title: 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.
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.
  
  
  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-dependent transcriptional activity.
authors.affiliation: General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Belinda K
authors.initials: BK
authors.lastname: Cornes
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Brody
authors.affiliation: Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Naghmeh
authors.initials: N
authors.lastname: Nikpoor
authors.affiliation: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.affiliation: Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Huan
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Byung Soo
authors.initials: BS
authors.lastname: Ahn
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona Medical School and Hospital Trust of Verona, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Dauriz
authors.affiliation: Division of Endocrinology, Kaiser Permanente of Georgia and Emory University School of Medicine.
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Barzilay
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.|National Heart, Lung, and Blood Institute's The Framingham Heart Study, Cardiovascular Epidemiology and Human Genomics Center, Framingham, MA, USA.
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Center for Human Genetic Research, Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.affiliation: Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.|Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, University of Texas Health Science Center, Houston, TX.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: W H Linda
authors.initials: WHL
authors.lastname: Kao
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Ching-Ti
authors.initials: CT
authors.lastname: Liu
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.|Department of Biostatistics, University of Washington, Seattle, WA, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: McKnight
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, University of Texas Health Science Center, Houston, TX.
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.affiliation: Division of Epidemiology and Community Health (J.S.P.), University of Minnesota, MN, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.affiliation: Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Reid
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: White
authors.affiliation: National Heart, Lung, and Blood Institute's The Framingham Heart Study, Cardiovascular Epidemiology and Human Genomics Center, Framingham, MA, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Duke-NUS Graduate Medical School, Singapore.|Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Tien Y
authors.initials: TY
authors.lastname: Wong
authors.affiliation: Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA; Group Health Research Institute, Group Health Cooperative, Seattle, WA.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.|Human Genome Sequencing Center, Baylor College of Medicine, University of Texas Health Science Center, Houston, TX.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Reasearch Institute and Department of Pediatrics, Harbor-UCLA Medical Center Torrance, California, USA.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.|Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, WA, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
authors.affiliation: Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Sladek
authors.affiliation: General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D001786:Blood Glucose / Q000378:metabolism*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D015331:Cohort Studies; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics*; D005215:Fasting / Q000097:blood; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D023281:Genomics; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006331:Heart Diseases / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D001786:Blood Glucose; D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; C105852:MADD protein, human
keywords: genetic epidemiology; glucose; human genetics; insulin; molecular genetics