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.

TitleAssociation 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 TypeJournal Article
Year of Publication2014
AuthorsCornes, BK, Brody, JA, Nikpoor, N, Morrison, AC, Chu, H, Ahn, BSoo, Wang, S, Dauriz, M, Barzilay, JI, Dupuis, J, Florez, JC, Coresh, J, Gibbs, RA, Kao, WHLinda, 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
JournalCirc Cardiovasc Genet
Volume7
Issue3
Pagination374-382
Date Published2014 Jun
ISSN1942-3268
KeywordsAged, Aged, 80 and over, Aging, Blood Glucose, Chromosomes, Human, Pair 11, Cohort Studies, Death Domain Receptor Signaling Adaptor Proteins, Diabetes Mellitus, Type 2, Fasting, Female, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Genomics, Guanine Nucleotide Exchange Factors, Heart Diseases, Humans, Insulin, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA
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.

DOI10.1161/CIRCGENETICS.113.000169
Alternate JournalCirc Cardiovasc Genet
PubMed ID24951664
PubMed Central IDPMC4066205
Grant ListR01 DK078616 / DK / NIDDK NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
N01HC55222 / HC / NHLBI NIH HHS / United States
HHSN268201000010C / HL / NHLBI NIH HHS / United States
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RC2 HL102419 / HL / NHLBI NIH HHS / United States
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HHSN268201100008C / HL / NHLBI NIH HHS / United States
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R01DK078616 / DK / NIDDK NIH HHS / United States
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HHSN268201100008I / HL / NHLBI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
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HHSN268201100009C / / PHS HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
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R01 HL105756 / HL / NHLBI NIH HHS / United States
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P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
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HHSN268201200036C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
N01HC85086 / HC / NHLBI NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
HHSN2682011000012C / / PHS HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
N01HC85082 / HC / NHLBI NIH HHS / United States
HHSN268201100007C / / PHS HHS / United States
HHSN268200800007C / / PHS HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
HHSN268201200036C / / PHS HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
N01HC85083 / HC / NHLBI NIH HHS / United States
HHSN268201000012C / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
AG023629 / AG / NIA NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States
HHSN268201100001C / WH / WHI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
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