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)