SORCS1: A Novel Human Type 2 Diabetes Susceptibility Gene Suggested by the Mouse

Abstract

OBJECTIVE—A small number of susceptibility genes for human type 2 diabetes have been identified by candidate gene analysis or positional cloning. Genes found to influence diabetes or related traits in mice are likely to be susceptibility genes in humans. SorCS1 is the gene identified as responsible for the mouse chromosome 19 T2dm2 quantitative trait locus for fasting insulin levels, acting via impaired insulin secretion and increased islet disruption in obese females. Genes that impair compensatory insulin secretion in response to obesity-induced insulin resistance may be particularly relevant to human diabetes. Thus, we sought to determine whether variation in the human SORCS1 gene was associated with diabetes-related traits. RESEARCH DESIGN AND METHODS—We assessed the contribution of variation in SORCS1 to human insulin–related traits in two distinct Mexican-American cohorts. One cohort (the Mexican-American Coronary Artery Disease [MACAD] cohort) consisted of nondiabetic individuals, allowing assessment of genetic association with subclinical intermediate insulin-related traits; the second cohort (the San Antonio Family Diabetes Study [SAFADS]) contained individuals with diabetes, allowing association analyses with overt disease. RESULTS—We first found association of SORCS1 single nucleotide polymorphisms and haplotypes with fasting insulin levels and insulin secretion in the MACAD cohort. Similar to our results in the mice, the genetic association was strongest in overweight women. We then observed association with diabetes risk and age at diagnosis in women of the SAFADS cohort. CONCLUSIONS—Identification of SORCS1 as a novel gene affecting insulin secretion and diabetes risk is likely to provide important insight into the biology of obesity-induced type 2 diabetes.