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Genetic variation in APOJ, LPL, and TNFRSF10B affects plasma fatty acid distribution in Alaskan Eskimos.

ABSTRACT: Alterations in plasma fatty acid distribution are linked to metabolic abnormalities related to type 2 diabetes and cardiovascular disease.The aim of this study was to investigate genetic factors influencing plasma fatty acid distribution in Alaskan Eskimos from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study.Fatty acids in plasma were measured by gas chromatography in 761 related individuals (>35 y of age).Quantitative genetic analyses showed that fatty acid distribution is significantly heritable (P < 0.001), with heritabilities ranging from 0.33 to 0.55. A genome-wide scan for plasma fatty acids identified a 20-cM region on chromosome 8 (p12-p21) with a quantitative trait locus for monounsaturated fatty acids (logarithm of odds score = 3.8). The same region had a quantitative trait locus for polyunsaturated fatty acids (logarithm of odds score = 2.6). We genotyped single nucleotide polymorphisms (SNPs) in candidate genes in 8p12-p21 and found a significant association between fatty acids and SNPs in apolipoprotein J (APOJ), lipoprotein lipase (LPL), macrophage scavenger receptor 1 (MSR1), and tumor necrosis factor receptor superfamily member 10b (TNFRSF10B). A Bayesian quantitative trait nucleotide analysis based on a measured genotype model showed that SNPs in LPL, TNFRSF10B, and APOJ had strong statistical evidence of a functional effect (posterior probability > or =75%) on plasma fatty acid distribution.The results indicate that there is strong genetic influence on plasma fatty acid distribution and that genetic variation in APOJ, LPL, and TNFRSF10B may play a role. The GOCADAN study was registered at www.clinicaltrials.gov as NCT00006192.

SUBMITTER: Voruganti VS

PROVIDER: S-EPMC2869509 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Genetic variation in APOJ, LPL, and TNFRSF10B affects plasma fatty acid distribution in Alaskan Eskimos.

Voruganti V Saroja VS Cole Shelley A SA Ebbesson Sven O E SO Göring Harald H H HH Haack Karin K Laston Sandra S Wenger Charlotte R CR Tejero M Elizabeth ME Devereux Richard B RB Fabsitz Richard R RR MacCluer Jean W JW Umans Jason G JG Howard Barbara V BV Comuzzie Anthony G AG

The American journal of clinical nutrition 20100421 6

<h4>Background</h4>Alterations in plasma fatty acid distribution are linked to metabolic abnormalities related to type 2 diabetes and cardiovascular disease.<h4>Objective</h4>The aim of this study was to investigate genetic factors influencing plasma fatty acid distribution in Alaskan Eskimos from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study.<h4>Design</h4>Fatty acids in plasma were measured by gas chromatography in 761 related individuals (>35 y of age).<h4>Results< ...[more]

PMID: 20410100

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Project description:BackgroundThe discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets.MethodsThrough DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes.ResultsWe confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P=4.2×10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0×10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P=0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P=0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P=2.0×10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10(-7)).ConclusionsWe found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.).

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Genetic variation in APOJ, LPL, and TNFRSF10B affects plasma fatty acid distribution in Alaskan Eskimos.

Publications

Genetic variation in APOJ, LPL, and TNFRSF10B affects plasma fatty acid distribution in Alaskan Eskimos.

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