Intake of Long-Chain ω-3 Fatty Acids From Diet and Supplements in Relation to Mortality

Griffith Bell

Elizabeth Kantor

Johanna Lampe

Alan Kristal

Susan Heckbert

Emily White

^{Correspondence to Griffith A. Bell, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109 (e-mail:}ude.wu@llebrg).

Abbreviations: CI, confidence interval; CVD, cardiovascular disease; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FFQ, food frequency questionnaire; HR, hazard ratio; ICD-10, International Classification of Diseases, Tenth Revision; PUFA, polyunsaturated fatty acid; RR, relative risk; VITAL, Vitamins and Lifestyle.

Received 2013 Apr 22; Accepted 2013 Dec 4.

Copyright © The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Abstract

Evidence from experimental studies suggests that the long-chain ω-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid have beneficial effects that may lead to reduced mortality from chronic diseases, but epidemiologic evidence is mixed. Our objective was to evaluate whether intake of long-chain ω-3 fatty acids from diet and supplements is associated with cause-specific and total mortality. Study participants (n = 70,495) were members of a cohort study (the Vitamins and Lifestyle Study) who were residents of Washington State aged 50–76 years at the start of the study (2000–2002). Participants were followed for mortality through 2006 (n = 3,051 deaths). Higher combined intake of eicosapentaenoic acid and docosahexaenoic acid from diet and supplements was associated with a decreased risk of total mortality (hazard ratio (HR) = 0.82, 95% confidence interval (CI): 0.73, 0.93) and mortality from cancer (HR = 0.77, 95% CI: 0.64, 0.92) but only a small reduction in risk of death from cardiovascular disease (HR = 0.87, 95% CI: 0.68, 1.10). These results suggest that intake of long-chain ω-3 fatty acids may reduce risk of total and cancer-specific mortality.

Keywords: cancer, cohort studies, dietary supplements, fish oil, mortality, ω-3 fatty acids

Abstract

Omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), particularly the long-chain ω-3 PUFAs eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6), have been a subject of scientific interest for over 40 years (1). While long-chain ω-3 PUFAs are consumed primarily through fatty fish in the diet, use of ω-3-containing fish oil supplements is increasing in the United States (2). Several lines of research suggest that long-chain ω-3 PUFAs have antiinflammatory properties, and given that inflammation has been linked to the development of cardiovascular disease (CVD) and several cancers, there is great interest in better understanding the potential health benefits of ω-3 PUFAs (3, 4). While trials of ω-3 supplements and CVD mortality have been inconsistent (5–7), a recent review of experimental animal studies, human trials, and observational studies concluded that ω-3 intake reduces coronary heart disease mortality (8). However, epidemiologic evidence of benefit for other major causes of mortality remains mixed (9, 10).

In a previous exploratory study of supplement use and total mortality in the Vitamins and Lifestyle (VITAL) cohort, we found a borderline decreased risk of total mortality associated with use of fish oil supplements (hazard ratio (HR) = 0.83, 95% confidence interval (CI): 0.70, 1.00) (11). Here, we present data on the association between long-chain ω-3 intake from diet and supplements and cause-specific mortality in the VITAL cohort. Few previous cohort studies of healthy populations have examined the effect of long-chain ω-3 PUFA consumption on total, cancer, and CVD mortality (10), and to our knowledge none have included combined intake from both dietary and supplemental sources.

Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; MET, metabolic equivalent of task; VITAL, Vitamins and Lifestyle.

^{Weight (kg)/height (m)}^.

^{Former users were omitted.}

^{Aspirin use (baby aspirin omitted) over the 10 years before baseline.}

Abbreviations: AA, arachidonic acid; CI, confidence interval; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HR, hazard ratio; MET, metabolic equivalent of task; VITAL, Vitamins and Lifestyle.

^{Numbers may not sum to totals because of missing data.}

^{Adjusted for age (as the time scale), sex, race/ethnicity, marital status (married/living together, never married, separated/divorced, widowed, or missing), education (high school graduate or less, some college, or college/advanced degree), total energy intake (kcal/day; continuous), body mass index (weight (kg)/height (m)}^{) at age 45 years (<18.5, 18.5–<25.0, 25.0–29.9, ≥30.0, or missing), average alcohol intake at age 45 years (none, <1 drink/day, 1–2 drinks/day, >2 drinks/day, or missing), average physical activity in the 10 years before baseline (MET-hours/week; tertiles), self-rated health (excellent, very good, good, fair, or poor), mammogram in the last 2 years (yes/no), prostate-specific antigen test in the last 2 years (yes/no), sigmoidoscopy in the last 10 years (yes/no), current use of cholesterol-lowering medication (yes/no), aspirin use in the past 10 years (none, low, high, or missing), use of nonaspirin nonsteroidal antiinflammatory drugs in the past 10 years (none, low, high, or missing), smoking (never, 1–12.5 pack-years, 12.6–35.0 pack-years, or >35.0 pack-years), morbidity score,}^{percentage of calories derived from}trans fat (quartiles), percentage of calories derived from saturated fat (quartiles), number of servings per day of fruits (quartiles), number of servings per day of vegetables (quartiles), years of estrogen therapy (none, <5, 5–9, ≥10, or missing), years of estrogen + progestin therapy (none, <5, 5–9, ≥10, or missing), age at menopause (≤39 years, 40–44 years, 45–49 years, 50–54 years, ≥55 years, or missing), age at death of father (≤59 years, 60–69 years, 70–79 years, 80–89 years, or ≥90 years), and age at death of mother (≤59 years, 60–69 years, 70–79 years, 80–89 years, or ≥90 years).

^{By using Cox regression, the following conditions, categorized as yes or no, were modeled simultaneously in sex-specific and age-adjusted models to obtain the morbidity score: depression or anxiety; hypertension; a history of lung cancer, colon cancer, bladder cancer, leukemia, non-Hodgkin's lymphoma, pancreatic cancer, melanoma, prostate cancer, breast cancer, cervical cancer, uterine cancer, or ovarian cancer (as separate variables), and all other cancers except nonmelanoma skin cancer combined; ischemic heart disease (defined as history of heart attack, coronary bypass surgery, angioplasty, or diagnosis of angina); stroke; congestive heart failure; rheumatoid arthritis; diabetes; viral hepatitis; cirrhosis of the liver; other chronic liver disease; emphysema, chronic bronchitis, or chronic obstructive pulmonary disease; kidney disease; ulcerative colitis or Crohn's disease; Parkinson's disease; and osteoporosis in women. Depression or anxiety, hypertension, and diabetes were defined as use of medications for these conditions at baseline.}

Abbreviations: CI, confidence interval; CVD, cardiovascular disease; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HR, hazard ratio; MET, metabolic equivalent of task; VITAL, Vitamins and Lifestyle.

^{Numbers may not sum to totals because of missing data. All models adjusted for age (as the time scale), sex, race/ethnicity, marital status (married/living together, never married, separated/divorced, widowed, or missing), education (high school graduate or less, some college, or college/advanced degree), body mass index (weight (kg)/height (m)}^{) at age 45 years (<18.5, 18.5–<25.0, 25.0–29.9, ≥30.0, or missing), average physical activity in the 10 years before baseline (MET-hours/week; tertiles), smoking (never, 1–12.5 pack-years, 12.6–35.0 pack-years, >35.0 pack-years, or missing), average alcohol intake at age 45 years (none, <1 drink/day, 1–2 drinks/day, >2 drinks/day, or missing), total energy intake (kcal/day; continuous), number of servings per day of fruits (quartiles), number of servings per day of vegetables (quartiles), dietary intake of arachidonic acid (g/day; continuous), aspirin use in the past 10 years (none, low, high, or missing), use of nonaspirin nonsteroidal antiinflammatory drugs in the past 10 years (none, low, high, or missing), self-rated health (excellent, very good, good, fair, or poor), sigmoidoscopy in the last 10 years (yes/no), mammogram in the last 2 years (yes/no), prostate-specific antigen test in the last 2 years (yes/no), and current use of cholesterol-lowering medication (yes/no).}

^{Reference category (HR = 1).}

^{Results were additionally adjusted for morbidity score (see footnote c of}Table 2), percentage of calories derived from trans fat (quartiles), percentage of calories derived from saturated fat (quartiles), years of estrogen therapy (none, <5, 5–9, ≥10, or missing), years of estrogen + progestin therapy (none, <5, 5–9, ≥10, or missing), age at menopause (≤39 years, 40–44 years, 45–49 years, 50–54 years, ≥55 years, or missing), age at death of father (≤59 years, 60–69 years, 70–79 years, 80–89 years, or ≥90 years), and age at death of mother (≤59 years, 60–69 years, 70–79 years, 80–89 years, or ≥90 years).

^{Results were additionally adjusted for history of cardiovascular disease (yes/no; defined as history of heart attack, coronary bypass surgery, angioplasty, stroke, congestive heart failure, or diagnosis of angina) family history of heart attack (number of relatives: 0, 1, or ≥2), current use of blood pressure medication (yes/no), percentage of calories derived from}trans fat (quartiles), percentage of calories derived from saturated fat (quartiles), years of estrogen therapy (none, <5, 5–9, or ≥10), and years of estrogen + progestin therapy (none, <5, 5–9, or ≥10).

^{Results were additionally adjusted for history of ischemic heart disease (yes/no; defined as history of heart attack, coronary bypass surgery, angioplasty, or diagnosis of angina), family history of heart attack (number of relatives: 0, 1, or ≥2), current use of blood pressure medication (yes/no), percentage of calories derived from}trans fat (quartiles), percentage of calories derived from saturated fat (quartiles), years of estrogen therapy (none, <5, 5–9, or ≥10), and years of estrogen + progestin therapy (none, <5, 5–9, or ≥10).

^{Results were additionally adjusted for history of cancer other than nonmelanoma skin cancer (yes/no), family history of cancer (number of relatives: 0, 1, or ≥2), years of estrogen therapy (none, <5, 5–9, or ≥10), years of estrogen + progestin therapy (none, <5, 5–9, or ≥10), age at menopause (≤39, 40–44, 45–49, 50–54, or ≥55 years), age at menarche (≤11, 12, 13, or ≥14 years), and number of servings of red/processed meat per week (quartiles).}

^{Results were additionally adjusted for history of lung cancer (yes/no), family history of lung cancer (number of relatives: 0, 1, or ≥2), history of emphysema, chronic bronchitis, or chronic obstructive pulmonary disease (yes/no), years of smoking, and pack-years squared.}

^{Results were additionally adjusted for history of leukemia/lymphoma (yes/no), family history of leukemia/lymphoma (number of relatives: 0, 1, or ≥2), history of any cancer (yes/no), history of rheumatoid arthritis (yes/no), and history of fatigue/lack of energy (yes/no).}

^{Results were additionally adjusted for history of colorectal cancer (yes/no), family history of colorectal cancer (number of relatives: 0, 1, or ≥2), history of diabetes (yes/no), years of estrogen therapy (none, <5, 5–9, or ≥10), years of estrogen + progestin therapy (none, <5, 5–9, or ≥10), calcium intake from diet, calcium intake from supplements, and number of servings of red/processed meat per week (quartiles).}

^{Results were additionally adjusted for history of breast cancer (yes/no), family history of breast cancer (number of relatives: 0, 1, or ≥2), years of estrogen therapy (none, <5, 5–9, or ≥10), years of estrogen + progestin therapy (none, <5, 5–9, or ≥10), age at first birth, history of hysterectomy (none, simple, total), age at menopause (≤39, 40–44, 45–49, 50–54, or ≥55 years), and age at menarche (≤11, 12, 13, or ≥14 years).}

^{Results were additionally adjusted for history of pancreatic cancer (yes/no), family history of pancreatic cancer (number of relatives: 0, 1, or ≥2), number of servings of red/processed meat per week (quartiles), and history of diabetes (yes/no).}

^{Hazard ratios and 95% confidence intervals were not calculated because of small numbers of deaths.}

ACKNOWLEDGMENTS

Author affiliations: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington (Griffith A. Bell, Elizabeth D. Kantor, Johanna W. Lampe, Alan R. Kristal, Emily White); Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington (Griffith A. Bell, Elizabeth D. Kantor, Johanna W. Lampe, Alan R. Kristal, Susan R. Heckbert, Emily White); Interdisciplinary Program in Nutritional Sciences, School of Public Health, University of Washington, Seattle, Washington (Johanna W. Lampe); and Department of Pharmacy and Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (Susan R. Heckbert).

This work was supported by grants R01-CA142545;, R25-CA94880;, and K05-CA154337 from the National Cancer Institute and the Office of Dietary Supplements, National Institutes of Health.

Conflict of interest: none declared.

ACKNOWLEDGMENTS

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