Plasma Phospholipid Fatty Acid Biomarkers of Dietary Fat Quality and Endogenous Metabolism Predict Coronary Heart Disease Risk: A Nested Case‐Control Study Within the Women's Health Initiative Observational Study

BACKGROUND: Although the relationship between dietary fat quality and coronary heart disease (CHD) risk has been evaluated, typically using diet questionnaires, results are inconsistent and data in postmenopausal women are limited. Plasma phospholipid fatty acid (PL‐FA) profiles, reflecting dietary intake and endogenous FA metabolism, may better predict diet–CHD risk. METHODS AND RESULTS: Using a nested case‐control design, we assessed the association between plasma PL‐FA profiles and CHD risk in 2448 postmenopausal women (1224 cases with confirmed CHD and 1224 controls matched for age, enrollment date, race/ethnicity, and absence of CHD at baseline and after 4.5 years of follow‐up) participating in the Women's Health Initiative observational study. PL‐FA profile was measured using gas chromatography. Product/precursor ratios were used to estimate stearoyl‐CoA‐desaturase (16:1n‐7/16:0, 18:1n‐9/18:0), Δ6‐desaturase (20:3n‐6/18:2n‐6), and Δ5‐desaturase (20:4n‐6/20:3n‐6) activities, indicators of endogenous FA metabolism. Multivariate conditional logistic regression was used to obtain odds ratios (95% CIs) for CHD risk. While no associations were observed for the predominant PL fatty acid (16:0, 18:0, 18:1n‐9, and 18:2n‐6), plasma PL–saturated fatty acid (1.20 [1.08 to 1.32]) and endogenously synthesized PL ω6 fatty acids (20:3n‐6; 3.22 [1.95 to 5.32]), 22:5n‐6; 1.63 [1.20 to 2.23]) and Δ6‐desaturase (1.25 [1.11 to 1.41]) were positively associated with CHD risk. PL‐ω3 fatty acids (20:5n‐3; 0.73 [0.58 to 0.93], 22:5n‐3; 0.56 [0.33 to 0.94], 22:6n‐3; 0.56 [0.39 to 0.80]), 18:1n‐7 (0.54 [0.29 to 0.99]), and Δ5‐desaturase (0.78 [0.70 to 0.88]) were inversely associated with CHD risk. Results support current guidelines regarding regular fish consumption. Additional findings include associations between endogenously synthesized fatty acids and CHD risk, which were partly explained by changes in Δ6‐desaturase and Δ5‐desaturase indexes, suggesting that in vivo metabolism may also play an important role in predicting CHD risk in this cohort of postmenopausal women. CLINICAL TRIAL REGISTRATION: URL: http://ClinicalTrials.gov, Unique identifier: NCT01864122.