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

Kira C. Taylor, Cara L. Carty, Logan Dumitrescu, Petra Bůžková, Shelley A. Cole, Lucia Hindorff, Fred R. Schumacher, Lynne R. Wilkens, Ralph V. Shohet, P. Miguel Quibrera, Karen C. Johnson, Brian E. Henderson, Jeff Haessler, Nora Franceschini, Charles B. Eaton, David J. Duggan, Barbara Cochran, Iona Cheng, Chris S. Carlson, Kristin Brown-GentryGarnet Anderson, Jose L. Ambite, Christopher Haiman, Loïc Le Marchand, Charles Kooperberg, Dana C. Crawford, Steven Buyske, Kari E. North, Myriam Fornage

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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.

Original languageEnglish (US)
Article number33
JournalBMC genetics
StatePublished - May 1 2013

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


  • Association study
  • Cardiovascular disease
  • Genetics
  • Heterogeneity
  • Lipids
  • Sex-specific effect

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