Genetic predisposition scores for dyslipidaemia influence plasma lipid concentrations at baseline, but not the changes after controlled intake of n-3 polyunsaturated fatty acids

Genes & Nutrition, Jun 2014

Inconsistent effects of fish oil supplementation on plasma lipids may be influenced by genetic variation. We investigated 12 single nucleotide polymorphisms (SNPs) associated with dyslipidaemia in genome-wide association studies, in 310 participants randomised to treatment with placebo or 0.45, 0.9 and 1.8 g/day eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA) (1.51:1) in a 12-month parallel controlled trial. Effects of risk alleles were assessed as trait-specific genetic predisposition scores (GPS) and singly. GPS were positively associated with baseline concentrations of plasma total cholesterol, low-density-lipoprotein cholesterol and triglyceride (TG) and negatively with high-density-lipoprotein cholesterol. The TG-GPS was associated with 0.210 mmol/L higher TG per risk allele (P < 0.0001), but no effects of single TG SNPs were significant at baseline. After treatment with EPA and DHA, TG-GPS was associated with 0.023 mmol/L lower TG per risk allele (P = 0.72). No interactions between GPS and treatment were significant; however, FADS1 SNP rs174546 C/T interaction with treatment was a significant determinant of plasma TG concentration (P = 0.047, n = 267). Concentration differed between genotype groups after the 1.8 g/day dose (P = 0.026), decreasing by 3.5 (95 % CI −15.1 to 8.2) % in non-carriers of the risk T-allele (n = 30) and by 21.6 (95 % CI −32.1 to −11.2) % in carriers (n = 37), who showed a highly significant difference between treatments (P = 0.007). Carriers of the FADS1 rs174546 risk allele could benefit from a high intake of EPA and DHA in normalising plasma TG.

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Genetic predisposition scores for dyslipidaemia influence plasma lipid concentrations at baseline, but not the changes after controlled intake of n-3 polyunsaturated fatty acids

Genes Nutr Genetic predisposition scores for dyslipidaemia influence plasma lipid concentrations at baseline, but not the changes after controlled intake of n-3 polyunsaturated fatty acids Aseel AlSaleh 0 Zoitsa Maniou 0 Fiona J. Lewis 0 Wendy L. Hall 0 Thomas A. B. Sanders 0 Sandra D. O'Dell 0 0 A. AlSaleh Z. Maniou F. J. Lewis W. L. Hall T. A. B. Sanders S. D. O'Dell (&) Diabetes and Nutritional Sciences Division, School of Medicine, King's College London , Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH , UK Inconsistent effects of fish oil supplementation on plasma lipids may be influenced by genetic variation. We investigated 12 single nucleotide polymorphisms (SNPs) associated with dyslipidaemia in genome-wide association studies, in 310 participants randomised to treatment with placebo or 0.45, 0.9 and 1.8 g/day eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA) (1.51:1) in a 12-month parallel controlled trial. Effects of risk alleles were assessed as trait-specific genetic predisposition scores (GPS) and singly. GPS were positively associated with baseline concentrations of plasma total cholesterol, low-density-lipoprotein cholesterol and triglyceride (TG) and negatively with high-density-lipoprotein cholesterol. The TG-GPS was associated with 0.210 mmol/L higher TG per risk allele (P \ 0.0001), but no effects of single TG SNPs were significant at baseline. After treatment with EPA and DHA, TG-GPS was associated with 0.023 mmol/L lower TG per risk allele (P = 0.72). No interactions between GPS and treatment were significant; however, FADS1 SNP rs174546 C/T interaction with treatment was a significant determinant of plasma TG concentration (P = 0.047, n = 267). Concentration differed between genotype groups after the 1.8 g/ day dose (P = 0.026), decreasing by 3.5 (95 % CI -15.1 to 8.2) % in non-carriers of the risk T-allele (n = 30) and by 21.6 (95 % CI -32.1 to -11.2) % in carriers (n = 37), who showed a highly significant difference between treatments (P = 0.007). Carriers of the FADS1 rs174546 risk allele could benefit from a high intake of EPA and DHA in normalising plasma TG. Docosahexaenoic acid; Eicosapentaenoic acid; Genetic predisposition score; Gene-nutrient interaction; Plasma lipids; Single nucleotide polymorphism - On behalf of the MARINA study team. Introduction Plasma lipids are risk factors for cardiovascular disease (CVD) and are well known to be influenced by dietary intake (Marais 2013) . A large number of human intervention trials have shown that eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA) in fish oil exert cardioprotective effects (reviewed by Mozaffarian and Wu 2011; Delgado-Lista et al. 2012) . However, some studies and meta-analyses have failed to demonstrate any significant protection from CVD risk by n-3 PUFA treatment (Kromhout et al. 2010; ORIGIN Trial Investigators et al. 2012; Rizos et al. 2012) . Effects of fish oil on plasma lipids are also inconsistent (see Minihane (2013) for recent review) and this may reflect genetic variation as well as different treatments. Heritability estimates for fasting plasma lipids range from 32 % for triglyceride (TG) to 55 % for total cholesterol (TC) (Pe´russe et al. 1997) . Interaction between genetic and environmental factors such as dietary intake may contribute to the variation in lipid traits between individuals (Corella and Ordovas 2005) . Genome-wide association studies (GWAS) have identified a number of single nucleotide polymorphisms (SNPs) associated with dyslipidaemia in cross-sectional studies (Chasman et al. 2008; Kathiresan et al. 2008, 2009; Wallace et al. 2008; Willer et al. 2008; Aulchenko et al. 2009; Sabatti et al. 2009; Teslovich et al. 2010) . However, few attempts have been made to discover whether these common SNPs also influence the responses to dietary interventions. As intervention studies are necessarily limited in size, significant interactions with single SNPs may be difficult to establish, but interaction with sets of SNPs potentially offer more power. We hypothesised that carriage of alleles predisposing to dyslipidaemia may influence changes in the plasma lipid profile in response to intake of EPA and DHA. We tested the hypothesis in a cohort of 310 participants from the MARINA (Modulation of Atherosclerosis Risk by Increasing doses of N-3 fatty Acids) study (Sanders et al. 2011), a highly controlled randomised dietary intervention trial to investigate the effect of olive oil placebo and EPA and DHA (1.51:1) supplemented at 0.45, 0.9 and 1.8 g/day for 12 months on CVD risk factors in healthy subjects. We investigated effects of 12 SNPs with reported associations with plasma lipids at genome-wide levels of significance, in combination and individually, on plasma lipid concentrations at baseline and on changes in response to treatment. Methods Subjects The MARINA trial was a single-centre dietary intervention s (...truncated)


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Aseel AlSaleh, Zoitsa Maniou, Fiona J. Lewis, Wendy L. Hall, Thomas A. B. Sanders, Sandra D. O’Dell. Genetic predisposition scores for dyslipidaemia influence plasma lipid concentrations at baseline, but not the changes after controlled intake of n-3 polyunsaturated fatty acids, Genes & Nutrition, 2014, pp. 412, Volume 9, Issue 4, DOI: 10.1007/s12263-014-0412-8