Response to Letters Regarding Article, “Circulating Omega-6 Polyunsaturated Fatty Acids and Total and Cause-Specific Mortality: The Cardiovascular Health Study”
Authors: Jason HY Wu, Rozenn N. Lemaitre, Irena B. King, Xiaoling Song, Bruce M. Psaty, David S. Siscovick, Dariush Mozaffarian
Journal: Circulation (2015)

Sertoglu and colleagues express concern about the measurement of circulating fatty acid biomarkers in plasma.However, our investigation did not measure fatty acids in total plasma (the sum of fatty acids in nonesterified fatty acids, cholesterol esters, triglycerides, and phospholipids) but in the plasma phospholipid fraction.The plasma phospholipid fraction reflects fatty acid concentrations in cell membranes.Furthermore, phospholipid fatty acids in plasma and erythrocyte membranes interexchange, reflect fatty acid consumption over a similar period of time, and are reasonably correlated. 1 Thus, either plasma phospholipid or erythrocyte fatty acid composition is a valid and reliable biomarker of dietary consumption.This explains why numerous longitudinal investigations have evaluated the associations of fatty acids in plasma phospholipids or erythrocyte phospholipids in relation to cardiometabolic disease risk. 2,3e appreciate the interest of Sertoglu et al in omega-3 polyunsaturated fatty acids (n-3 PUFAs).As described and cited in the present investigation, we previously measured and reported associations between plasma phospholipid n-3 PUFA biomarkers and risk of total and cardiovascular mortality in this cohort. 4In addition, in the present investigation, we evaluated and found little evidence of an interaction between linoleic acid (the major dietary omega-6 fatty acid) and n-3 PUFAs (P=0.54).Indeed, our findings suggested an additive benefit in that those with highest levels of both linoleic acid and n-3 PUFAs had the lowest risk of total and cardiovascular mortality (Figure 3 and Figure II in the online-only Data Supplement). 5This important finding would have been obscured in an analysis based on the ratio of n-6 to n-3.The conceptual and biological flaws of the ratio of n-6 to n-3 have been described. 6A key flaw is the inability to discern very different conditions of dietary intake or underlying physiology (eg, a ratio may be identical when consumption and circulating levels of both n-6 and n-3 are high or when both are low, two very different circumstances).In addition, the ratio cannot distinguish increases in n-6 PUFAs from decreases in n-3 PUFAs.Finally, the conceptual basis of the ratio depends on the notion that n-6 PUFAs and n-3 PUFAs have opposing effects.However, substantial evidence indicates that both are beneficial 6 ; indeed, a recent meta-analysis found that individuals with higher circulating levels of arachidonic acid, the prototypical n-6 PUFAs thought to be proinflammatory and harmful, had lower risk of coronary disease. 7Given these considerations, we agree with Lucas that existing evidence suggests beneficial effect of dietary linoleic acid for cardiovascular outcomes, not harm, and use of the ratio of n-6 to n-3 is unlikely to impart meaningful information over and above assessment of the individual fatty acids alone.