Epidemiology and genetic determinants of progressive deterioration of glycaemia in American Indians: the Strong Heart Family Study

Abstract

Aims/hypothesis Type 2 diabetes is a chronic, heterogeneous disease and a major risk factor for cardiovascular diseases. The underlying mechanisms leading to progression to type 2 diabetes are not fully understood and genetic tools may help to identify important pathways of glycaemic deterioration. Methods Using prospective data on American Indians from the Strong Heart Family Study, we identified 373 individuals defined as progressors (diabetes incident cases), 566 individuals with transitory impaired fasting glucose (IFG) and 1,011 controls (normal fasting glycaemia at all visits). We estimated the heritability (h2) of the traits and the evidence for association with 16 known variants identified in type 2 diabetes genome-wide association studies. Results We noted high h2 for diabetes progression (h2=0.65±0.16, p=2.7×10−6) but little contribution of genetic factors to transitory IFG (h2=0.09±0.10, p=0.19) for models adjusted for multiple risk factors. At least three variants (in WFS1, TSPAN8 and THADA) were nominally associated with diabetes progression in age- and sex-adjusted analyses with estimates showing the same direction of effects as reported in the discovery European ancestry studies. Conclusions/interpretation Our findings do not exclude these loci for diabetes susceptibility in American Indians and suggest phenotypic heterogeneity of the IFG trait, which may have implications for genetic studies when diagnosis is based on a single time-point measure.

Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study

“…In vitro and murine studies have shown that the overactivity of the potassium channels from overexpression of KCNQ1 can create a current across the plasma membrane and impair insulin secretion, thereby resulting in hyperglycemia ( McCarthy and Zeggini, 2009 ; Yamagata et al, 2011 ). In a study among American Indians from central Arizona, KCNQ1 variants were associated with incident diabetes ( Franceschini et al, 2013 ; Hanson et al, 2014 ). In our study, KCNQ1 variants are related to both a decrease in HOMA-IR (effect -0.11) and with an increase in cHOMA-B (effect 0.04).…”

Genetics of kidney disease and related cardiometabolic phenotypes in Zuni Indians: the Zuni Kidney Project

“…Genetic studies, including candidate gene and genome-wide association studies (GWAS), have been conducted to elucidate the effects of specific genes on the variation in CKD and cardiometabolic risk factors. These include studies conducted in Caucasians ( Hwang et al, 2007 ; Parsa et al, 2013 ), African Americans ( Edwards et al, 2008 ; Willer et al, 2013 ; Bidulescu et al, 2014 ), Asians ( Yamakawa-Kobayashi et al, 2012 ; Willer et al, 2013 ), Mexican Americans ( Farook et al, 2013 ; Thameem et al, 2013 ), Pima Indians ( Bian et al, 2013 ; Hanson et al, 2013 , 2014 ), and in the 13 American Indian tribes participating in the Strong Heart Family Study ( Franceschini et al, 2013 ; Voruganti et al, 2014 ). To decrease the burden of kidney disease and related intermediate phenotypes in the Zuni Pueblo, we established the Zuni Kidney Project (ZKP) in partnership with the Indian Health Service, University of New Mexico Health Sciences Center, Texas Biomedical Research Institute and Dialysis Clinic, Inc. (DCI; Stidley et al, 2002 ).…”