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

Background Vitamin E (vitE) is hypothesized to attenuate age-related decline in pulmonary function. Objectives We investigated the association between change in plasma vitE ( increment vitE) and pulmonary function decline [forced expiratory volume in the first second (FEV1)] and examined genetic and nongenetic factors associated with increment vitE. Methods We studied 1144 men randomly assigned to vitE in SELECT (Selenium and Vitamin E Cancer Prevention Trial). increment vitE 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 (MEGA(ex)). We used mixed-effects linear regression modeling to examine the increment vitE-FEV1 association. Results Higher increment vitE was associated with lower baseline alpha-tocopherol (alpha-TOH), higher baseline gamma-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 mu mol/L higher increment vitE, SE: 0.8 mu mol/L; P = 0.0032). Higher increment vitE was associated with attenuated FEV1 decline, with stronger effects in adherent participants (>= 80% of supplements consumed): a statistically significant increment vitE x time interaction (P = 0.014) indicated that a 1-unit increase in increment vitE was associated with a 2.2-mL/y attenuation in FEV1 decline (SE: 0.9 mL/y). The effect size for 1 SD higher increment vitE (+4 mu mol/mmol free-cholesterol-adjusted alpha-TOH) was roughly one-quarter of the effect of 1 y of aging, but in the opposite direction. The increment vitE-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.