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

• Type of Material: Article
• 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
• Language: English
• Date: 2014-06-01
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCGENETICS.113.000169
• Title of Journal or Parent Work: Circulation: Cardiovascular Genetics
• ISSN: 1942-325X
• Volume: 7
• Issue: 3
• Start Page: 374
• End Page: 382
• Grant/Funding Information: A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; also supported by R01DK078616, K24 DK080140 and an American Diabetes Association Mentored Post Doctoral Fellowship Award (Dr. Meigs).; The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195), and its contract with Affymetrix, Inc., for genome-wide genotyping services (Contract No. N02-HL-6-4278), for quality control by Framingham Heart Study investigators using genotypes in the SNP Health Association Resource (SHARe) project.; Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419).; Data for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium” was provided by Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities (ARIC) Study, L. Adrienne Cupples, principal investigator for the Framingham Heart Study, and Bruce Psaty, principal investigator for the Cardiovascular Health Study.; Additional support was provided through AG023629 from the National Institute on Aging (NIA).; The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN2682011000010C, HHSN2682011000011C, and HHSN2682011000012C).; Support was also received from the Baylor Genome Center (U54 HG003273); Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS).
• Keywords: DNA; Cardiovascular System & Cardiology; Cardiac & Cardiovascular Systems; RISK; POPULATION; PATHOPHYSIOLOGY; insulin; HUMAN GENE-EXPRESSION; GLYCEMIC TRAITS; human genetics; molecular genetics; WIDE ASSOCIATION; Genetics & Heredity; TRANSCRIPTION FACTOR; genetic epidemiology; Science & Technology; CARDIOVASCULAR HEALTH; BETA-CELL; glucose; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics; Biology, Physiology

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.