• Belinda K Cornes, Jennifer A Brody, Naghmeh Nikpoor, Alanna C Morrison, Huan Chu, Byung Soo Ahn, Shuai Wang, Marco Dauriz, Joshua I Barzilay, Josée Dupuis, Jose C Florez, Josef Coresh, Richard A Gibbs, Kao W H Linda WHL Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA., Ching-Ti Liu, Barbara McKnight, Donna Muzny, James S Pankow, Jeffrey G Reid, Charles C White, Andrew D Johnson, Tien Y Wong, Bruce M Psaty, Eric Boerwinkle, Jerome I Rotter, David S Siscovick, Robert Sladek, and James B Meigs.
• General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
• Circ Cardiovasc Genet. 2014 Jun 1; 7 (3): 374-382.

BackgroundCommon 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 ResultsSequencing (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.ConclusionsSequencing 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.© 2014 American Heart Association, Inc.

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