Abstract
BackgroundIntakes of n-3 polyunsaturated fatty acids (PUFAs), especially EPA (C20∶5n-3) and DHA (C22∶6n-3), are known to prevent fatal coronary heart disease (CHD). The effects of n-6 PUFAs including arachidonic acid (C20∶4n-6), however, remain unclear. δ-5 and δ-6 desaturases are rate-limiting enzymes for synthesizing long-chain n-3 and n-6 PUFAs. C20∶4n-6 to C20∶3n-6 and C18∶3n-6 to C18∶2n-6 ratios are markers of endogenous δ-5 and δ-6 desaturase activities, but have never been studied in relation to incident CHD. Therefore, the aim of this study was to investigate the relation between these ratios as well as genotypes of FADS1 rs174547 and CHD incidence.MethodsWe applied a case-cohort design within the CAREMA cohort, a large prospective study among the general Dutch population followed up for a median of 12.1 years. Fatty acid profile in plasma cholesteryl esters and FADS1 genotype at baseline were measured in a random subcohort (n = 1323) and incident CHD cases (n = 537). Main outcome measures were hazard ratios (HRs) of incident CHD adjusted for major CHD risk factors.ResultsThe AA genotype of rs174547 was associated with increased plasma levels of C204n-6, C20∶5n-3 and C22∶6n-3 and increased δ-5 and δ-6 desaturase activities, but not with CHD risk. In multivariable adjusted models, high baseline δ-5 desaturase activity was associated with reduced CHD risk (P for trend = 0.02), especially among those carrying the high desaturase activity genotype (AA): HR (95% CI) = 0.35 (0.15–0.81) for comparing the extreme quintiles. High plasma DHA levels were also associated with reduced CHD risk.ConclusionIn this prospective cohort study, we observed a reduced CHD risk with an increased C20∶4n-6 to C20∶3n-6 ratio, suggesting that δ-5 desaturase activity plays a role in CHD etiology. This should be investigated further in other independent studies.
Highlights
Polyunsaturated fatty acids (PUFAs) are generally believed to reduce coronary heart disease (CHD) risk [1,2,3,4]
They were linked to the cardiology information system of the Department of Cardiology to obtain information about the occurrence of myocardial infarction (MI), unstable angina pectoris (UAP), coronary artery bypass grafting (CABG), or percutanous transluminal coronary angioplasty surgery (PTCA)
A 30% reduction in CHD risk was observed among the participants in the second, third, fourth and fifth quintile of C20:4n-6 to C20:3n-6 ratio compared with those in the first quintile after adjustment for age, sex, systolic blood pressure, hypertensive medication use, current smoking, diabetes, total cholesterol, and high-density lipoprotein cholesterol (P for trend = 0.02)
Summary
Polyunsaturated fatty acids (PUFAs) are generally believed to reduce coronary heart disease (CHD) risk [1,2,3,4]. Potential functional genetic variants in these genes have been identified including rs174547 [18], and confirmed in recent genome-wide association studies [19,20,21] They have an impact on FADS1 mRNA abundance [22,23,24,25,26], and, as a result, on desaturase activity, plasma PUFA levels, and endogenous PUFA pools [18,19,20,21,26,27,28,29]. D-5 and d-6 desaturases are rate-limiting enzymes for synthesizing long-chain n-3 and n-6 PUFAs. C20:4n-6 to C20:3n-6 and C18:3n-6 to C18:2n-6 ratios are markers of endogenous d-5 and d-6 desaturase activities, but have never been studied in relation to incident CHD. The aim of this study was to investigate the relation between these ratios as well as genotypes of FADS1 rs174547 and CHD incidence
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