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Rare variant associations with waist-to-hip ratio in European-American and African-American women from the NHLBI-Exome Sequencing Project.

TitleRare variant associations with waist-to-hip ratio in European-American and African-American women from the NHLBI-Exome Sequencing Project.
Publication TypeJournal Article
Year of Publication2016
AuthorsKan M, Auer PL, Wang GT, Bucasas KL, Hooker S, Rodriguez A, Li B, Ellis J, L Cupples A, Chen Y-DIda, Dupuis J, Fox CS, Gross MD, Smith JD, Heard-Costa N, Meigs JB, Pankow JS, Rotter JI, Siscovick D, Wilson JG, Shendure J, Jackson R, Peters U, Zhong H, Lin D, Hsu L, Franceschini N, Carlson C, Abecasis G, Gabriel S, Bamshad MJ, Altshuler D, Nickerson DA, North KE, Lange LA, Reiner AP
Secondary AuthorsLeal SM
Corporate AuthorsNHLBI-Exome Sequencing Project
JournalEur J Hum Genet
Volume24
Issue8
Pagination1181-7
Date Published2016 08
ISSN1476-5438
KeywordsAdult, African Americans, Aged, Aged, 80 and over, Alleles, European Continental Ancestry Group, Exome, Female, Humans, I-kappa B Kinase, Middle Aged, Polymorphism, Genetic, Transcription Factors, Waist-Hip Ratio
Abstract

Waist-to-hip ratio (WHR), a relative comparison of waist and hip circumferences, is an easily accessible measurement of body fat distribution, in particular central abdominal fat. A high WHR indicates more intra-abdominal fat deposition and is an established risk factor for cardiovascular disease and type 2 diabetes. Recent genome-wide association studies have identified numerous common genetic loci influencing WHR, but the contributions of rare variants have not been previously reported. We investigated rare variant associations with WHR in 1510 European-American and 1186 African-American women from the National Heart, Lung, and Blood Institute-Exome Sequencing Project. Association analysis was performed on the gene level using several rare variant association methods. The strongest association was observed for rare variants in IKBKB (P=4.0 × 10(-8)) in European-Americans, where rare variants in this gene are predicted to decrease WHRs. The activation of the IKBKB gene is involved in inflammatory processes and insulin resistance, which may affect normal food intake and body weight and shape. Meanwhile, aggregation of rare variants in COBLL1, previously found to harbor common variants associated with WHR and fasting insulin, were nominally associated (P=2.23 × 10(-4)) with higher WHR in European-Americans. However, these significant results are not shared between African-Americans and European-Americans that may be due to differences in the allelic architecture of the two populations and the small sample sizes. Our study indicates that the combined effect of rare variants contribute to the inter-individual variation in fat distribution through the regulation of insulin response.

DOI10.1038/ejhg.2015.272
Alternate JournalEur J Hum Genet
PubMed ID26757982
PubMed Central IDPMC4970686
Grant ListR01 CA082659 / CA / NCI NIH HHS / United States
UL1 TR001070 / TR / NCATS NIH HHS / United States
R01 DK078616 / DK / NIDDK NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
R01 HL053560 / HL / NHLBI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
U01 DK078616 / DK / NIDDK NIH HHS / United States
R01 DK089256 / DK / NIDDK NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
T32 GM008307 / GM / NIGMS NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States