Markers of endogenous desaturase activity and risk of coronary heart disease in the CAREMA cohort study.
BACKGROUND
Intakes 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.


METHODS
We 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.


RESULTS
The 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.


CONCLUSIONS
In 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.
Division of Human Nutrition, Wageningen University and Research Center, Wageningen, The Netherlands. kevin.lu@wur.nl
Yingchang
Y
Lu
Anika
A
Vaarhorst
Audrey H H
AH
Merry
Martijn E T
ME
Dollé
Robert
R
Hovenier
Sandra
S
Imholz
Leo J
LJ
Schouten
Bastiaan T
BT
Heijmans
Michael
M
Müller
P Eline
PE
Slagboom
Piet A
PA
van den Brandt
Anton P M
AP
Gorgels
Jolanda M A
JM
Boer
Edith J M
EJ
Feskens
D000328:Adult; D015415:Biomarkers / Q000097:blood; D002788:Cholesterol Esters / Q000097:blood; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D000090943:Delta-5 Fatty Acid Desaturase; D044943:Fatty Acid Desaturases / Q000235:genetics*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
D015415:Biomarkers; D002788:Cholesterol Esters; D000090943:Delta-5 Fatty Acid Desaturase; D005231:Fatty Acids, Unsaturated; D044943:Fatty Acid Desaturases; C000716847:FADS1 protein, human