British Journal of Nutrition

Systematic Review

n-6 Fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials

Christopher E. Ramsdena1 c1, Joseph R. Hibbelna1, Sharon F. Majchrzaka1 and John M. Davisa2

a1 Section on Nutritional Neurosciences, Laboratory of Membrane Biochemistry and Biophysics, NIAAA, NIH, Bethesda, MD, USA

a2 Department of Psychiatry, School of Medicine, University of Illinois, Chicago, IL, USA


Randomised controlled trials (RCT) of mixed n-6 and n-3 PUFA diets, and meta-analyses of their CHD outcomes, have been considered decisive evidence in specifically advising consumption of ‘at least 5–10 % of energy as n-6 PUFA’. Here we (1) performed an extensive literature search and extracted detailed dietary and outcome data enabling a critical examination of all RCT that increased PUFA and reported relevant CHD outcomes; (2) determined if dietary interventions increased n-6 PUFA with specificity, or increased both n-3 and n-6 PUFA (i.e. mixed n-3/n-6 PUFA diets); (3) compared mixed n-3/n-6 PUFA to n-6 specific PUFA diets on relevant CHD outcomes in meta-analyses; (4) evaluated the potential confounding role of trans-fatty acids (TFA). n-3 PUFA intakes were increased substantially in four of eight datasets, and the n-6 PUFA linoleic acid was raised with specificity in four datasets. n-3 and n-6 PUFA replaced a combination of TFA and SFA in all eight datasets. For non-fatal myocardial infarction (MI)+CHD death, the pooled risk reduction for mixed n-3/n-6 PUFA diets was 22 % (risk ratio (RR) 0·78; 95 % CI 0·65, 0·93) compared to an increased risk of 13 % for n-6 specific PUFA diets (RR 1·13; 95 % CI 0·84, 1·53). Risk of non-fatal MI+CHD death was significantly higher in n-6 specific PUFA diets compared to mixed n-3/n-6 PUFA diets (P = 0·02). RCT that substituted n-6 PUFA for TFA and SFA without simultaneously increasing n-3 PUFA produced an increase in risk of death that approached statistical significance (RR 1·16; 95 % CI 0·95, 1·42). Advice to specifically increase n-6 PUFA intake, based on mixed n-3/n-6 RCT data, is unlikely to provide the intended benefits, and may actually increase the risks of CHD and death.

(Received August 18 2010)

(Accepted September 01 2010)


c1 Corresponding author: Dr C. E. Ramsden, Tel. +1 301 435 6591, fax +1 301 402 0016, email


Abbreviations: AHA, American Heart Association; ALA, α-linolenic acid; DART, Diet and Reinfarction Trial; Hosp N, hospital N; Hosp K, hospital K; LA, linoleic acid; LDHS, Lyon Diet Heart Study; MCS, Minnesota Coronary Survey; MI, myocardial infarction; ODHS, Oslo Diet-Heart Study; PHFO, partially hydrogenated fish oil; RR, risk ratio; RCOT, Rose Corn Oil Trial; RCT, randomised controlled trial; SDHS, Sydney Diet-Heart Study; STARS, St Thomas Atherosclerosis Regression Study; TFA, trans-fatty acid