04045nas a2200733 4500008004100000022001400041245022200055210006900277260001300346300001200359490000600371520185400377653000902231653002202240653001002262653001802272653003202290653001902322653005302341653003002394653001202424653001102436653001902447653002202466653003402488653001302522653004002535653001902575653001102594653001202605653000902617653001602626653003602642653002702678100002302705700002302728700002102751700002402772700001402796700002002810700001602830700001802846700002402864700001902888700002002907700001802927700002202945700002002967700001802987700002203005700001703027700002103044700002103065700002203086700002303108700001803131700002003149700002103169700002203190700002403212700001903236700002003255856003603275 2014 eng d a1942-326800aAssociation 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.0 aAssociation of levels of fasting glucose and insulin with rare v c2014 Jun a374-3820 v73 a
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.
10aAged10aAged, 80 and over10aAging10aBlood Glucose10aChromosomes, Human, Pair 1110aCohort Studies10aDeath Domain Receptor Signaling Adaptor Proteins10aDiabetes Mellitus, Type 210aFasting10aFemale10aGene Frequency10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aGuanine Nucleotide Exchange Factors10aHeart Diseases10aHumans10aInsulin10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA1 aCornes, Belinda, K1 aBrody, Jennifer, A1 aNikpoor, Naghmeh1 aMorrison, Alanna, C1 aChu, Huan1 aAhn, Byung, Soo1 aWang, Shuai1 aDauriz, Marco1 aBarzilay, Joshua, I1 aDupuis, Josée1 aFlorez, Jose, C1 aCoresh, Josef1 aGibbs, Richard, A1 aKao, Linda, W H1 aLiu, Ching-Ti1 aMcKnight, Barbara1 aMuzny, Donna1 aPankow, James, S1 aReid, Jeffrey, G1 aWhite, Charles, C1 aJohnson, Andrew, D1 aWong, Tien, Y1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aSiscovick, David, S1 aSladek, Robert1 aMeigs, James, B uhttps://chs-nhlbi.org/node/6555