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.


Journal Article

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.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.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.

Full Text

Duke Authors

Cited Authors

  • Cornes, BK; Brody, JA; Nikpoor, N; Morrison, AC; Chu, H; Ahn, BS; Wang, S; Dauriz, M; Barzilay, JI; Dupuis, J; Florez, JC; Coresh, J; Gibbs, RA; Kao, WHL; Liu, C-T; McKnight, B; Muzny, D; Pankow, JS; Reid, JG; White, CC; Johnson, AD; Wong, TY; Psaty, BM; Boerwinkle, E; Rotter, JI; Siscovick, DS; Sladek, R; Meigs, JB

Published Date

  • June 2014

Published In

Volume / Issue

  • 7 / 3

Start / End Page

  • 374 - 382

PubMed ID

  • 24951664

Pubmed Central ID

  • 24951664

Electronic International Standard Serial Number (EISSN)

  • 1942-3268

International Standard Serial Number (ISSN)

  • 1942-325X

Digital Object Identifier (DOI)

  • 10.1161/CIRCGENETICS.113.000169


  • eng