Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study

BMC Genetics

Myriam Fornage⁸  Kari E North¹  Steven Buyske⁹  Dana C Crawford^1,19  Charles Kooperberg^1,16  Loïc Le Marchand^1,17  Christopher Haiman^1,17  Jose Luis Ambite^1,11  Garnet Anderson^1,16  Kristin Brown-Gentry^1,19  Chris S Carlson^1,16  Iona Cheng^1,15  Barbara Cochran²  David J Duggan⁷  Charles B Eaton^1,10  Nora Franceschini^1,18  Jeff Haessler^1,16  Brian E Henderson^1,17  Karen C Johnson^1,13  P Miguel Quibrera^1,18  Ralph V Shohet⁶  Lynne R Wilkens^1,12  Fred R Schumacher^1,17  Lucia Hindorff^1,14  Shelley A Cole⁵  Petra Bůžková³  Logan Dumitrescu^1,19  Cara L Carty^1,16  Kira C Taylor⁴ 

[1] Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA;Sponsored Programs, Baylor College of Medicine, Houston, TX, USA;Department of Biostatistics, University of Washington, Seattle, WA, USA;Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, Louisville, KY, USA;Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA;Center of Cardiovascular Research, Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA;Integrated Cancer Genomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA;Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, TX, USA;Department of Statistics and Biostatistics, Rutgers University, Piscataway, NJ, USA;Department of Family Medicine and Community Health, Alpert Medical School of Brown University, Providence, RI, USA;Information Sciences Institute, University of Southern California, Los Angeles, CA, USA;Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA;Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA;Office of Population Genomics, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA;Cancer Research Center, University of Hawaii, Honolulu, HI, USA;Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA;Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA;Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA

关键词: Association study;    Sex-specific effect;    Heterogeneity;    Cardiovascular disease;    Genetics;    Lipids;   

Others  :  1087183
DOI  :  10.1186/1471-2156-14-33

 received in 2012-08-14, accepted in 2013-04-17,  发布年份 2013

【 摘 要 】

Background

High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels are influenced by both genes and the environment. Genome-wide association studies (GWAS) have identified ~100 common genetic variants associated with HDL-C, LDL-C, and/or TG levels, mostly in populations of European descent, but little is known about the modifiers of these associations. Here, we investigated whether GWAS-identified SNPs for lipid traits exhibited heterogeneity by sex in the Population Architecture using Genomics and Epidemiology (PAGE) study.

Results

A sex-stratified meta-analysis was performed for 49 GWAS-identified SNPs for fasting HDL-C, LDL-C, and ln(TG) levels among adults self-identified as European American (25,013). Heterogeneity by sex was established when p_het < 0.001. There was evidence for heterogeneity by sex for two SNPs for ln(TG) in the APOA1/C3/A4/A5/BUD13 gene cluster: rs28927680 (p_het = 7.4x10^-7) and rs3135506 (p_het = 4.3x10^-4), one SNP in PLTP for HDL levels (rs7679; p_het = 9.9x10^-4), and one in HMGCR for LDL levels (rs12654264; p_het = 3.1x10^-5). We replicated heterogeneity by sex in five of seventeen loci previously reported by genome-wide studies (binomial p = 0.0009). We also present results for other racial/ethnic groups in the supplementary materials, to provide a resource for future meta-analyses.

Conclusions

We provide further evidence for sex-specific effects of SNPs in the APOA1/C3/A4/A5/BUD13 gene cluster, PLTP, and HMGCR on fasting triglyceride levels in European Americans from the PAGE study. Our findings emphasize the need for considering context-specific effects when interpreting genetic associations emerging from GWAS, and also highlight the difficulties in replicating interaction effects across studies and across racial/ethnic groups.

【 授权许可】

   
2013 Taylor et al.; licensee BioMed Central Ltd.

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