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. doi: 10.1161/CIRCGENETICS.113.000169.

Abstract

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.

Keywords: genetic epidemiology; glucose; human genetics; insulin; molecular genetics.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aging / genetics*
  • Blood Glucose / metabolism*
  • Chromosomes, Human, Pair 11 / genetics*
  • Cohort Studies
  • Death Domain Receptor Signaling Adaptor Proteins / genetics*
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / genetics*
  • Fasting / blood
  • Female
  • Gene Frequency
  • Genetic Variation*
  • Genome-Wide Association Study
  • Genomics
  • Guanine Nucleotide Exchange Factors / genetics*
  • Heart Diseases / epidemiology
  • Heart Diseases / genetics*
  • Humans
  • Insulin / blood*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA

Substances

  • Blood Glucose
  • Death Domain Receptor Signaling Adaptor Proteins
  • Guanine Nucleotide Exchange Factors
  • Insulin
  • MADD protein, human

Grant support