Relationship Between Serum Alpha-Tocopherol and Overall and Cause-Specific Mortality

Abstract

Rationale: Although there has been a long-standing interest in the human health effects of vitamin E, a comprehensive analysis of the association between circulating vitamin E and long-term mortality has not been conducted.

Objective: Determine whether serum α-tocopherol (the predominant form of vitamin E) is related to long-term overall and cause-specific mortality and elucidate the dose-response relationships with better quantification of the associations.

Methods and results: We conducted a biochemical analysis of 29 092 participants in the ATBC Study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention) that originally tested vitamin E and β-carotene supplementation. Serum α-tocopherol was measured at baseline using high-performance liquid chromatography, and during a 30-year follow-up we identified 23 787 deaths, including deaths from cardiovascular disease (9867), cancer (7687), respiratory disease (2161), diabetes mellitus (119), injuries and accidents (1255), and other causes (2698). After adjusting for major risk factors, we found that men with higher serum α-tocopherol had significantly lower all-cause mortality (hazard ratios=0.83, 0.79, 0.75, and 0.78 for quintile 2 (Q2)-Q5 versus Q1, respectively; P_trend<0.0001), and significantly decreased mortality from cardiovascular disease, heart disease, stroke, cancer, respiratory disease, and other causes, with risk reductions from 17% to 47% for the highest versus lowest quintile. The α-tocopherol association with overall mortality was similar across subgroups of smoking intensity, years of smoking, alcohol consumption, trial supplementation, and duration of follow-up. The association was, however, significantly modified by baseline age and body mass index, with stronger inverse associations for younger men and men with a lower body mass index ( P_interaction≤0.006).

Conclusions: In this long-term prospective cohort study, higher baseline serum α-tocopherol biochemical status was associated with lower risk of overall mortality and mortality from all major causes. Our data support the long-term health benefits of higher serum α-tocopherol for overall and chronic disease mortality and should be replicated in other more diverse populations.

Keywords: epidemiology; mortality; multivariate analysis; risk factors; vitamin E.

Figure 1.

Kaplan-Meier curves of overall and cause-specific mortality according to quintiles of serum alpha-tocopherol in 29,092 subjects in the ATBC Study. A) Overall mortality. B) Cardiovascular disease (CVD) mortality. C) Heart disease mortality. D) Stroke mortality.

Figure 2.

Kaplan-Meier curves of overall and cause-specific mortality according to quintiles of serum alpha-tocopherol in 16,610 subjects who do not have a history of CVD or diabetes mellitus in the ATBC Study. A) Overall mortality. B) Cardiovascular disease (CVD) mortality. C) Heart disease mortality. D) Stroke mortality.

Figure 3.

Cubic spline regression for estimated hazard ratios of overall and cause-specific death according to serum alpha-tocopherol concentrations in the ATBC Study. The reference value (9.3 mg/L; hazard ratio = 1) corresponds to the cutoff value of the first quintile of serum alpha-tocopherol concentration. A) Overall mortality. B) Cardiovascular disease (CVD) mortality. C) Heart disease mortality. D) Stroke mortality. The solid line suggests the hazard ratio for mortality and serum alpha-tocopherol with a 4-knot spline (knots were selected at the 5^th, 25^th, 75^th, and 95^th percentiles of the serum alpha-tocopherol); dashed lines denoted the 95% confidence intervals. Total number of participants: 29,092. Event number of overall-, CVD-, heart disease-, stroke death is 23,787, 9,867, 8,063, and 1,763, respectively.