INSIG2 SNPs associated with obesity and glucose homeostasis traits in Hispanics: the IRAS Family Study

Abstract

The genome-wide association study by Herbert et al. identified the INSIG2 single-nucleotide polymorphism (SNP) rs7566605 as contributing to increased BMI in ethnically distinct cohorts. The present study sought to further clarify the matter, by testing whether SNPs of INSIG2 influenced quantitative adiposity or glucose homeostasis traits in Hispanics of the Insulin Resistance Atherosclerosis Family Study (IRASFS). Using a tagging SNP approach, rs7566605 and 31 additional SNPs were genotyped in 1,425 IRASFS Hispanics. SNPs were tested for association with six adiposity measures: BMI, waist circumference (WAIST), waist-to-hip ratio (WHR), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and VAT to SAT ratio (VSR). SNPs were also tested for association with fasting glucose (GFAST), fasting insulin (FINS), and three measures obtained from the frequently sampled intravenous glucose tolerance test: insulin sensitivity (S(I)), acute insulin response (AIR), and disposition index (DI). Most prominent association was observed with direct computed tomography (CT)-measured adiposity phenotypes, including VAT, SAT, and VSR (P values range from 0.007 to 0.044 for rs17586756, rs17047718, rs17047731, rs9308762, rs12623648, and rs11673900). Multiple SNP associations were observed with all glucose homeostasis traits (P values range from 0.001 to 0.031 for rs17047718, rs17047731, rs2161829, rs10490625, rs889904, and rs12623648). Using BMI as a covariate in evaluation of glucose homeostasis traits slightly reduced their association. However, association with adiposity and glucose homeostasis phenotypes is not significant following multiple comparisons adjustment. Trending association after multiple comparisons adjustment remains suggestive of a role for genetic variation of INSIG2 in obesity, but these results require validation.

Figure 1

Single SNP Genotypic Association (2df test) Results in the IRASFS Hispanics. The minor allele frequency (MAF) and SNP designations are in the far left columns. Results adjusted by standard parameters (age, gender, center) and those adjusted by standard parameters and BMI are presented. SAT is not included in the BMI adjusted results due to high correlation with BMI (r²≥.90). Associated P-values are in bold (P<.05) and those trending towards association are italicized (P<.10). A dot (“.”) represents no association. These results have not been adjusted for multiple comparisons or inter-SNP correlation. BMI, WAIST, and BMI-ADJUSTED GFAST not included below due to scarce association. Body Mass Index (BMI); Waist Circumference (WAIST); Waist to Hip Ratio (WHR); Visceral Adipose Tissue (VAT); Subcutaneous Adipose Tissue (SAT); Visceral to Subcutaneous Ratio (VSR); Fasting Glucose (GFAST); Fasting Insulin (FINS); Insulin Sensitivity (SI); Acute Insulin Response (AIR); Disposition Index (DI)

Figure 2

Global P-values from QPDT association analysis of single and multi-marker SNP haplotypes with adiposity and glucose homeostasis phenotypes. Italicized numbers represent trending association of a single-SNP or haplotype with a trait (P<.08) and bold numbers in shaded boxes represent association (P<.05). Only those phenotypes with two or more trending/associated elements are shown here, others are excluded. SAT is not included under BMI adjusted results due to high correlation with BMI. Results adjusted for age, gender, and center are on the left and those adjusted for age, gender, center, and BMI are on the right. These results have not been adjusted for multiple comparisons or inter-SNP correlation. Waist to Hip Ratio (WHR); Visceral Adipose Tissue (VAT); Subcutaneous Adipose Tissue (SAT); Visceral to Subcutaneous Ratio (VSR); Fasting Glucose (GFAST); Fasting Insulin (FINS); Insulin Sensitivity (SI); Acute Insulin Response (AIR); Disposition Index (DI)