Change in plasma α-tocopherol associations with attenuated pulmonary function decline and with CYP4F2 missense variation

Abstract

Background: Vitamin E (vitE) is hypothesized to attenuate age-related decline in pulmonary function. Objectives: We investigated the association between change in plasma vitE (ΔvitE) and pulmonary function decline [forced expiratory volume in the first second (FEV1)] and examined genetic and nongenetic factors associated with ΔvitE. Methods: We studied 1144 men randomly assigned to vitE in SELECT (Selenium and Vitamin E Cancer Prevention Trial). ΔvitE was the difference between baseline and year 3 vitE concentrations measured with GC-MS. FEV1 was measured longitudinally by spirometry. We genotyped 555 men (vitE-only arm) using the Illumina Expanded Multi-Ethnic Genotyping Array (MEGAex). We used mixed-effects linear regression modeling to examine the ΔvitE-FEV1 association. Results: Higher ΔvitE was associated with lower baseline α-tocopherol (α-TOH), higher baseline γ-tocopherol, higher baseline free cholesterol, European ancestry (as opposed to African) (all P < 0.05), and the minor allele of a missense variant in cytochrome P450 family 4 subfamily F member 2 (CYP4F2) (rs2108622-T; 2.4 μmol/L higher ΔvitE, SE: 0.8 μmol/L; P = 0.0032). Higher ΔvitE was associated with attenuated FEV1 decline, with stronger effects in adherent participants (≥80% of supplements consumed): A statistically significant ΔvitE × time interaction (P = 0.014) indicated that a 1-unit increase in ΔvitE was associated with a 2.2-mL/y attenuation in FEV1 decline (SE: 0.9 mL/y). The effect size for 1 SD higher ΔvitE (+4 μmol/mmol free-cholesterol-adjusted α-TOH) was roughly one-quarter of the effect of 1 y of aging, but in the opposite direction. The ΔvitE-FEV1 association was similar in never smokers (2.4-mL/y attenuated FEV1 decline, SE: 1.0 mL/y; P = 0.017, n = 364), and current smokers (2.8-mL/y, SE: 1.6 mL/y; P = 0.079, n = 214), but there was little to no effect in former smokers (-0.64-mL/y, SE: 0.9 mL/y; P = 0.45, n = 564). Conclusions: Greater response to vitE supplementation was associated with attenuated FEV1 decline. The response to supplementation differed by rs2108622 such that individuals with the C allele, compared with the T allele, may need a higher dietary intake to reach the same plasma vitE concentration.