alpha-Linolenic acid, Δ6-desaturase gene polymorphism, and the risk of nonfatal myocardial infarction 1� 3

January 1, 2007 Human Health and Nutrition Data 0 Comments

alpha-Linolenic acid, Δ6-desaturase gene polymorphism, and the risk of nonfatal myocardial infarction 1� 3

Year: 2007
Authors: Baylin, A. Ruiz-Narvaez, E. Kraft, P. Campos, H.
Publication Name: Am. J. Clin. Nutr.
Publication Details: Volume 85; Pages 554 – 560.


Δ6-Desaturase (FADS2) is the rate-limiting step in the polyunsaturated fatty acid (PUFA) biosynthetic pathway.The aim was to test whether the common deletion [T/-] in the promoter of FADS2 affects the PUFA biosynthetic pathway and consequently modifies the effect of α-linolenic acid (ALA) on myocardial infarction (MI). Case subjects (n= 1694) with a first nonfatal acute MI were matched by age, sex, and area of residence to 1694 population-based control subjects in Costa Rica. PUFAs were quantified by gas-liquid chromatography from plasma and adipose tissue samples. Least squares means from generalized linear models and odds ratios (ORs) and 95% CIs from multiple conditional logistic regression models were estimated.The prevalence of the variant T/- allele was 48%. Eicosapentaenoic acid, y-linolenic acid, and arachidonic acid decreased in adipose tissue and plasma with increasing number of copies of the variant allele with a monotonic trend (P< 0.05 for all). Fasting plasma triacylglycerols by genotype were 2.08 mmol/L for TT, 2.16 mmol/L for T-, and 2.26 mmol/L for – – [ie, homozygous for the variant (deletion) allele] (P= 0.03). The FADS2 deletion was not associated with MI and did not significantly modify the association between adipose tissue ALA and the risk of MI.The FADS2 deletion may prevent the conversion of ALA into very-long-chain PUFAs .However, this metabolic effect is not translated into an attenuated risk between ALA and MI among carriers of the variant. It is possible that, at current intakes of ALA, any potential defect in the transcription of the gene is masked by the availability of substrate. Further research in populations deficient in ALA intake is warranted. (Author�s abstract)
The Δ6-desaturase gene (FADS2) is located in chromosome 11 and expressed in almost all human tissues, with the highest expression in the liver, heart, and brain. It is known that a large proportion of regulatory single-nucleotide polymorphisms (SNPs) that affect gene expression are located in the promoter regions. The rs3834458 (T/-) polymorphism could play an important role in metabolism because of its location near potential regulatory regions, such as binding sites for sterol regulatory element�binding protein 1c (SREBP-1c) and peroxisome proliferator activated receptor α (PPAR-α), which regulate the transcription of Δ6-desaturase. The authors
hypothesized that a deletion in the promoter region of FADS2 that potentially affect gene transcription modifies the conversion of α-linolenic and linoleic acid into very-long-chain PUFA and could attenuate the protective association between α-linolenic acid and MI. An attenuation of the α-linolenic acid effect on MI risk would suggest that this protection occurs via the conversion of α-linolenic acid to very-long-chain n-3fatty acids. It was found that a common deletion in the FADS2 promoter was associated with low EPA and arachidonic acid in tissues. The consistency of the observed pattern in both n-3 and n-6 fatty acids in 2 different tissues (adipose and plasma) together with the monotonic trend by genotype gives substantial plausibility to the hypothesis of decreased Δ6-desaturase activity with an increased number of copies of the common deletion (T/-). The mechanism for the observed effects of theT/- deletion on the PUFA biosynthetic pathway probably involves a decrease in Δ6-desaturase transcription that affects the conversion of α-linolenic acid and linoleic acid into the very long-chain PUFAs arachidonic acid and EPA. Carriers of the deletion have higher concentrations of 20:6n�6 than do noncarriers. Consistently, EPA concentrations decreased with the number of T/-deletions, and 20:3n�3 increased in both adipose tissue and plasma. The data also suggest that the findings cannot be attributed to substrate availability, because α-linolenic acid and linoleic acid (in adipose tissue, plasma, and diet) did not differ significantly by genotype. Thus, on one hand, the T/- deletion may prevent the synthesis of very-long-chain n-3 fatty acids, which are protective, and increase fasting triacylglycerols, which are an independent risk factor for IHD. A modifying effect of the FADS2 deletion on the protective effect of α-linolenic acid was not reported. A high intake of α -linolenic and linoleic acid down-regulates the Δ6-desaturase. It is possible that at current intakes of α-linolenic acid any potential defect in the transcription of the gene is masked by the availability of substrate. Further research in populations with low intake of α-linolenic acid and very-long chain n-3 fatty acids is warranted. Further studies on this polymorphism and others in the FADS2 gene are warranted to reassess the effect of n-3 and n-6 PUFA on IHD. These future studies will be of special importance in those populations in which the intake of α-linolenic acid and very-long-chain n-3 fatty acids from fish (EPA and DHA) is very low. (Editor�s comments)

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