FADS genetic variants and ω-6 polyunsaturated fatty acid metabolism in a homogeneous island population

Abstract

This article is available online at http://www.jlr.org Supplementary key words fatty acid desaturase • isolated population • genetic association Several changes in diet over the past century are hypothesized to have been maladaptive, thereby leading to an increase in the incidence of numerous chronic diseases in developed countries ( 1, 2 ). Many of these diseases (obesity, diabetes, asthma, allergies, arthritis and chronic joint disease, dementia, and cardiovascular disease) have a substantial infl ammatory component ( 3-6 ) with notable cooccurrences ( 7,8 ). Perhaps no changes in the modern diet have had a greater impact than the quantitative and qualitative changes in fat consumption. While the percentage of energy from fat ( ‫ف‬ 35%) is thought to be similar in ancestral and contemporary Western diets, the concentrations and ratios of the types of fat that humans eat ( 9, 10 ) have shifted, with marked increases in saturated and omega-6 ( 6) fatty acid consumption. Importantly, these changes have been suggested to alter human health and the incidence of chronic infl ammatory diseases ( 11-13 ).Long-chain serum polyunsaturated fatty acids (LC-PUFA; у 20 carbons), such as arachidonic acid (AA; C20:4 6), and their metabolic products orchestrate several critical events in immunity and infl ammation.Abstract Long-chain polyunsaturated fatty acids (PUFA) orchestrate immunity and infl ammation through their capacity to be converted to potent infl ammatory mediators. We assessed associations of FADS gene cluster polymorphisms and fasting serum PUFA concentrations in a fully ascertained, geographically isolated founder population of European descent. Concentrations of 22 PUFAs were determined by gas chromatography, of which ten fatty acids and fi ve ratios defi ning FADS1 and FADS2 activity were tested for genetic association against 16 single nucleotide polymorphisms (SNP) in 224 individuals. A cluster of SNPs in tight linkage disequilibrium in the FADS1 gene (rs174537, rs174545, rs174546, rs174553, rs174556, rs174561, rs174568, and rs99780) were strongly associated with arachidonic acid (AA) ( P = 5.8 × 10؊ 7 -1.7 × 10 ؊ 8 ) among other PUFAs, but the strongest associations were with the ratio measuring FADS1 activity in the -6 series ( P = 2.11 × 10 ؊ 13 -1.8 × 10 ؊ 20 ). The minor allele across all SNPs was consistently associated with decreased -6 PUFAs, with the exception of dihomo-␥ -linoleic acid (DHGLA), where the minor allele was consistently associated with increased levels. Our fi ndings in a geographically isolated population with a homogenous dietary environment suggest that variants in the ⌬ -5 desaturase enzymatic step likely regulate the effi ciency of conversion of medium-chain PUFAs to potentially infl ammatory PUFAs, such as AA. -Mathias, R. A., C. Vergara, L. Gao, N. Rafaels, T. Hand, M. Campbell, C. Bickel, P. Ivester, S. Sergeant, K. C. Barnes, and F. H. Chilton. FADS genetic variants and -6 polyunsaturated fatty acid metabolism in a homogeneous island population.

Human Cyclooxygenase-2 Is a Sequence Homodimer That Functions as a Conformational Heterodimer

“…We hypothesize that prostanoid production in vivo is directly and importantly influenced by the effective concentration and FA composition of the milieu in which PGHSs operate, what we term the FA tone. We presume that every individual establishes a fairly constant FA tone as a consequence of dietary habits and genetic profile (45,46). We imagine that having a FA tone outside some normal range would change prostanoid formation to an extent sufficient to affect the health of an individual.…”

Dietary arachidonic acid in perinatal nutrition: a commentary

“…Overall, the data suggest that the n-6 PUFAs in breast milk, plasma and blood cell membranes across all ages are more affected by FADS polymorphisms than n-3 PUFAs, typically with an increase in LA and a decrease in AA-levels in minor allele carriers (55,56,(60)(61)(62)(63). However, we have recently found that FADS polymorphisms contributed substantially to DHAstatus in late infancy, and some SNP minor alleles were even found to up-regulate DHA-status (60), whereas minor alleles of all the investigated SNPs lowered AA in a consistent way (64).…”

Compensatory induction of Fads1 gene expression in heterozygous Fads2-null mice and by diet with a high n-6/n-3 PUFA ratio

“…Briefly, 100 mg tissue was added to a glass tube containing 2 ml of 4:1 methanol and hexane and 100 µg butylated hydroxytoluene. After homogenization on ice and flushing a tube with nitrogen for 20 s, 200 µl of acetyl NCBI dbSNP database) in the FADS gene cluster, where two desaturase genes, FADS1 and FADS2, for the ARA and DHA synthesis are located, were generally associated with a lower product/substrate ratio of n-6 and n-3 PUFAs in serum or red blood cells (RBCs), indicating lower capacity of ARA, DHA synthesis (18)(19)(20)(21)(22). Furthermore, the allele frequency of the FADS cluster differs among populations; some minor alleles in most populations occur predominantly in certain populations (23,24), suggesting environmental effects on the allele frequency.…”