Reproduction Materials for: Change in Plasma Alpha-tocopherol Associations with Attenuated Pulmonary Function Decline and with CYP4F2 Missense Variation

<p><strong>PI-Provided Abstract:</strong> Background: Vitamin E (vitE) is hypothesized to attenuate age-related decline in pulmonary function.Objective: We investigated the association between change in plasma vitE (∆vitE) and pulmonary function decline (forced expiratory volume in the first second [FEV1]) and examined genetic and non-genetic factors associated with ∆vitE. Design: We studied 1,144 men randomized to vitE in the Selenium and Vitamin E Cancer Prevention Trial. ∆vitE was the difference between baseline and year 3 vitE concentrations measured with gas chromatography-mass spectrometry. FEV1 was measured longitudinally by spirometry. We genotyped 555 men (vitE-only arm) using the Illumina MEGAex array. We used mixed-effects linear regression modeling to examine the ∆vitE-FEV1 association.Results: Higher ∆vitE was associated with lower baseline α-tocopherol, higher baseline γ-tocopherol, higher baseline free cholesterol, European ancestry (vs. African) (all P<0.05), and the minor allele of a missense variant in CYP4F2 (rs2108622-T; 2.4 µmol/L higher ∆vitE, SE=0.8, P=0.0032). Higher ∆vitE was associated with attenuated FEV1 decline, with stronger effects in adherent participants (>80% of supplements consumed): a statistically significant ∆vitE × time interaction (P=0.014) indicated that a 1-unit increase in ∆vitE was associated with a 2.2 mL/year attenuation in FEV1 decline (SE=0.9). The effect size for 1 standard deviation higher ∆vitE (+4 µmol/mmol free-cholesterol-adjusted α-tocopherol) is ~¼ of the effect of one year of aging, but in the opposite direction. The ∆vitE-FEV1 association was similar in never smokers (2.4 mL/year attenuated FEV1 decline, SE=1.0, p=0.017, n=364), and current smokers (2.8 mL/year, SE=1.6, p=0.079, n=214), but there was little to no effect in former smokers (-0.64 mL/year, SE=0.9, p=0.45, n=564). Conclusions: Greater response to vitamin E supplementation was associated with attenuated FEV1 decline. The response to supplementation differed by rs2108622 such that individuals with the C allele, compared to the T allele, may need a higher dietary intake to reach the same plasma vitamin E concentration.Keywords: vitamin E, pulmonary function tests, CYP4F2, human, male, clinical trial, smoking, continental population groups, genome-wide association study</p>