ1 with potential regulatory function. This region harbors four SNPs which are in high linkage disequilibrium with each other. To identify the gene(s) affected by these SNPs, Dr. Nair’s group has generated isogenic iPSC lines for each haplotype (Risk/Risk, Risk/Non-Risk and Non-Risk/Non-Risk) that differ at these four SNPs using Pima Indian iPSCs and CRISPR/CAS9. The isogenic iPSC lines were subsequently characterized for genomic stability, pluripotency and differentiation potential. Dr. Nair proposes to use these isogenic iPSCs with targeted base changes at the four putative functional variants to identify the causal gene(s) at the KCNQ1 locus.
Specific aims are:
- Identification of the effector gene at the KCNQ1 locus which gives rise to the GWAS signal.
- Determining whether these SNPs affect the generation of pancreatic beta-like cells from iPSCs.
