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Open Access Research article

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

Kira C Taylor12*, Cara L Carty3, Logan Dumitrescu4, Petra Bůžková5, Shelley A Cole6, Lucia Hindorff7, Fred R Schumacher8, Lynne R Wilkens9, Ralph V Shohet10, P Miguel Quibrera1, Karen C Johnson11, Brian E Henderson128, Jeff Haessler3, Nora Franceschini1, Charles B Eaton13, David J Duggan14, Barbara Cochran15, Iona Cheng16, Chris S Carlson3, Kristin Brown-Gentry4, Garnet Anderson3, Jose Luis Ambite17, Christopher Haiman128, Loïc Le Marchand8, Charles Kooperberg3, Dana C Crawford184, Steven Buyske19, Kari E North120, Myriam Fornage2122 and for the PAGE Study

Author Affiliations

1 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

2 Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, Louisville, KY, USA

3 Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

4 Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA

5 Department of Biostatistics, University of Washington, Seattle, WA, USA

6 Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA

7 Office of Population Genomics, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

8 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

9 Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA

10 Center of Cardiovascular Research, Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA

11 Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

12 Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, USA

13 Department of Family Medicine and Community Health, Alpert Medical School of Brown University, Providence, RI, USA

14 Integrated Cancer Genomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA

15 Sponsored Programs, Baylor College of Medicine, Houston, TX, USA

16 Cancer Research Center, University of Hawaii, Honolulu, HI, USA

17 Information Sciences Institute, University of Southern California, Los Angeles, CA, USA

18 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA

19 Department of Statistics and Biostatistics, Rutgers University, Piscataway, NJ, USA

20 Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

21 Division of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Sciences Center at Houston, Houston, TX, USA

22 Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, TX, USA

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BMC Genetics 2013, 14:33  doi:10.1186/1471-2156-14-33

Published: 1 May 2013

Abstract

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 phet < 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 (phet = 7.4x10-7) and rs3135506 (phet = 4.3x10-4), one SNP in PLTP for HDL levels (rs7679; phet = 9.9x10-4), and one in HMGCR for LDL levels (rs12654264; phet = 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.

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