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. Author manuscript; available in PMC: 2017 Aug 1.
Published in final edited form as: JAMA Intern Med. 2016 Aug 1;176(8):1134–1145. doi: 10.1001/jamainternmed.2016.2417

Table 3.

Associations between dietary n-6 and n-3 polyunsaturated fatty acid intake and total mortality (comparison is isocaloric substitution for carbohydrate)

Quintile of dietary fatty acid intake
 P trend HR (95% CI) a
Q1 Q2 Q3 Q4 Q5
n-6 polyunsaturated fatty acid
Total n-6 polyunsaturated fatty acids
 NHS
  Median (% energy) 3.4 4.3 4.9 5.5 6.7
  Deaths (n) 4124 4346 4158 3897 3789
  Age-adjusted model Ref. 0.89 (0.85, 0.92) 0.83 (0.79, 0.87) 0.77 (0.74, 0.81) 0.72 (0.69, 0.76) <.001 0.82 (0.80, 0.84)
  MV-adjusted model b Ref. 0.99 (0.95, 1.04) 0.94 (0.90, 0.99) 0.90 (0.85, 0.95) 0.88 (0.83, 0.93) <.001 0.92 (0.89, 0.95)
 HPFS
  Median (% energy) 3.7 4.5 5.1 5.8 6.9
  Deaths (n) 2874 2679 2622 2477 2338
  Age-adjusted model Ref. 0.90 (0.85, 0.95) 0.89 (0.85, 0.94) 0.84 (0.80, 0.89) 0.80 (0.76, 0.85) <.001 0.88 (0.85, 0.91)
  MV-adjusted model Ref. 0.91 (0.86, 0.96) 0.92 (0.87, 0.97) 0.85 (0.79, 0.90) 0.81 (0.75, 0.87) <.001 0.88 (0.84, 0.92)
 Pooled c
  Age-adjusted model Ref. 0.89 (0.86, 0.92) 0.85 (0.83, 0.88) 0.80 (0.77, 0.83) 0.75 (0.73, 0.78) <.001 0.84 (0.82, 0.86)
  MV-adjusted model Ref. 0.96 (0.93, 0.99) 0.93 (0.90, 0.97) 0.88 (0.84, 0.92) 0.85 (0.81, 0.89) <.001 0.90 (0.88, 0.93)
Linoleic acid
 NHS
  Median (% energy) 3.3 4.2 4.8 5.4 6.5
  Deaths (n) 4165 4358 4148 3896 3747
  Age-adjusted model Ref. 0.89 (0.85, 0.93) 0.83 (0.80, 0.87) 0.78 (0.74, 0.81) 0.70 (0.67, 0.74) <.001 0.80 (0.78, 0.82)
  MV-adjusted model Ref. 0.98 (0.94, 1.03) 0.93 (0.89, 0.98) 0.89 (0.84, 0.94) 0.84 (0.79, 0.89) <.001 0.89 (0.86, 0.92)
 HPFS
  Median (% energy) 3.6 4.4 5.0 5.6 6.7
  Deaths (n) 2910 2670 2569 2508 2333
  Age-adjusted model Ref. 0.92 (0.88, 0.97) 0.90 (0.85, 0.95) 0.85 (0.81, 0.90) 0.79 (0.75, 0.83) <.001 0.86 (0.83, 0.89)
  MV-adjusted model Ref. 0.94 (0.89, 1.00) 0.90 (0.85, 0.96) 0.86 (0.81, 0.92) 0.80 (0.74, 0.86) <.001 0.86 (0.82, 0.90)
 Pooled
  Age-adjusted model Ref. 0.90 (0.87, 0.93) 0.86 (0.83, 0.89) 0.81 (0.78, 0.84) 0.74 (0.71, 0.76) <.001 0.82 (0.81, 0.84)
  MV-adjusted model Ref. 0.97 (0.93, 1.00) 0.92 (0.89, 0.96) 0.88 (0.84, 0.91) 0.82 (0.79, 0.86) <.001 0.88 (0.86, 0.91)
Arachidonic acid
 NHS
  Median (% energy) 0.05 0.06 0.07 0.09 0.11
  Deaths (n) 5809 4329 3648 3419 3109
  Age-adjusted model Ref. 0.99 (0.95, 1.03) 0.96 (0.92, 1.00) 0.97 (0.93, 1.02) 0.94 (0.90, 0.99) 0.01 0.77 (0.63, 0.94)
  MV-adjusted model Ref. 0.99 (0.95, 1.03) 0.94 (0.89, 0.98) 0.94 (0.89, 0.99) 0.90 (0.85, 0.96) <.001 0.61 (0.46, 0.81)
 HPFS
  Median (% energy) 0.05 0.06 0.07 0.09 0.11
  Deaths (n) 2644 2595 2519 2546 2686
  Age-adjusted model Ref. 1.03 (0.97, 1.08) 1.01 (0.95, 1.06) 1.04 (0.99, 1.10) 1.02 (0.96, 1.08) 0.45 1.08 (0.85, 1.38)
  MV-adjusted model Ref. 1.00 (0.94, 1.06) 0.94 (0.88, 1.00) 0.96 (0.90, 1.03) 0.89 (0.82, 0.96) 0.005 0.55 (0.38, 0.78)
 Pooled
  Age-adjusted model Ref. 1.00 (0.97, 1.04) 0.98 (0.94, 1.01) 1.00 (0.97, 1.03) 0.97 (0.94, 1.01) 0.14 0.89 (0.76, 1.03)
  MV-adjusted model Ref. 0.99 (0.96, 1.03) 0.94 (0.90, 0.97) 0.94 (0.91, 0.98) 0.90 (0.85, 0.94) <.001 0.58 (0.47, 0.73)
n-3 polyunsaturated fatty acid
Total n-3 polyunsaturated fatty acids
 NHS
  Median (% energy) 0.48 0.57 0.63 0.72 0.88
  Deaths (n) 4132 3786 3875 4090 4431
  Age-adjusted model Ref. 0.90 (0.86, 0.94) 0.87 (0.83, 0.91) 0.82 (0.78, 0.86) 0.63 (0.60, 0.66) <.001 0.71 (0.69, 0.74)
  MV-adjusted model Ref. 1.00 (0.95, 1.04) 1.01 (0.96, 1.06) 1.03 (0.98, 1.08) 0.95 (0.90, 1.00) 0.04 0.96 (0.93, 1.00)
 HPFS
  Median (% energy) 0.46 0.57 0.65 0.75 0.94
  Deaths (n) 2441 2548 2645 2644 2712
  Age-adjusted model Ref. 0.87 (0.83, 0.93) 0.85 (0.80, 0.90) 0.82 (0.78, 0.87) 0.72 (0.68, 0.77) <.001 0.83 (0.80, 0.86)
  MV-adjusted model Ref. 0.98 (0.92, 1.04) 0.99 (0.94, 1.05) 1.00 (0.94, 1.06) 0.96 (0.90, 1.02) 0.26 0.97 (0.94, 1.01)
 Pooled
  Age-adjusted model Ref. 0.89 (0.86, 0.92) 0.86 (0.83, 0.89) 0.82 (0.79, 0.85) 0.66 (0.64, 0.69) <.001 0.77 (0.75, 0.78)
  MV-adjusted model Ref. 0.99 (0.96, 1.03) 1.00 (0.97, 1.04) 1.02 (0.98, 1.06) 0.95 (0.91, 0.99) 0.03 0.97 (0.94, 0.99)
α-linolenic acid
 NHS
  Median (% energy) 0.41 0.48 0.53 0.59 0.70
  Deaths (n) 4274 3800 3831 3839 4570
  Age-adjusted model Ref. 0.95 (0.91, 0.99) 0.97 (0.93, 1.01) 0.91 (0.87, 0.95) 0.75 (0.72, 0.78) <.001 0.75 (0.72, 0.78)
  MV-adjusted model Ref. 1.00 (0.95, 1.04) 1.05 (1.00, 1.10) 1.02 (0.97, 1.07) 0.98 (0.93, 1.04) 0.49 0.98 (0.93, 1.04)
 HPFS
  Median (% energy) 0.38 0.45 0.50 0.56 0.68
  Deaths (n) 2398 2431 2544 2700 2917
  Age-adjusted model Ref. 0.97 (0.91, 1.02) 0.95 (0.90, 1.01) 0.95 (0.90, 1.00) 0.85 (0.80, 0.90) <.001 0.86 (0.81, 0.90)
  MV-adjusted model Ref. 1.00 (0.94, 1.06) 1.02 (0.96, 1.08) 1.04 (0.98, 1.10) 1.01 (0.94, 1.08) 0.67 0.99 (0.93, 1.05)
 Pooled
  Age-adjusted model Ref. 0.96 (0.92, 0.99) 0.96 (0.93, 1.00) 0.93 (0.90, 0.96) 0.79 (0.76, 0.81) <.001 0.79 (0.77, 0.82)
  MV-adjusted model Ref. 1.00 (0.96, 1.03) 1.04 (1.00, 1.08) 1.03 (0.99, 1.07) 0.99 (0.95, 1.03) 0.80 0.98 (0.94, 1.02)
Marine n-3 fats (DHA+EPA)
 NHS
  Median (% energy) 0.03 0.05 0.08 0.12 0.21
  Deaths (n) 3725 4123 4247 4019 4200
  Age-adjusted model Ref. 0.98 (0.94, 1.03) 0.93 (0.89, 0.97) 0.83 (0.80, 0.87) 0.68 (0.65, 0.72) <.001 0.52 (0.48, 0.55)
  MV-adjusted model Ref. 1.06 (1.02, 1.11) 1.05 (1.01, 1.10) 1.03 (0.98, 1.08) 0.96 (0.91, 1.01) <.001 0.87 (0.81, 0.94)
 HPFS
  Median (% energy) 0.04 0.08 0.12 0.18 0.31
  Deaths (n) 2558 2655 2635 2490 2652
  Age-adjusted model Ref. 0.97 (0.91, 1.02) 0.97 (0.91, 1.02) 0.90 (0.85, 0.95) 0.82 (0.78, 0.87) <.001 0.80 (0.76, 0.85)
  MV-adjusted model Ref. 1.00 (0.95, 1.06) 1.05 (1.00, 1.12) 1.03 (0.97, 1.09) 0.98 (0.92, 1.04) 0.28 0.97 (0.91, 1.04)
 Pooled
  Age-adjusted model Ref. 0.98 (0.94, 1.01) 0.94 (0.91, 0.98) 0.86 (0.83, 0.89) 0.74 (0.71, 0.76) <.001 0.67 (0.64, 0.70)
  MV-adjusted model Ref. 1.04 (1.00, 1.07) 1.05 (1.02, 1.09) 1.03 (0.99, 1.07) 0.96 (0.93, 1.00) 0.002 0.93 (0.89, 0.98)
n-6/n-3 ratio
 NHS
  Median 5.5 6.7 7.6 8.4 9.9
  Deaths (n) 4070 4316 4275 4147 3506
  Age-adjusted model Ref. 1.14 (1.09, 1.19) 1.18 (1.13, 1.23) 1.22 (1.16, 1.27) 1.23 (1.18, 1.29) <.001 1.05 (1.04, 1.06)
  MV-adjusted model Ref. 1.06 (1.02, 1.11) 1.05 (1.01, 1.10) 1.06 (1.01, 1.11) 1.02 (0.97, 1.07) 0.55 1.00 (0.99, 1.01)
 HPFS
  Median 5.5 6.9 7.9 8.9 10.8
  Deaths (n) 2968 2782 2642 2432 2166
  Age-adjusted model Ref. 1.07 (1.02, 1.13) 1.11 (1.05, 1.17) 1.13 (1.07, 1.19) 1.11 (1.05, 1.18) <.001 1.02 (1.01, 1.03)
  MV-adjusted model Ref. 1.00 (0.95, 1.06) 0.97 (0.92, 1.03) 0.96 (0.90, 1.02) 0.94 (0.88, 1.00) 0.03 0.99 (0.98, 1.00)
 Pooled
  Age-adjusted model Ref. 1.11 (1.07, 1.15) 1.15 (1.11, 1.19) 1.18 (1.14, 1.22) 1.18 (1.14, 1.23) <.001 1.03 (1.03, 1.04)
  MV-adjusted model Ref. 1.04 (1.01, 1.08) 1.02 (0.99, 1.06) 1.02 (0.98, 1.06) 0.99 (0.95, 1.03) 0.29 1.00 (0.99, 1.00)

Abbreviations: HR, hazard ratio; CI, confidence interval; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; MV, multivariable; NHS, Nurses’ Health Study; HPFS, Health Professional Follow-up Study.

a

Hazard ratios (95% confidence interval) of total mortality for substituting 2% of energy from total n-6 polyunsaturated fatty acids and linoleic acid, and 0.3% of energy from total n-3 polyunsaturated fatty acids, arachidonic acid, and α-linolenic acid and marine n-3 fats, for the same energy from carbohydrate. For n-6/n-3 ration, the Hazard ratios (95% confidence interval) of total mortality were calculated for 1-unit increment.

b

Multivariable-adjusted model adjusted for age (in month), Caucasian (yes vs. no), marital status (with spouse, yes or no), body-mass index (<23, 23-24.9, 25-29.9, 30-34.9, ≥35 kg/m2), physical activity (<3.0, 3.0-8.9, 9.0-17.9, 18.0-26.9, ≥27.0 hours of metabolic equivalent tasks per week), smoking status (never, past, current 1-14 cigarettes/d, current 15-24 cigarettes/d, current ≥25 cigarettes/d), alcohol consumption (women: 0, 0.1-4.9, 5.0-14.9, ≥15 g/d; men: 0, 0.1-4.9, 5.0-29.9, ≥30 g/d), multivitamin use (yes vs. no), vitamin E supplementation use (yes vs. no), current aspirin use (yes vs. no), family history of myocardial infarction (yes vs. no), family history of diabetes (yes vs. no), family history of cancer (yes vs. no), history of hypertension (yes vs. no), history of hypercholesterolemia (yes vs. no), intakes of total energy, dietary cholesterol and percentage of energy intake from dietary protein(quintiles), and menopausal status and hormone use in women (premenopausal, postmenopausal never users, postmenopausal past users, postmenopausal current users). All models also included percentages of energy intake from remaining fatty acids (saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, trans fatty acids, n-6 polyunsaturated fatty acids, n-3 polyunsaturated fatty acids, linoleic acid, arachidonic acid, α-linolenic acid and marine n-3 fats, all in quintiles).

c

Results for NHS and HPFS from the multivariate model were combined using the fixed-effects model.