TY - JOUR T1 - 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. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Cornes, Belinda K A1 - Brody, Jennifer A A1 - Nikpoor, Naghmeh A1 - Morrison, Alanna C A1 - Chu, Huan A1 - Ahn, Byung Soo A1 - Wang, Shuai A1 - Dauriz, Marco A1 - Barzilay, Joshua I A1 - Dupuis, Josée A1 - Florez, Jose C A1 - Coresh, Josef A1 - Gibbs, Richard A A1 - Kao, W H Linda A1 - Liu, Ching-Ti A1 - McKnight, Barbara A1 - Muzny, Donna A1 - Pankow, James S A1 - Reid, Jeffrey G A1 - White, Charles C A1 - Johnson, Andrew D A1 - Wong, Tien Y A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Sladek, Robert A1 - Meigs, James B KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Glucose KW - Chromosomes, Human, Pair 11 KW - Cohort Studies KW - Death Domain Receptor Signaling Adaptor Proteins KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Gene Frequency KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Guanine Nucleotide Exchange Factors KW - Heart Diseases KW - Humans KW - Insulin KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA AB -

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-dependent transcriptional activity.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951664?dopt=Abstract ER -