Genome-wide association study identifies common variants associated with circulating vitamin E levels

Abstract

In genome-wide association studies (GWAS) of common genetic variants associated with circulating alpha- and gamma-tocopherol concentrations in two adult cohorts comprising 5006 men of European descent, we observed three loci associated with alpha-tocopherol levels, two novel single-nucleotide polymorphisms (SNPs), rs2108622 on 19pter-p13.11 (P= 1.7 × 10−8) and rs11057830 on 12q24.31 (P= 2.0 × 10−8) and confirmed a previously reported locus marked by rs964184 on 11q23.3 (P= 2.7 × 10−10). The three SNPs have been reported to be associated with lipid metabolism and/or regulation. We replicated these findings in a combined meta-analysis with two independent samples, P= 7.8 × 10−12 (rs964184 on 11q23.3 near BUD13, ZNF259 and APOA1/C3/A4/A5), P= 1.4 × 10−10 (rs2108622 on 19pter-p13.11 near CYP4F2) and P= 8.2 × 10−9 (rs11057830 on 12q24.31 near SCARB1). Combined, these SNPs explain 1.7% of the residual variance in log alpha-tocopherol levels. In one of the two male GWAS cohorts (n= 992), no SNPs were significantly associated with gamma-tocopherol concentrations after including data from the replication sample for 71 independent SNPs with P< 1 × 10−4 identified.

Complexity of vitamin E metabolism

“…Borel et al [217] analyzed polymorphisms in genes involved in lipid metabolism, namely APOA4, APOB, APOE, LPL and SRBI, and found α-or γ-TOH levels to be different in subjects with SNPs in APO4, APOE and SRBI or APO4 and SRBI, respectively. Major et al [218] found three SNPs to be associated with circulating α-TOH serum levels, rs964184 near APOA1, APOA4, APOA5 and APOC3, rs2108622 in CYP4F2 as well as rs11057830 in SCARB1. As the importance of proteins involved in lipoprotein metabolism for vitamin E transport and serum levels has been highlighted by these findings, Sundl et al [219] emphasized that vitamin E serum levels should be adjusted for plasma or serum lipids.…”

“…In addition, three SNPs in the coding region of the SEC14L2 gene encoding TAP1 are associated with increased serum vitamin E concentrations [224] . Major et al [218] identified a new SNP in the CYP4F2 gene (rs2108622) which encodes the vitamin E ω-hydroxylase. The physiological relevance of this SNP and the SNP rs3093105 has been characterized by Bardowell et al [225] .…”

Mechanisms for the prevention of vitamin E excess

“…Hacquebard et al ( 96 ) propose that CETP ␦ -tocopherol concentrations when ␦ -tocopherol and the inhibitor were simultaneously given to mice ( 123 ). Additionally, human CYP4F2 variants demonstrated varying -hydroxylation in vitro ( 124 ), but in a genome-wide association study, they were not found to dramatically change tocopherol concentrations or be associated with plasma ␥ -tocopherol concentrations ( 125 ). The CYP4F2 variant Rs2108622 was associated with increased circulating ␣ -tocopherol in subjects from the ATBC trial ( 126 ), suggesting that this variant has reduced -hydroxylation activity.…”

Disruption of Mouse Cytochrome P450 4f14 (Cyp4f14 Gene) Causes Severe Perturbations in Vitamin E Metabolism

“…For example, short term ingestion of sesame seeds, which contain sesamin, an inhibitor of CYP4F2 (28), results in elevation of serum ␥-TOH (29). A recent genome-wide association study reported that the V433M variant of CYP4F2 was positively associated with plasma vitamin E concentration (30). We previously reported that this variant exhibited a reduction in enzyme-specific activity by 40 -60% depending on the substrate (31).…”