Association of Levels of Fasting Glucose and Insulin With Rare Variants at the Chromosome 11p11.2-MADD Locus Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study

• Authors: Belinda K. Cornes, Massachusetts General Hospital; Jennifer A. Brody, University of Washington; Naghmeh Nikpoor, McGill University; Alanna C. Morrison, University of Texas Houston; Huan Chu, McGill University; Byung Soo Ahn, McGill University; Shuai Wang, Boston University; Marco Dauriz, Massachusetts General Hospital; Joshua I. Barzilay, Emory University; Josee Dupuis, Boston University; Jose C. Florez, Massachusetts General Hospital; Josef Coresh, Johns Hopkins Medical Institutions; Richard A. Gibbs, University of Texas Houston; W.H. Linda Kao, Johns Hopkins University; Ching-Ti Liu, Boston University; Barbara McKnight, University of Washington; Donna Muzny, University of Texas Houston; James S. Pankow, University of Minnesota; Jeffrey G. Reid, Johns Hopkins University; Charles C. White, Boston University; Andrew D. Johnson, National Heart, Lung, and Blood Institute; Tien Y. Wong, Duke University; Bruce M. Psaty, University of Washington; Eric Boerwinkle, University of Texas Houston; Jerome I. Rotter, University of California Los Angeles; David S. Siscovick, University of Washington; Robert Sladek, McGill University; James B. Meigs, Massachusetts General Hospital
• Journal Title: Circulation: Cardiovascular Genetics
• Volume: Volume 7, Number 3
• Publisher: American Heart Association | 2014-06-01, Pages 374-382
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1161/CIRCGENETICS.113.000169
• Subjects: Health Sciences, Medicine and Surgery; Biology, Genetics; Biology, Physiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cardiac & Cardiovascular Systems; Genetics & Heredity; Cardiovascular System & Cardiology; genetic epidemiology; glucose; human genetics; insulin; molecular genetics; HUMAN GENE-EXPRESSION; TRANSCRIPTION FACTOR; CARDIOVASCULAR HEALTH; WIDE ASSOCIATION; GLYCEMIC TRAITS; BETA-CELL; DNA; POPULATION; RISK; PATHOPHYSIOLOGY

Abstract

Background-Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels. Methods and Results-Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10-3); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10-3). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity. Conclusions-Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1- dependenttranscriptional activity.