Functional characterization of a novel p.Ser76Thr variant in IGFBP4 that associates with body mass index in American Indians.

Insulin-like growth factor binding protein 4 (IGFBP4) is involved in adipogenesis, and IGFBP4 null mice have decreased body fat through decreased PPAR-γ expression. In the current study, we assessed whether variation in the IGFBP4 coding region influences body mass index (BMI) in American Indians who are disproportionately affected by obesity. Whole exome sequence data from a population-based sample of 6779 American Indians with longitudinal measures of BMI were used to identify variation in IGFBP4 that associated with BMI.

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 of 21 Bardet-Biedl Syndrome (BBS) Genes to Identify Obesity Variants in 6,851 American Indians.

Objective: In an ongoing effort to identify the genetic variation that contributes to obesity in American Indians, known Bardet-Biedl syndrome (BBS) genes were analyzed for an effect on BMI and leptin signaling.

Methods: Potentially deleterious variants (Combined Annotation Dependent Depletion score > 20) in BBS genes were identified in whole-exome sequence data from 6,851 American Indians informative for BMI. Common variants (detected in ≥ 10 individuals) were analyzed for association with BMI; rare variants (detected in < 10 individuals) were analyzed for mean BMI of carriers.

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.

Weight tracking in childhood and adolescence and type 2 diabetes risk.

Aims/hypothesis: The aim of this work was to examine the associations of average weight and weight velocity in three growth periods from birth through adolescence with type 2 diabetes incidence.

Methods: Child participants were selected from a 43 year longitudinal study of American Indians to represent three growth periods: pre-adolescence (birth to ~8 years); early adolescence (~8 to ~13 years); and late adolescence (~13 to ~18 years). Age-, sex- and height-standardised weight z score mean and weight z score velocity (change/year) were computed for each period.

Low Serum Insulinlike Growth Factor II Levels Correlate with High BMI in American Indian Adults.

Objective: Insulinlike growth factor II (IGF-II) regulates metabolism and growth. In humans, both positive and negative relationships have been reported between serum IGF-II levels and obesity. This study assessed the relationship between serum IGF-II levels and BMI and determined whether IGF-II levels predict weight gain.

Assessing the Role of 98 Established Loci for BMI in American Indians.

Objective: Meta-analyses of genome-wide association studies in Europeans have identified > 98 loci for BMI. Transferability of these established associations in Pima Indians was analyzed.

Methods: Among 98 lead single nucleotide polymorphisms (SNPs), 82 had minor allele frequency ≥ 0.

Identification and functional analysis of a novel G310D variant in the insulin-like growth factor 1 receptor (IGF1R) gene associated with type 2 diabetes in American Indians.

Aims: Insulin-like growth factor 1 receptor (IGF1R) is involved in cell growth and glucose homeostasis. In the current study, the IGF1R locus was analysed as a candidate gene for type 2 diabetes (T2D) in American Indians.

Materials And Methods: Whole genome sequence data from 335 American Indians identified 3 novel missense variants in IGF1R.

A Genome-Wide Association Study Using a Custom Genotyping Array Identifies Variants in Associated With Reduced Energy Expenditure in American Indians.

Pima Indians living in Arizona have a high prevalence of obesity, and we have previously shown that a relatively lower energy expenditure (EE) predicts weight and fat mass gain in this population. EE is a familial trait (heritability = 0.52); therefore, in the current study, we aimed to identify genetic variants that affect EE and thereby influence BMI and body fatness in Pima Indians.

Assessing variation across 8 established East Asian loci for type 2 diabetes mellitus in American Indians: Suggestive evidence for new sex-specific diabetes signals in GLIS3 and ZFAND3.

Background: Eight new loci for type 2 diabetes mellitus (T2DM) were identified in an East Asian genome-wide association study meta-analysis. We assess tag SNPs across these loci for associations with T2DM in American Indians.

Methods: A total of 435 SNPs that tag (R  ≥ .

Assessing FOXO1A as a potential susceptibility locus for type 2 diabetes and obesity in American Indians.

Objective: A prior genome-wide association study (GWAS) in Pima Indians identified variation within FOXO1A that modestly associated with early-onset (onset age < 25 years) type 2 diabetes (T2D). FOXO1A encodes the forkhead transcription factor involved in pancreatic β-cell growth and hypothalamic energy balance; therefore, FOXO1A was analyzed as a candidate gene for T2D and obesity in a population-based sample of 7,710 American Indians.

Methods: Tag SNPs in/near FOXO1A (minor allele frequency ≥ 0.

The effect of differing patterns of childhood body mass index gain on adult physiology in American Indians.

Objective: Identifying groups of individuals with similar patterns of body mass index (BMI) change during childhood may increase understanding of the relationship between childhood BMI and adult health.

Methods: Discrete classes of BMI z-score change were determined in 1,920 American Indian children with at least four non diabetic health examinations between the ages of 2 and 18 years using latent class trajectory analysis. In subsets of subjects, data were available for melanocortin-4 receptor (MC4R) sequencing; in utero exposure to type 2 diabetes (T2D); or, as adults, oral glucose tolerance tests, onset of T2D, or body composition.

ABCC8 R1420H Loss-of-Function Variant in a Southwest American Indian Community: Association With Increased Birth Weight and Doubled Risk of Type 2 Diabetes.

Missense variants in KCNJ11 and ABCC8, which encode the KIR6.2 and SUR1 subunits of the β-cell KATP channel, have previously been implicated in type 2 diabetes, neonatal diabetes, and hyperinsulinemic hypoglycemia of infancy (HHI). To determine whether variation in these genes affects risk for type 2 diabetes or increased birth weight as a consequence of fetal hyperinsulinemia in Pima Indians, missense and common noncoding variants were analyzed in individuals living in the Gila River Indian Community.

Role of Established Type 2 Diabetes-Susceptibility Genetic Variants in a High Prevalence American Indian Population.

Several single nucleotide polymorphisms (SNPs) associated with type 2 diabetes mellitus (T2DM) have been identified, but there is little information on their role in populations at high risk for T2DM. We genotyped SNPs at 63 T2DM loci in 3,421 individuals from a high-risk American Indian population. Nominally significant (P < 0.

A cis-eQTL in PFKFB2 is associated with diabetic nephropathy, adiposity and insulin secretion in American Indians.

A prior genome-wide association study (GWAS) in Pima Indians identified a variant within PFKFB2 (rs17258746) associated with body mass index (BMI). PFKFB2 encodes 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase isoform 2, which plays a role in glucose metabolism. To follow-up on the GWAS, tag SNPs across PFKFB2 were genotyped in American Indians (AI) who had longitudinal data on BMI (n = 6839), type 2 diabetes (T2D; n = 7710), diabetic nephropathy (DN; n = 2452), % body fat (n = 555) and insulin secretion (n = 298).

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.

Common genetic variation in and near the melanocortin 4 receptor gene (MC4R) is associated with body mass index in American Indian adults and children.

Six rare functional coding mutations were previously identified in melanocortin 4 receptor (MC4R) in 6,760 American Indians. Individuals heterozygous for one of these mutations become obese while young. We now investigate whether common non-coding variation near MC4R also contributes to obesity.

Common genetic variation in the glucokinase gene (GCK) is associated with type 2 diabetes and rates of carbohydrate oxidation and energy expenditure.

Aims/hypothesis: Glucokinase (GCK) plays a role in glucose metabolism and glucose-stimulated insulin secretion. Rare mutations in GCK cause MODY. We investigated whether common variation (minor allele frequency ≥0.

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.

A genome-wide association study in American Indians implicates DNER as a susceptibility locus for type 2 diabetes.

Most genetic variants associated with type 2 diabetes mellitus (T2DM) have been identified through genome-wide association studies (GWASs) in Europeans. The current study reports a GWAS for young-onset T2DM in American Indians. Participants were selected from a longitudinal study conducted in Pima Indians and included 278 cases with diabetes with onset before 25 years of age, 295 nondiabetic controls ≥45 years of age, and 267 siblings of cases or controls.

MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation.

To identify genes that affect body mass index (BMI) in American Indians who are predominately of Pima Indian heritage, we previously completed a genome-wide association study in 1120 American Indians. That study also included follow-up genotyping for 9 SNPs in 2133 additional subjects. A comprehensive follow-up study has subsequently been completed where 292 SNPs were genotyped in 3562 subjects, of which 128 SNPs were assessed for replication in 3238 additional subjects.

Strong parent-of-origin effects in the association of KCNQ1 variants with type 2 diabetes in American Indians.

Parent-of-origin effects were observed in an Icelandic population for several genetic variants associated with type 2 diabetes, including those in KLF14 (rs4731702), MOB2 (rs2334499), and KCNQ1 (rs2237892, rs231362). We analyzed parent-of-origin effects for these variants, along with two others in KCNQ1 identified in previous genome-wide association studies (rs2237895, rs2299620), in 7,351 Pima Indians from 4,549 nuclear families; 34% of participants had diabetes. In a subset of 287 normoglycemic individuals, acute insulin secretion was measured by an intravenous glucose tolerance test.

Identification of genetic variation that determines human trehalase activity and its association with type 2 diabetes.

A prior linkage scan in Pima Indians identified a putative locus for type two diabetes (T2D) and body mass index (BMI) on chromosome 11q23-25. Association mapping across this region identified single nucleotide polymorphisms (SNPs) in the trehalase gene (TREH) that were associated with T2D. To assess the putative connection between trehalase activity and T2D, we performed a linkage study for trehalase activity in 570 Pima Indians who had measures of trehalase activity.