Intakes of n-3 LC-PUFAs ≤1.8 g/d do not improve endothelial function in healthy adults. The trial is registered at controlled-trials.com as ISRCTN66664610.

This article is available online at http://www.jlr.org infl ammatory eicosanoids ( 1 ). The major dietary LC-PUFA is linoleic acid (LA,, with lower amounts of n-3 fatty acids, chiefl y ␣ -linolenic acid (ALA, 18:3n-3), eicosapentaenoic acid (EPA,, and docosahexaenoic acid (DHA,. The composition of fatty acids in tissues refl ects both dietary fat ( 2 ) and the effi ciency of elongation and desaturation of their dietary precursors, the two essential fatty acids LA and ALA ( Fig. 1 ).Delta-5 and delta-6 desaturases (D5D and D6D) are the key enzymes in endogenous desaturation ( 3, 4 ), expressed at high levels in liver, brain, heart, and lung ( 5, 6 ). D5D and D6D are encoded, respectively, by the FADS1 and FADS2 genes, which lie in a region of strong linkage disequilibrium (LD) on chromosome 11. Several single nucleotide polymorphisms (SNP) in the FADS1-FADS2 cluster have been shown to be associated with plasma or erythrocyte phosphoglyceride LC-PUFA concentrations in genome-wide association (GWA) studies ( 7,8 ). Associations of SNPs and haplotypes in this region have been shown with fatty acids in plasma ( 4, 9-14 ), erythrocyte membranes ( 4,8,(10)(11)(12)15 ), and adipose tissue ( 16 ). Surrogate estimates of desaturase activity based on ratios of product:substrate ( 15, 17 ) suggest lower levels are associated with the minor alleles of SNPs in the FADS1-FADS2 LD block. GWA studies have also identifi ed several loci in the FADS gene cluster, at which minor alleles were associated with lower total cholesterol ( 18 )

No abstract

Fish oil supplementation provides an inconsistent degree of protection from cardiovascular disease (CVD), which may be attributed to genetic variation. Single nucleotide polymorphisms (SNPs) in the elongation-ofvery-long-chain-fatty-acids-2 (ELOVL2) gene have been strongly associated with plasma proportions of n-3 longchain polyunsaturated fatty acids (LC-PUFA). We investigated the effect of genotype interaction with fish oil dosage on plasma n-3 LC-PUFA proportions in a parallel doubleblind controlled trial, involving 367 subjects randomised to treatment with 0.45, 0.9 and 1.8 g/day eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (1.51:1) or olive oil placebo for 6 months. We genotyped 310 subjects for ELOVL2 gene SNPs rs3734398, rs2236212 and rs953413. At baseline, carriers of all minor alleles had lower proportions of plasma DHA than non-carriers (P = 0.021-0.030). Interaction between genotype and treatment was a significant determinant of plasma EPA (P \ 0.0001) and DHA (P = 0.004-0.032). After the 1.8 g/day dose, carriers of ELOVL2 SNP minor alleles had approximately 30 % higher proportions of EPA (P = 0.002-0.004) and 9 % higher DHA (P = 0.013-0.017) than non-carriers. Minor allele carriers could therefore particularly benefit from a high intake of EPA and DHA in maintaining high levels of plasma n-3 PUFA conducive to protection from CVD.

The sequence of growth hormone (GH) is generally strongly conserved in mammals, but episodes of rapid change occurred during the evolution of primates and artiodactyls, when the rate of GH evolution apparently increased substantially. As a result the sequences of higher primate and ruminant GHs differ markedly from sequences of other mammalian GHs. In order to increase knowledge of GH evolution in Cetartiodactyla (Artiodactyla plus Cetacea) we have cloned and characterized GH genes from camel (Camelus dromedarius), hippopotamus (Hippopotamus amphibius), and giraffe (Giraffa camelopardalis), using genomic DNA and a polymerase chain reaction technique. As in other mammals, these GH genes comprise five exons and four introns. Two very similar GH gene sequences (encoding identical proteins) were found in each of hippopotamus and giraffe. The deduced sequence for the mature hippopotamus GH is identical to that of dolphin, in accord with current ideas of a close relationship between Cetacea and Hippopotamidae. The sequence of camel GH is identical to that reported previously for alpaca GH. The sequence of giraffe GH is very similar to that of other ruminants but differs from that of nonruminant cetartiodactyls at about 18 residues. The results demonstrate that the apparent burst of rapid evolution of GH occurred largely after the separation of the line leading to ruminants from other cetartiodactyls.

Marine n3 polyunsaturated fatty acids (PUFAs) activate the transcription factor peroxisome proliferator-activated receptor (PPARγ), which modulates the expression of adiponectin. We investigated the interaction of dietary n3 PUFAs with adiponectin gene (ADIPOQ) single nucleotide polymorphism (SNP) genotypes as a determinant of serum adiponectin concentration. The Modulation of Atherosclerosis Risk by Increasing Doses of n3 Fatty Acids study is a parallel design, double-blind, controlled trial. Serum adiponectin was measured in 142 healthy men and 225 women aged 45-70 y randomized to treatment with doses of 0.45, 0.9, and 1.8 g/d 20:5n3 and 22:6n3 (1.51:1), or placebo for 12 mo. The 310 participants who completed the study were genotyped for 5 SNPs at the ADIPOQ locus: -11391 G/A (rs17300539), -11377 C/G (rs266729), -10066 G/A (rs182052), +45 T/G (rs2241766), and +276 G/T (rs1501299). The -11391 A-allele was associated with a higher serum adiponectin concentration at baseline (n = 290; P < 0.001). The interaction between treatment and age as a determinant of adiponectin was significant in participants aged >58 y after the highest dose (n = 92; P = 0.020). The interaction between +45 T/G and treatment and age was a nominally significant determinant of serum adiponectin after adjustment for BMI, gender, and ethnicity (P = 0.029). Individuals homozygous for the +45 T-allele aged >58 y had a 22% increase in serum adiponectin concentration compared with baseline after the highest dose (P-treatment effect = 0.008). If substantiated in a larger sample, a diet high in n3 PUFAs may be recommended for older individuals, especially those of the +45 TT genotype who have reported increased risk of hypoadiponectinemia, type 2 diabetes, and obesity.

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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.