Generation of Isogenic hiPSCs with Targeted Edits at Multiple Intronic SNPs to Study the Effects of the Type 2 Diabetes Associated Locus in American Indians.

The top genetic association signal for type 2 diabetes (T2D) in Southwestern American Indians maps to intron 15 of , an imprinted gene. We aim to understand the biology whereby variation at this locus affects T2D specifically in this genomic background. To do so, we obtained human induced pluripotent stem cells (hiPSC) derived from American Indians.

A missense variant Arg611Cys in LIPE which encodes hormone sensitive lipase decreases lipolysis and increases risk of type 2 diabetes in American Indians.

Aims: Hormone sensitive lipase (HSL), encoded by the LIPE gene, is involved in lipolysis. Based on prior animal and human studies, LIPE was analysed as a candidate gene for the development of type 2 diabetes (T2D) in a community-based sample of American Indians.

Materials And Methods: Whole-exome sequence data from 6782 participants with longitudinal clinical measures were used to identify variation in LIPE.

Exome Sequencing Identifies A Nonsense Variant in DAO Associated With Reduced Energy Expenditure in American Indians.

Background: Obesity and energy expenditure (EE) are heritable and genetic variants influencing EE may contribute to the development of obesity. We sought to identify genetic variants that affect EE in American Indians, an ethnic group with high prevalence of obesity.

Methods: Whole-exome sequencing was performed in 373 healthy Pima Indians informative for 24-hour EE during energy balance.

Using Luciferase Reporter Assays to Identify Functional Variants at Disease-Associated Loci.

The genomic era, highlighted by large scale, genome-wide association studies (GWAS) for both common and rare diseases, have identified hundreds of disease-associated variants. However, most of these variants are not disease causing, but instead only provide information about a potential proximal functional variant through linkage disequilibrium. It is critical that these functional variants be identified, so that their role in disease risk can be ascertained.

Functional and association analysis of an Amerindian-derived population-specific p.(Thr280Met) variant in RBPJL, a component of the PTF1 complex.

PTF1 complex is critical for pancreatic development and maintenance of adult exocrine pancreas. As a part of our ongoing studies to identify genetic variation that contributes to type 2 diabetes (T2D) in American Indians, we analyzed variation in genes that form this complex, namely PTF1A, RBPJ, and its paralogue RBPJL. A c.

Identity-by-Descent Mapping Identifies Major Locus for Serum Triglycerides in Amerindians Largely Explained by an Founder Mutation.

Background: Identity-by-descent mapping using empirical estimates of identity-by-descent allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment the inherent genetic information that can be used for localization.

Methods And Results: Through identity-by-descent mapping, using ≈400 000 single-nucleotide polymorphisms (SNPs), of serum lipid profiles, we identified a major linkage signal for triglycerides in 1007 Pima Indians (LOD=9.23; =3.

Complex Genetics of Type 2 Diabetes and Effect Size: What have We Learned from Isolated Populations?

Genetic studies in large outbred populations have documented a complex, highly polygenic basis for type 2 diabetes (T2D). Most of the variants currently known to be associated with T2D risk have been identified in large studies that included tens of thousands of individuals who are representative of a single major ethnic group such as European, Asian, or African. However, most of these variants have only modest effects on the risk for T2D; identification of definitive 'causal variant' or 'causative loci' is typically lacking.

Assessment of established HDL-C loci for association with HDL-C levels and type 2 diabetes in Pima Indians.

Aims/hypothesis: Epidemiological studies in Pima Indians identified elevated levels of HDL-cholesterol (HDL-C) as a protective factor against type 2 diabetes risk in women. We assessed whether HDL-C-associated single-nucleotide polymorphisms (SNPs) also associate with type 2 diabetes in female Pima Indians.

Methods: Twenty-one SNPs in established HDL-C loci were initially analysed in 2,675 full-heritage Pima Indians.

Variants associated with type 2 diabetes identified by the transethnic meta-analysis study: assessment in American Indians and evidence for a new signal in LPP.

Aim/hypothesis: A recent genome-wide trans-ancestry meta-analysis identified seven new loci associated with type 2 diabetes. We assessed the replication of the seven lead single nucleotide polymorphisms (SNPs) and evaluated these loci for additional signals in American Indians.

Methods: Seven SNPs were genotyped in 7,710 individuals from a longitudinally studied American Indian population, and associations with type 2 diabetes, BMI and related phenotypes were assessed.

Whole exome sequencing identifies variation in CYB5A and RNF10 associated with adiposity and type 2 diabetes.

Objective: Few coding variants in genes associated with type 2 diabetes (T2D) have been identified, and the underlying physiologic mechanisms whereby susceptibility genes influence T2D risk are often unknown. The objective of this study was to identify coding variation that increases risk for T2D via an effect on a pre-diabetic trait.

Methods: Whole exome sequencing was done in 177 Pima Indians.

Association analysis of common variants in FOXO3 with type 2 diabetes in a South Indian Dravidian population.

Recent studies have identified common variants in forkhead box O3 gene (FOXO3) to be strongly associated with longevity in different populations. But studies have not been carried out to analyse the role of common variants in FOXO3 with type 2 diabetes. Since type 2 diabetes is an age related disorder and FOXO proteins play an important role in the regulation of metabolism, we studied the role of common variants in FOXO3 for association with type 2 diabetes.

A case-control analysis of common variants in GIP with type 2 diabetes and related biochemical parameters in a South Indian population.

Background: Glucose-dependent insulinotropic polypeptide (GIP) is one of the incretins, which plays a crucial role in the secretion of insulin upon food stimulus and in the regulation of postprandial glucose level. It also exerts an effect on the synthesis and secretion of lipoprotein lipase, from adipocytes, important for lipid metabolism. The aim of our study was to do a case-control association analysis of common variants in GIP in association with type 2 diabetes and related biochemical parameters.

Case-control analysis of SNPs in GLUT4, RBP4 and STRA6: association of SNPs in STRA6 with type 2 diabetes in a South Indian population.

Background: The inverse relationship between GLUT4 and RBP4 expression is known to play a role in the pathogenesis of type 2 diabetes. Elevated levels of RBP4 were shown to cause insulin resistance in muscles and liver. Identification of STRA6 as a cell surface receptor for RBP4 provides further link in this axis and hence we analyzed SNPs in these three genes for association with type 2 diabetes in a South Indian population.