BACKGROUND: Leukotrienes are proinflammatory molecules derived from dietary PUFAs and have been associated with cardiovascular disease (CVD). We previously reported that an A→G variant (rs12746200) of the cytosolic phospholipase A2 group IVA gene (PLA2G4A), which encodes the enzyme that liberates PUFAs from cellular membranes for leukotriene synthesis, decreases the risk of CVD. OBJECTIVE: We sought to replicate these initial observations with a more clinically relevant phenotype, such as myocardial infarction (MI), and to determine whether dietary PUFAs mediate this association. DESIGN: In a Costa Rican case-control data set (n = 3971), rs12746200 was genotyped and was tested for an association with MI. Functional experiments were carried out to determine whether rs12746200 led to differences in mRNA expression. RESULTS: Risk of MI was significantly lower in AG/GG subjects than in AA homozygotes (OR: 0.86; 95% CI: 0.75, 0.99; P = 0.040). The reduced risk of MI was observed primarily in AG/GG subjects who were above the median for intake of dietary omega-6 (n-6) PUFAs (OR: 0.71; 95% CI: 0.59, 0.87; P-interaction = 0.005). A similar analysis with dietary omega-3 (n-3) PUFAs did not show a statistically significant nutrigenetic association (P-interaction = 0.23). Functional analysis in human aortic endothelial cells showed that the carriers of the G allele had significantly lower PLA2G4A gene expression (P = 0.014), consistent with the atheroprotective association of this variant. CONCLUSION: These results replicate the association of rs12746200 with CVD phenotypes and provide evidence that the protective association of this functional PLA2G4A variant is mediated by dietary PUFAs.
BACKGROUND:Leukotrienes are proinflammatory molecules derived from dietary PUFAs and have been associated with cardiovascular disease (CVD). We previously reported that an A→G variant (rs12746200) of the cytosolic phospholipase A2 group IVA gene (PLA2G4A), which encodes the enzyme that liberates PUFAs from cellular membranes for leukotriene synthesis, decreases the risk of CVD. OBJECTIVE: We sought to replicate these initial observations with a more clinically relevant phenotype, such as myocardial infarction (MI), and to determine whether dietary PUFAs mediate this association. DESIGN: In a Costa Rican case-control data set (n = 3971), rs12746200 was genotyped and was tested for an association with MI. Functional experiments were carried out to determine whether rs12746200 led to differences in mRNA expression. RESULTS: Risk of MI was significantly lower in AG/GG subjects than in AA homozygotes (OR: 0.86; 95% CI: 0.75, 0.99; P = 0.040). The reduced risk of MI was observed primarily in AG/GG subjects who were above the median for intake of dietary omega-6 (n-6) PUFAs (OR: 0.71; 95% CI: 0.59, 0.87; P-interaction = 0.005). A similar analysis with dietary omega-3 (n-3) PUFAs did not show a statistically significant nutrigenetic association (P-interaction = 0.23). Functional analysis in human aortic endothelial cells showed that the carriers of the G allele had significantly lower PLA2G4A gene expression (P = 0.014), consistent with the atheroprotective association of this variant. CONCLUSION: These results replicate the association of rs12746200 with CVD phenotypes and provide evidence that the protective association of this functional PLA2G4A variant is mediated by dietary PUFAs.
Authors: Eric A Heller; Emerson Liu; Andrew M Tager; Sumita Sinha; Jesse D Roberts; Stephanie L Koehn; Peter Libby; Elena Rabkin Aikawa; Ji Qiu Chen; Paul Huang; Mason W Freeman; Kathryn J Moore; Andrew D Luster; Robert E Gerszten Journal: Circulation Date: 2005-07-26 Impact factor: 29.690
Authors: Anna Helgadottir; Andrei Manolescu; Gudmar Thorleifsson; Solveig Gretarsdottir; Helga Jonsdottir; Unnur Thorsteinsdottir; Nilesh J Samani; Gudmundur Gudmundsson; Struan F A Grant; Gudmundur Thorgeirsson; Sigurlaug Sveinbjornsdottir; Einar M Valdimarsson; Stefan E Matthiasson; Halldor Johannsson; Olof Gudmundsdottir; Mark E Gurney; Jesus Sainz; Margret Thorhallsdottir; Margret Andresdottir; Michael L Frigge; Eric J Topol; Augustine Kong; Vilmundur Gudnason; Hakon Hakonarson; Jeffrey R Gulcher; Kari Stefansson Journal: Nat Genet Date: 2004-02-08 Impact factor: 38.330
Authors: Jaana Hartiala; Dalin Li; David V Conti; Susanna Vikman; Yesha Patel; W H Wilson Tang; Marie-Louise Brennan; John W Newman; Charles B Stephensen; Patrice Armstrong; Stanley L Hazen; Hooman Allayee Journal: Hum Genet Date: 2011-02-04 Impact factor: 4.132
Authors: Luz M González; Nicolás R Robles; Sonia Mota-Zamorano; José C Arévalo-Lorido; José Manuel Valdivielso; Juan López-Gómez; Guillermo Gervasini Journal: Front Pharmacol Date: 2022-05-02 Impact factor: 5.988
Authors: Floyd H Chilton; Robert C Murphy; Bryan A Wilson; Susan Sergeant; Hannah Ainsworth; Michael C Seeds; Rasika A Mathias Journal: Nutrients Date: 2014-05-21 Impact factor: 5.717
Authors: Jane F Ferguson; Hooman Allayee; Robert E Gerszten; Folami Ideraabdullah; Penny M Kris-Etherton; José M Ordovás; Eric B Rimm; Thomas J Wang; Brian J Bennett Journal: Circ Cardiovasc Genet Date: 2016-04-19