Genome-Wide Detection of Allele Specific Copy Number Variation Associated with Insulin Resistance in African Americans from the HyperGEN Study

Marguerite R Irvin,Hemant K Tiwari,Jemma B Wilk,Nicholas M Pajewski,Jim Pankow,Barry I Freedman,Treva K Rice,Uli Broeckel,Donna K Arnett,Edmond K Kabagambe,Nathan E Wineinger,Nora Franceschini,Kari E North,Charles C Gu,Giorgio Sesti

doi:10.1371/journal.pone.0024052

Abstract

African Americans have been understudied in genome wide association studies of diabetes and related traits. In the current study, we examined the joint association of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with fasting insulin and an index of insulin resistance (HOMA-IR) in the HyperGEN study, a family based study with proband ascertainment for hypertension. This analysis is restricted to 1,040 African Americans without diabetes. We generated allele specific CNV genotypes at 872,243 autosomal loci using Birdsuite, a freely available multi-stage program. Joint tests of association for SNPs and CNVs were performed using linear mixed models adjusting for covariates and familial relationships. Our results highlight SNPs associated with fasting insulin and HOMA-IR (rs6576507 and rs8026527, 3.7*10−7≤P≤1.1*10−5) near ATPase, class V, type 10A (ATP10A), and the L Type voltage dependent calcium channel (CACNA1D, rs1401492, P≤5.2*10−6). ATP10A belongs to a family of aminophospholipid-transporting ATPases and has been associated with type 2 diabetes in mice. CACNA1D has been linked to pancreatic beta cell generation in mice. The two most significant copy variable markers (rs10277702 and rs361367; P<2.0*10−4) were in the beta variable region of the T-cell receptor gene (TCRVB). Human and mouse TCR has been shown to mimic insulin and its receptor and could contribute to insulin resistance. Our findings differ from genome wide association studies of fasting insulin and other diabetes related traits in European populations, highlighting the continued need to investigate unique genetic influences for understudied populations such as African Americans.

Highlights

Long term insulin resistance is the major precursor to type 2 diabetes (T2D), a condition which currently affects more than 10% of Americans older than 20 years of age [1,2]
The risk of developing insulin resistance and subsequent T2D varies between different ethnic populations and is at least two times greater among African Americans compared to Caucasians [3]
We report the most significant markers derived from the full model for each outcome. For both fasting insulin and Homeostasis Model Assessment Insulin Resistance Index (HOMA-IR) the most significant findings were not copy number variable and the model defaulted to a model of single nucleotide polymorphisms (SNPs) effects

Summary

Introduction

Long term insulin resistance is the major precursor to type 2 diabetes (T2D), a condition which currently affects more than 10% of Americans older than 20 years of age [1,2]. While there are various tests used to detect insulin resistance, fasting insulin levels and the Homeostasis Model Assessment Insulin Resistance Index (HOMA-IR) are widely used in population based studies [4] Based on these measures, the risk of developing insulin resistance and subsequent T2D varies between different ethnic populations and is at least two times greater among African Americans compared to Caucasians [3]. There is a need for such studies as replicated variants derived from Caucasian samples have not consistently generalized to T2D related risk in African Americans [6,7,8] This could be due to different disease pathology with unique genetic risk variants amongst African Americans or reflect differences in allele frequencies or patterns of linkage disequilibrium [6,9,10,11]

Methods

Results

Conclusion