title: Systems genetics analysis of gene-by-environment interactions in human cells.
abstract: Gene by environment (GxE) interactions are clearly important in many human diseases, but they have proven to be difficult to study on a molecular level. We report genetic analysis of thousands of transcript abundance traits in human primary endothelial cell (EC) lines in response to proinflammatory oxidized phospholipids implicated in cardiovascular disease. Of the 59 most regulated transcripts, approximately one-third showed evidence of GxE interactions. The interactions resulted primarily from effects of distal-, trans-acting loci, but a striking example of a local-GxE interaction was also observed for FGD6. Some of the distal interactions were validated by siRNA knockdown experiments, including a locus involved in the regulation of multiple transcripts involved in the ER stress pathway. Our findings add to the understanding of the overall architecture of complex human traits and are consistent with the possibility that GxE interactions are responsible, in part, for the failure of association studies to more fully explain common disease variation.
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, CA, 90095, USA. casey.romanoski@ucla.edu
authors.forename: Casey E
authors.initials: CE
authors.lastname: Romanoski
authors.forename: Sangderk
authors.initials: S
authors.lastname: Lee
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Kim
authors.forename: Leslie
authors.initials: L
authors.lastname: Ingram-Drake
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Plaisier
authors.forename: Roumyana
authors.initials: R
authors.lastname: Yordanova
authors.forename: Charles
authors.initials: C
authors.lastname: Tilford
authors.forename: Bo
authors.initials: B
authors.lastname: Guan
authors.forename: Aiqing
authors.initials: A
authors.lastname: He
authors.forename: Peter S
authors.initials: PS
authors.lastname: Gargalovic
authors.forename: Todd G
authors.initials: TG
authors.lastname: Kirchgessner
authors.forename: Judith A
authors.initials: JA
authors.lastname: Berliner
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004777:Environment; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D010713:Phosphatidylcholines / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D034741:RNA, Small Interfering / Q000235:genetics; D049490:Systems Biology; D014158:Transcription, Genetic
chemical_list: D010713:Phosphatidylcholines; D034741:RNA, Small Interfering; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine