title: Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study.
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 (p(het) = 7.4 x 10(-7)) and rs3135506 (p(het) = 4.3 x 10(-4)one SNP in PLTP for HDL levels (rs7679; p(het) = 9.9 x 10(-4)), and one in HMGCR for LDL levels (rs12654264; p(het) = 3.1 x 10(-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.
authors: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. kctayl04@louisville.edu
authors: Kira C
authors: KC
authors: Taylor
authors: Cara L
authors: CL
authors: Carty
authors: Logan
authors: L
authors: Dumitrescu
authors: Petra
authors: P
authors: Bůžková
authors: Shelley A
authors: SA
authors: Cole
authors: Lucia
authors: L
authors: Hindorff
authors: Fred R
authors: FR
authors: Schumacher
authors: Lynne R
authors: LR
authors: Wilkens
authors: Ralph V
authors: RV
authors: Shohet
authors: P Miguel
authors: PM
authors: Quibrera
authors: Karen C
authors: KC
authors: Johnson
authors: Brian E
authors: BE
authors: Henderson
authors: Jeff
authors: J
authors: Haessler
authors: Nora
authors: N
authors: Franceschini
authors: Charles B
authors: CB
authors: Eaton
authors: David J
authors: DJ
authors: Duggan
authors: Barbara
authors: B
authors: Cochran
authors: Iona
authors: I
authors: Cheng
authors: Chris S
authors: CS
authors: Carlson
authors: Kristin
authors: K
authors: Brown-Gentry
authors: Garnet
authors: G
authors: Anderson
authors: Jose Luis
authors: JL
authors: Ambite
authors: Christopher
authors: C
authors: Haiman
authors: Loïc
authors: L
authors: Le Marchand
authors: Charles
authors: C
authors: Kooperberg
authors: Dana C
authors: DC
authors: Crawford
authors: Steven
authors: S
authors: Buyske
authors: Kari E
authors: KE
authors: North
authors: Myriam
authors: M
authors: Fornage
mesh_terms: D005260:Female; D018740:Genetic Heterogeneity; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008055:Lipids / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D044382:Population Groups / Q000235:genetics
chemical_list: D008055:Lipids
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