In:
Circulation: Cardiovascular Genetics, Ovid Technologies (Wolters Kluwer Health), Vol. 7, No. 3 ( 2014-06), p. 374-382
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1942-325X
,
1942-3268
DOI:
10.1161/CIRCGENETICS.113.000169
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2014
detail.hit.zdb_id:
2927603-2
detail.hit.zdb_id:
2457085-0
Bookmarklink