Peroxisome proliferator-activated receptor genetic variation interacts with n6 and long-chain n3 fatty acid intake to affect total cholesterol and LDL-cholesterol concentrations in the Atherosclerosis Risk in Communities Study1-3

Human Genetics Center, University of Texas Health Science Center, Houston, TX 77030, USA.
American Journal of Clinical Nutrition (Impact Factor: 6.77). 07/2008; 87(6):1926-31.
Source: PubMed


Background:Peroxisomeproliferator-activatedreceptor-(PPARA) regulates the expression of genes involved in lipid metabolism. The bindingofpolyunsaturatedfattyacids(PUFAs)toPPARAresultsin rapidchangesintheexpressionofgenesinvolvedinlipidoxidation, with long-chain n3 fatty acids being potent activators of PPARA. Objective: We evaluated the potential effect modification of PPARA genetic variation on the association between PUFA intake, specificallyn6andlong-chainn3fattyacidintakes,andmultiple lipid measures in the large biethnic Atherosclerosis Risk in Com- munities (ARIC) Study. Design: Study participants (10 134 whites and 3480 African Amer- icans)wereselectedfromtheARICStudy—aprospectiveinvestigation of atherosclerosis and its clinical sequelae. Multiple linear regression models were used to assess the relation between PPARA genotypes, as well as dietary fatty acid intake, and baseline lipid measures. PPARA- specific effects of variation were assessed by including genotype-by- fatty acid interaction terms in each statistical model. Results: PPARA genotype frequencies were significantly different between whites and African Americans. No significant associations between lipid measures and PPARA genotype were observed in either whites or African Americans. Significant genotype-by-n6 fatty acid intake interactions were observed only in whites for the 3'untranslatedregion(UTR)G3Asinglenucleotidepolymorphism

115 Reads
  • Source
    • "With regard to the human PPARA gene, there are multiple synonymous and nonsynonymous genetic variants associated with metabolic features such as dyslipidemia, cardiovascular risk factors lipid concentrations, and type 2 diabetes development, localized in the coding and noncoding regions of the gene (Contreras et al., 2013). Among these located in the 3′ UTR region, there were G>A (rs6008259) and C>T (rs3892755) that were found as modifiers of association between plasma total cholesterol and low-density lipoprotein-cholesterol concentrations (Volcik et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The PPARA (peroxisome proliferator-activated receptor-alpha) gene encodes a nuclear receptor that plays an important role in fatty acid catabolism by transcriptional regulation of genes involved in fatty acid oxidation and can be considered as a candidate gene for fatness traits in the pig. The aim of the study was to search for a functional polymorphism in 3'UTR, their association with production traits and postnatal PPARA transcript level in two skeletal muscles (longissimus and semimembranosus) of five commercial pig breeds (Polish Landrace - PL, Polish Large White - PLW, Duroc, Pietrain and Pulawska). Altogether, 9 novel polymorphisms (8 SNP and 1 indel) were found in the 3'UTR. The in silico analysis revealed six putative microRNA target sequences in the analyzed region. The c.*636A>G substitution was widely distributed across breeds and located near the putative target sequence for miR-224. The relative PPARA transcript level was higher (P<0.05) in longissimus muscle of AA than in those of GG homozygous animals for SNP c.*636A>G. The luciferase assay revealed that miR-224 probably acts as a negative regulator of the PPARA expression in pig adipocytes (P = 2.9×10-7), but we did not observe the effect of the A or G alleles on the interaction between miR-224 and its putative target sequence. We hypothesize that the two predominant haplotypes, differing at 4 sites (including c.*636A>G), present different architecture of its 3'UTR and it could affect the level of the transcript. The c.*636A>G SNP, analyzed in PL and PLW, was significantly associated with backfat thickness at 3 points (P<0.05) and intramuscular fat content (P<0.01) in PL. Suggestive associations were found between 4 SNP (c.*321A>C, c.*324G>C, c.*626T>C and c.*636A>G) and fatty acid contents in longissimus muscle, subcutaneous and visceral fat tissue of PL, PLW, Duroc and Pietrain pigs. The PPARA mRNA level was higher in semimembranosus than in longissimus muscle (P = 8.38×10-12) in a general comparison and the same trend was found in most breeds (except for PL) and at all tested days of age (60, 90, 120, 150, 180 and 210). The effect of breed was highly significant in a general comparison (P = 0.48×10-8), but there was no common expression pattern in both muscles among different age groups. We conclude that the c.*636A>G SNP in the PPARA gene can be considered in PL breed as a useful genetic marker for adipose tissue accumulation.
    Journal of Animal Science 03/2014; 92(6). DOI:10.2527/jas.2013-7509 · 2.11 Impact Factor
  • Source
    • "For that, a dedicated web-service available online without fees [28] can be used. The results show that the input list of regulated transcripts and the output list of proposed regulatory candidates shared clusters related to fatty acid and cholesterol metabolisms (Table  5), which was expected considering roles of PPARs [22,29]. Importantly, clusters included fewer genes when calculated from the list of candidates than from the input list of regulated genes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Most of the existing methods to analyze high-throughput data are based on gene ontology principles, providing information on the main functions and biological processes. However, these methods do not indicate the regulations behind the biological pathways. A critical point in this context is the extraction of information from many possible relationships between the regulated genes, and its combination with biochemical regulations. This study aimed at developing an automatic method to propose a reasonable number of upstream regulatory candidates from lists of various regulated molecules by confronting experimental data with encyclopedic information. A new formalism of regulated reactions combining biochemical transformations and regulatory effects was proposed to unify the different mechanisms contained in knowledge libraries. Based on a related causality graph, an algorithm was developed to propose a reasonable set of upstream regulators from lists of target molecules. Scores were added to candidates according to their ability to explain the greatest number of targets or only few specific ones. By testing 250 lists of target genes as inputs, each with a known solution, the success of the method to provide the expected transcription factor among 50 or 100 proposed regulatory candidates, was evaluated to 62.6% and 72.5% of the situations, respectively. An additional prioritization among candidates might be further realized by adding functional ontology information. The benefit of this strategy was proved by identifying PPAR isotypes and their partners as the upstream regulators of a list of experimentally-identified targets of PPARA, a pivotal transcriptional factor in lipid oxidation. The proposed candidates participated in various biological functions that further enriched the original information. The efficiency of the method in merging reactions and regulations was also illustrated by identifying gene candidates participating in glucose homeostasis from an input list of metabolites involved in cell glycolysis. This method proposes a reasonable number of regulatory candidates for lists of input molecules that may include transcripts of genes and metabolites. The proposed upstream regulators are the transcription factors themselves and protein complexes, so that a multi-level description of how cell metabolism is regulated is obtained.
    BMC Systems Biology 03/2014; 8(1):32. DOI:10.1186/1752-0509-8-32 · 2.44 Impact Factor
    • "Previous studies have shown the PPARα L162V SNP to be associated with multiple lipid and lipoprotein measures, with one study finding the effect of the L162V SNP on triacylglycerol and ApoCIII concentrations to be dependent on PUFA intake.[910111233] "
    [Show abstract] [Hide abstract]
    ABSTRACT: We determined the blood lipid-lowering effects of eicosapentaenoic acid (EPA) on hypertriglyceridemic subjects with Leu162/Val in exon 5 and G/C in intron7 polymorphism of peroxisome proliferator-activated receptor alpha (PPARα)genotypes that, to our knowledge, have not been previously studied. A total of 170 hypertriglyceridemic subjects were enrolled and genotyped for Ala54Thr, Leu162Val, and intron7 polymorphism by the use of a polymerase chain reaction-restriction fragment length polymorphism method. After determination of their genotypes, the first 23 eligible subjects who were found as Ala54 carriers and the first 23 eligible Thr54 carriers were enrolled in the study and stratified for PPARα genotypes. Participants took 2 g of pure EPA daily for 8 weeks. Fasting blood lipid and lipoprotein profiles were determined and changes from baseline were measured. We observed significant difference between EPA supplementation and Leu162 and Val162, Interon 7 (GG and GC) carriers (P < 0.001). We did not observe significant associations between the PPARα L162V single nucleotide polymorphism and multiple lipid and lipoprotein measures. Although EPA consumption lowered lipid and lipoprotein concentrations in Leu162 and Val162 carriers and Interon 7 CC and GC carriers, these differences between the studied groups were not statistically significant. EPA consumption has a lipid-lowering effect in hypertriglyceridemic subjects in both Leu162 and Val162 carriers. But there was no significant interaction between EPA supplementation and PPARα genotypes. Thus, genetic variation within the PPARα Leu162/Val cannot modulate the association of EPA intakes with lipid and lipoprotein profile. However, we must note that the sample size in this study was small.
    International journal of preventive medicine 03/2014; 5(3):333-40.
Show more

Preview (2 Sources)

115 Reads
Available from