title: Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol.
abstract: Cardiovascular disease (CVD) is the leading cause of death in developed countries. Plasma cholesterol level is a key risk factor in CVD pathogenesis. Genetic and dietary variation both influence plasma cholesterol; however, little is known about dietary interactions with genetic variants influencing the absorption and transport of dietary cholesterol. We sought to determine whether gut expressed variants predicting plasma cholesterol differentially affected the relationship between dietary and plasma cholesterol levels in 1,128 subjects (772/356 in the discovery/replication cohorts, respectively). Four single nucleotide polymorphisms (SNPs) within three genes (APOB, CETP, and NPC1L1) were significantly associated with plasma cholesterol in the discovery cohort. These were subsequently evaluated for gene-by-environment (GxE) interactions with dietary cholesterol for the prediction of plasma cholesterol, with significant findings tested for replication. Novel GxE interactions were identified and replicated for two variants: rs1042034, an APOB Ser4338Asn missense SNP and rs2072183 (in males only), a synonymous NPC1L1 SNP in linkage disequilibrium with SNPs 5' of NPC1L1. This study identifies the presence of novel GxE and gender interactions implying that differential gut absorption is the basis for the variant associations with plasma cholesterol. These GxE interactions may account for part of the "missing heritability" not accounted for by genetic associations.
authors.affiliation: Department of Medicine, Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Kim
authors.forename: Amber A
authors.initials: AA
authors.lastname: Burt
authors.forename: Jane E
authors.initials: JE
authors.lastname: Ranchalis
authors.forename: Ella R
authors.initials: ER
authors.lastname: Jarvik
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Rosenthal
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Hatsukami
authors.forename: Clement E
authors.initials: CE
authors.lastname: Furlong
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
mesh_terms: D000328:Adult; D001055:Apolipoproteins B / Q000235:genetics*; D002784:Cholesterol / Q000097:blood*; D002791:Cholesterol, Dietary / Q000097:blood*; D004032:Diet; D005260:Female; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D020641:Polymorphism, Single Nucleotide
chemical_list: D001055:Apolipoproteins B; D002791:Cholesterol, Dietary; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; D002784:Cholesterol