Faculty Collaboration Database

Genome-wide detection of allele specific copy number variation associated with insulin resistance in African Americans from the HyperGEN study. PLoS One 2011;6(8):e24052

Date

09/09/2011

Pubmed ID

21901158

Pubmed Central ID

PMC3162025

DOI

10.1371/journal.pone.0024052

Scopus ID

2-s2.0-80052067433 (requires institutional sign-in at Scopus site)   38 Citations

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.

Author List

Irvin MR, Wineinger NE, Rice TK, Pajewski NM, Kabagambe EK, Gu CC, Pankow J, North KE, Wilk JB, Freedman BI, Franceschini N, Broeckel U, Tiwari HK, Arnett DK

Author

Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Alleles
DNA Copy Number Variations
Fasting
Female
Genome-Wide Association Study
Humans
Hypertension
Insulin Resistance
Male
Middle Aged
Polymorphism, Single Nucleotide