Genome-wide association study identifies three common variants associated with serologic response to vitamin E supplementation in men

Abstract

Vitamin E inhibits lipid peroxidation in cell membranes, prevents oxidative damage to DNA by scavenging free radicals, and reduces carcinogen production. No study to our knowledge, however, has examined the association between genetic variants and response to long-term vitamin E supplementation. We conducted a genome-wide association study (GWAS) of common variants associated with circulating α-tocopherol concentrations following 3 y of controlled supplementation. The study population included 2112 middle-aged, male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort who received a trial supplementation of α-tocopherol (50 mg/d) and had fasting serum α-tocopherol concentrations measured after 3 y. Serum concentrations were log-transformed for statistical analysis and general linear models adjusted for age, BMI, serum total cholesterol, and cancer case status. Associations with serum response to α-tocopherol supplementation achieved genome-wide significance for 2 single nucleotide polymorphisms (SNP): rs964184 on 11q23.3 (P = 2.6 × 10(-12)) and rs2108622 on 19pter-p13.11 (P = 2.2 × 10(-7)), and approached genome-wide significance for one SNP, rs7834588 on 8q12.3 (P = 6.2 × 10(-7)). Combined, these SNP explain 3.4% of the residual variance in serum α-tocopherol concentrations during controlled vitamin E supplementation. A GWAS has identified 3 genetic variants at different loci that appear associated with serum concentrations after vitamin E supplementation in men. Identifying genetic variants that influence serum nutrient biochemical status (e.g., α-tocopherol) under supplementation conditions improves our understanding of the biological determinants of these nutritional exposures and their associations with cancer etiology.

Trial registration: ClinicalTrials.gov NCT00342992.

Conflict of interest statement

Author disclosures: J. M. Major, K. Yu, C. C. Chung, S. J. Weinstein, M. Yeager, W. Wheeler, K. Snyder, M. E. Wright, J. Virtamo, S. Chanock, and D. Albanes, no conflicts of interest.

Figures

FIGURE 1

Manhattan plots for GWAS of serum α-tocopherol following 3 y of vitamin E supplementation in men (ATBC Study) (A). The x-axis represents chromosomal positions and the y-axis shows P values on a logarithmic scale. For chromosome 8, P values for association testing across a region of 8q12.3 bounded by rs10808726 and rs4739053 were plotted (B). The orange line graph shows likelihood ratio statistics for recombination hotspot by SequenceLDhot software. The horizontal line indicates a likelihood ratio statistic cutoff to predict the presence of a hotspot with a false-positive rate of 1 in 3700 independent tests. The top SNP rs7834588 (P = 6.19 × 10−7) is in red. The bottom panel depicts a linkage disequilibrium pattern of the region in r2 and solid black arrows indicate recombination hotspots. ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; GWAS, genome-wide association study; SNP, single nucleotide polymorphism.