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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.

bmc genomic data

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