Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol

Abstract

This article is available online at http://www.jlr.org Supplementary key words dietary cholesterol • total cholesterol • cardiovascular disease • Niemann-Pick C1-like 1 Cardiovascular disease (CVD), including coronary heart disease and carotid artery disease (CAAD), is the leading cause of death in developed countries, accounting for approximately one-third of all deaths in adults over age 35 ( 1 ). One of the key risk factors for CVD is hypercholesterolemia ( 2 ), with epidemiologic studies demonstrating a graded relationship between total plasma cholesterol and CVD risk ( 3 ). Levels of total cholesterol and other lipids and lipoproteins are both heritable and targets for pharmacologic and lifestyle interventions ( 4 ). One of the primary methods of lifestyle intervention to alter lipid levels is through dietary changes, such as decreasing total fat intake ( 5, 6 ).Genome-wide association studies (GWASs) have implicated numerous genetic loci for association with total cholesterol levels. A recent meta-analysis by Teslovich et al. ( 7 ) of over 100,000 individuals of European ancestry confi rmed numerous previous GWAS fi ndings and identifi ed novel variants and loci for prediction of total lipid phenotypes, including total cholesterol levels.While genetic evidence is accumulating for many of these loci, less is known about the specifi c mechanisms through which these genetic variants affect cholesterol levels. We hypothesized that one pathway through which these genetic variants could alter cholesterol homeostasis is through differential absorption or processing of dietary 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 infl uence plasma cholesterol; however, little is known about dietary interactions with genetic variants infl uencing 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 signifi cantly associated with plasma cholesterol in the discovery cohort. These were subsequently evaluated for geneby-environment (GxE) interactions with dietary cholesterol for the prediction of plasma cholesterol, with signifi cant fi ndings tested for replication. Novel GxE interactions were identifi ed 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 identifi es 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" no...

PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

“…Further work is needed to elaborate the role that PCIF1 plays in PLTPa. on lipid levels ( 47,59 ), leading to a more conservative estimate of the effect of PLTPa on CAAD status.…”

“…The study population is a subset (n = 1,115) of the previously described CLEAR study ( 8,(10)(11)(12)(40)(41)(42)(43)(44)(45)(46)(47) PLTP region SNP associations with PLTPa. SNPs with у 1% frequency identifi ed in the PLTP region between 50 kb upstream of the fi rst codon or downstream of the last (n = 124 SNPs) were included in our analyses of the genetic predictors of PLTPa.…”

“…Therefore, in the model predicting CAAD status, we adjusted PLTPa for the effects of statin use by subtracting the covariate-adjusted difference in PLTPa from statin use in controls ( Ϫ 1.02, n = 601) using a previously described method ( 47,59,60 ).…”

Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project

“…One of these hypotheses is that geneby-environment interactions among common SNVs comprise a large portion of heritability ( 18,19 ). Given the wide variety of pharmacologic and dietary determinants on PON1 expression and enzyme activity ( 20 ), the potential interaction of these environmental factors with PON1 variants could represent another important source of trait heritability.…”

Potential Effects of NPC1L1 Polymorphisms in Protecting against Clinical Disease in a Chinese Family with Sitosterolaemia

“…The rs2072183 polymorphism is the top SNP within the NPC1L1 gene most significantly associated with an increased plasma LDL-C level according to a genomewide analysis of Caucasians. However, this polymorphism appears to be associated with reduced LDL-C levels in East Asians 17) , and other recent studies have demonstrated that the rs2072183 polymorphism is associated with increased cholesterol levels in men only and may interact with dietary cholesterol to determine the cholesterol levels 18,19) . It is also possible that mutations in NPC1L1 or polymorphisms in some other genes influencing cholesterol absorption or other pathways inherited from the mother, who also had a low LDL-C level (1.7 mmol/L), may have contributed to the reduced plasma sitosterol, campesterol and LDL-C levels in the affected sibling relative to the proband.…”