Apolipoprotein B genetic variants modify the response to fenofibrate: a GOLDN study

Wojczynski, Mary K.; Gao, Guimin; Borecki, Ingrid B.; Hopkins, Paul N.; Parnell, Laurence D.; Lai, Chao‐Qiang; Ordovas, José M.; Chung, Byung Hong; Arnett, Donna K.

doi:10.1194/jlr.p001834

Cited by 30 publications

(22 citation statements)

References 45 publications

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“…APOB SNP rs676210 ( r 2 = 0.996) was associated with a genotype-dependent response to fenofi brate ( 41 ). This is consistent with the GxE interaction we observed, and based on differential dietary cholesterol absorption or processing by an APOB variant in LD with this SNP .…”

Section: Discussionsupporting

confidence: 77%

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

Kim

Burt

Ranchalis

et al. 2013

Journal of Lipid Research

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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...

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Section: Discussionsupporting

confidence: 77%

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

Kim

Burt

Ranchalis

et al. 2013

Journal of Lipid Research

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“…We indeed found the greatest reductions in TC and LDL-C concentrations in homozygous G carriers of SNP rs676210 in the APOB gene. It is not known how this polymorphism influences TC and LDL-C responses to GH, but one possible explanation is that it promotes structural changes in APOB, affecting the conversion of VLDL to LDL (36,37,38). This could result in a reduction in the number of VLDL particles, or it might affect VLDL surface properties, or both.…”

Section: Snpsmentioning

confidence: 99%

Genotypes associated with lipid metabolism contribute to differences in serum lipid profile of GH-deficient adults before and after GH replacement therapy

Barbosa

Glad

Nilsson

et al. 2012

European Journal of Endocrinology

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ObjectiveGH deficiency (GHD) in adults is associated with an altered serum lipid profile that responds to GH replacement therapy (GHRT). This study evaluated the influence of polymorphisms in genes related to lipid metabolism on serum lipid profile before and after 1 year of GHRT in adults.Design and methodsIn 318 GHD patients, total cholesterol (TC) serum concentrations, LDL-C, HDL-C, and triglycerides (TG) were assessed. Using a candidate gene approach, 20 single nucleotide polymorphisms (SNPs) were genotyped. GH dose was individually titrated to obtain normal serum IGF1 concentrations.ResultsAt baseline, the minor alleles of cholesteryl ester transfer protein (CETP) gene SNPs rs708272 and rs1800775 were associated with higher serum TC and apolipoprotein E (APOE) gene SNP rs7412 with lower TC concentrations;CETPSNPs rs708272, rs1800775, and rs3764261 and apolipoprotein B (APOB) gene SNP rs693 with higher serum HDL-C;APOESNP rs7412, peroxisome proliferator-activated receptor gamma (PPARG) gene SNP rs10865710 with lower LDL-C, andCETPSNP rs1800775 with higher LDL-C; andAPOE/C1/C4/C2cluster SNP rs35136575 with lower serum TG. After treatment,APOBSNP rs676210 GG genotype was associated with larger reductions in TC and LDL-C andPPARGSNP rs10865710 CC genotype with greater TC reduction. All associations remained significant when adjusted for age, sex, and BMI.ConclusionsIn GHD adults, multiple SNPs in genes related to lipid metabolism contributed to individual differences in baseline serum lipid profile. The GH treatment response in TC and LDL-C was influenced by polymorphisms in theAPOBandPPARGgenes.

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“…We then tested SNP associations with changes in TG levels post meal using slope of growth curve modeling (43), which distinguishes between TG appearance (0-3.5 h) and clearance (3.5-6.0 h) phases. As shown in Table 2, three common SNPs near the distal first exon 1D (rs304763, rs304798, rs304802) associated with slower TG appearance (or negative  estimate) and three other SNPs with delayed TG removal (rs37920, rs13228738, rs3211842).…”

Section: Snps Align Near Sites For Ppar and Dna Methylation In Adipomentioning

confidence: 99%

Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD36

Love‐Gregory

Kraja

Allum

et al. 2016

Journal of Lipid Research

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Elevated fasting lipid levels have traditionally been associated with increased risk of heart disease, diabetes, and stroke. More recently, similar and independent associations were found with levels of nonfasting or postprandial lipids (1, 2). Nonfasting measurements incorporate those of chylomicrons (CMs) produced in response to dietary fat Abstract Cluster of differentiation 36 (CD36) variants influence fasting lipids and risk of metabolic syndrome, but their impact on postprandial lipids, an independent risk factor for cardiovascular disease, is unclear. We determined the effects of SNPs within a 410 kb region encompassing CD36 and its proximal and distal promoters on chylomicron (CM) remnants and LDL particles at fasting and at 3.5 and 6 h following a high-fat meal (Genetics of Lipid Lowering Drugs and Diet Network study, n = 1,117). Five promoter variants associated with CMs, four with delayed TG clearance and five with LDL particle number. To assess mechanisms underlying the associations, we queried expression quantitative trait loci, DNA methylation, and ChIP-seq datasets for adipose and heart tissues that function in postprandial lipid clearance. Several SNPs that associated with higher serum lipids correlated with lower adipose and heart CD36 mRNA and aligned to active motifs for PPAR, a major CD36 regulator. The SNPs also associated with DNA methylation sites that related to reduced CD36 mRNA and higher serum lipids, but mixed-model analyses indicated that the SNPs and methylation independently influence CD36 mRNA. The findings support contributions of CD36 SNPs that reduce

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Apolipoprotein B genetic variants modify the response to fenofibrate: a GOLDN study

Cited by 30 publications

References 45 publications

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

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

Genotypes associated with lipid metabolism contribute to differences in serum lipid profile of GH-deficient adults before and after GH replacement therapy

Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD36

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