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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.

Publication ,  Journal Article
Cornes, BK; Brody, JA; Nikpoor, N; Morrison, AC; Chu, H; Ahn, BS; Wang, S; Dauriz, M; Barzilay, JI; Dupuis, J; Florez, JC; Coresh, J ...
Published in: Circ Cardiovasc Genet
June 2014

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.

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Published In

Circ Cardiovasc Genet

DOI

EISSN

1942-3268

Publication Date

June 2014

Volume

7

Issue

3

Start / End Page

374 / 382

Location

United States

Related Subject Headings

  • Sequence Analysis, DNA
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Male
  • Insulin
  • Humans
  • Heart Diseases
  • Guanine Nucleotide Exchange Factors
  • Genomics
  • Genome-Wide Association Study
 

Citation

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Cornes, B. K., Brody, J. A., Nikpoor, N., Morrison, A. C., Chu, H., Ahn, B. S., … Meigs, J. B. (2014). 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. Circ Cardiovasc Genet, 7(3), 374–382. https://doi.org/10.1161/CIRCGENETICS.113.000169
Cornes, Belinda K., Jennifer A. Brody, Naghmeh Nikpoor, Alanna C. Morrison, Huan Chu, Byung Soo Ahn, Shuai Wang, et al. “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.Circ Cardiovasc Genet 7, no. 3 (June 2014): 374–82. https://doi.org/10.1161/CIRCGENETICS.113.000169.
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. 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. Circ Cardiovasc Genet. 2014 Jun;7(3):374–382.

Published In

Circ Cardiovasc Genet

DOI

EISSN

1942-3268

Publication Date

June 2014

Volume

7

Issue

3

Start / End Page

374 / 382

Location

United States

Related Subject Headings

  • Sequence Analysis, DNA
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Male
  • Insulin
  • Humans
  • Heart Diseases
  • Guanine Nucleotide Exchange Factors
  • Genomics
  • Genome-Wide Association Study