Skip to main content
PMC home page
The Journal of Nutrition logoLink to The Journal of Nutrition
. 2012 Mar 21;142(5):866–871. doi: 10.3945/jn.111.156349

Genome-Wide Association Study Identifies Three Common Variants Associated with Serologic Response to Vitamin E Supplementation in Men123,4

Jacqueline M Major 5, Kai Yu 5, Charles C Chung 6, Stephanie J Weinstein 5, Meredith Yeager 6, William Wheeler 7, Kirk Snyder 7, Margaret E Wright 8, Jarmo Virtamo 9, Stephen Chanock 5,6, Demetrius Albanes 5,*
PMCID: PMC3327745  PMID: 22437554

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.

Introduction

Vitamin E is an essential fat-soluble vitamin encompassing 8 forms that have similar chromanol structures; trimethyl (α-), dimethyl (β- or γ-), and monomethyl (δ-) tocopherol, and the corresponding tocotrienols (1). α-Tocopherol is the most abundant form of vitamin E in humans. Proposed for the prevention and treatment of numerous health conditions, there is ongoing research of its role in several chronic diseases, particularly in cancer, diabetes, and cardiovascular disease. Vitamin E is a potent antioxidant with antiinflammatory properties (1–5) and is known to induce cell death and reduce cell proliferation (6–8). In part because antioxidants such as vitamin E are hypothesized to and may prevent several diseases, the prevalence of vitamin E supplement use is high in the US and elsewhere.

Several studies have examined the association between vitamin E supplementation and cancer risk, often with inconsistent results. Whereas some observational data suggest benefits for vitamin E supplement use (9), several recent large cohort and intervention studies of α-tocopherol have been mixed, with cancer-preventative (10, 11) and causal effects (12) as well as inconclusive and null findings (2, 13) having been demonstrated. Two recent systematic reviews concluded that the associations between vitamin E and 2 common cancers, colorectal and prostate, were inconclusive and suggested that additional studies are needed (14, 15).

The discovery of genetic determinants of circulating nutrients, including vitamins A (16), B-12 (17), D (18), and E (19), genome-wide association studies (GWAS)10 is enhancing our ability to investigate their associations with human disease. It was recently proposed that common variants in genes involved in vitamin E transport and metabolism may modify the potential beneficial effects of vitamin E supplementation (20), but the role of genetic variation in the biological response to long-term use of vitamin E supplements has not been investigated. Randomized, controlled trials of vitamin supplementation, such as the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Selenium and Vitamin E Cancer Prevention Trial, are suitable to such nutrigenomic analyses, particularly when pre- and postsupplementation nutrient concentrations have been measured. We conducted a GWAS analysis of serum α-tocopherol response to 3 y of vitamin E supplementation in the ATBC Study.

Participants and Methods

Study population.

The ATBC Study was a randomized, placebo-controlled, double-blind intervention trial of α-tocopherol and β-carotene supplementation that initially focused on the prevention of lung and other cancers (21). The study was approved by the institutional review boards of the National Cancer Institute (USA) and the National Public Health Institute of Finland, and all participants provided written informed consent. Male smokers aged 50–69 y were recruited from southwest Finland between 1985 and 1988. A total of 29,133 men who smoked ≥5 cigarettes/d and were free of cancer at study entry completed the baseline examination. The daily vitamin supplementation regimen (i.e., α-tocopherol, β-carotene, both vitamins, or a placebo) continued for 5–8 y until early 1993 when the active intervention ended as scheduled. For the present analysis, the study cohort was limited to the subset of men for whom GWAS data were available from nested case-control studies (n = 4014) and who received the trial vitamin E supplementation (dl-α-tocopheryl acetate, 50 mg/d; n = 2156). After excluding men with missing data for the 3-y serum α-tocopherol (n = 40) or HDL cholesterol (n = 2) concentration or baseline BMI (n = 2), the final analytic cohort included 2112 men.

Phenotype measurements and genotyping.

Fasting serum samples were collected at baseline and at year 3 of intervention and stored at −70°C until assayed. Determination of α-tocopherol was performed by HPLC (22), with a CV of 2.2%. Serum cholesterol was determined enzymatically by the CHOD-PAP Method (Boehringer Mannhein) (23). Serum HDL cholesterol was measured after precipitation with dextran sulfate and magnesium chloride. BMI was calculated from participants’ measured heights and weights at baseline. DNA was extracted from whole blood using the phenol-chloroform method on blood samples collected during the vitamin supplementation period. Samples were genotyped using the Illumina 550K and 610-Quad platforms (16, 19). Single nucleotide polymorphisms (SNP) with a missing rate >2% were excluded.

Statistical analysis.

GWAS analyses were performed using the GLM function of the R software. Log-transformed α-tocopherol was linearly regressed on genotype adjusted for age (continuous), BMI (continuous), and cancer case status. The correlation between baseline and follow-up serum concentrations was examined. Paired t tests were performed to evaluate changes in serum α-tocopherol from baseline to 3 y after trial supplementation. SNP were modeled additively. To account for serum TG that were not measured in the ATBC Study, models were further adjusted for non-HDL cholesterol (serum total cholesterol − HDL, or essentially, LDL + VLDL), which more closely reflect TG than total cholesterol. Additionally adjusting for alcohol consumption did not markedly change the findings. To test whether SNP and serum α-tocopherol associations differed between baseline and 3 y, we included a cross-product term for the interaction between timepoint and SNP in a repeated-measures regression model (SAS Proc MIXED). For this study, the threshold for achieving GWAS significance was P < 5 × 10−7. Sensitivity analyses were performed to additionally account for serum total cholesterol and β-carotene supplementation in the models; the results were not markedly different.

To identify recombination hotspots in the region, we used SequenceLDhot (24), a program that uses the approximate marginal likelihood method (25) and calculates likelihood ratio statistics at a set of possible hotspots. The 1000 Genomes Project data (CEU+TSI, June 2011 release) (26) were used to identify recombination hotspots. Specifically, 418 SNPs with minor allele frequency ≥0.2 within a ~268-kb region (chr8:63782563–64050563, UCSC genome build hg19) were phased using PHASE v2.1 (27, 28) to calculate background recombination rates. The PHASE outcome was used as direct input for the SequenceLDhot program. Linkage disequilibrium was calculated as r2 and a heat map was drawn using the snp.plotter package (29) in R (version 2.13.2) (30).

Results

The mean serum concentration of α-tocopherol after 3 y of the standard dose-trial supplementation was higher than the baseline concentrations, with means of 18.1 vs. 11.9 mg/L (42.0 vs. 27.6 μmol/L), respectively (P < 0.001) (Table 1). The wide range of response to 50 mg/d vitamin E supplementation is noteworthy. Change in the serum α-tocopherol concentrations from baseline to 3 y was also highly significant (P < 0.001) based on paired comparisons [mean change, 6.2 mg/L (14.4 μmol/L)]. By contrast, no significant changes were observed between baseline and 3-y serum total and non-HDL cholesterol concentrations. The correlation between the baseline and follow-up serum α-tocopherol concentrations was r = 0.63 (P < 0.0001).

TABLE 1.

Characteristics of the ATBC Study participants

Characteristic Baseline (n = 4014) Year 31 (n = 2112)
Age at randomization, y
 Mean ± SD 58.1 ± 5.0
 Median (range) 58 (49–70)
BMI at baseline, kg/m2
 Mean ± SD 26.2 ± 3.7
 Median (range) 25.9 (16.1–49.4)
Serum total cholesterol, mmol/L
 Mean ± SD 6.2 ± 1.2 6.1 ± 1.1
 Median (range) 6.2 (2.8–11.9) 6.0 (2.9–10.7)
Serum HDL cholesterol, mmol/L
 Mean ± SD 1.2 ± 0.3 1.2 ± 0.3
 Median (range) 1.1 (0..3–3.6) 1.1 (0.4–2.6)
Serum α-tocopherol,2mg/L
 Mean ± SD 11.9 ± 3.4 18.1 ± 5.3
 Median (range) 11.5 (1.9–52.9) 17.3 (5.3–86.4)
Open in a new tab
1

On-trial supplementation of α-tocopherol (50 mg/d). ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.

2

To convert serum tocopherol values from mg/L to mol/L, multiply by 2.322.

The P values for the association analysis of 549,989 SNP that passed the quality control metrics with 3-y supplementation α-tocopherol serum concentrations are displayed in the Manhattan plot (Fig. 1A), with each point representing a single SNP association plotted according to chromosome (x-axis) and -log(10) (y-axis) P value. Three SNP, rs964184 and rs12292921 in region 11q23.3 and rs2108622 in region 19p13.12, achieved genome-wide significance for the association with serum α-tocopherol concentration after 3 y of vitamin E supplementation (P value < 5.0 × 10−7), and 2 SNP, rs7834588 in 8q12.3 and rs12805061 in 11q23.3, approached genome-wide significance (P = 6.2 × 10−7 and P = 9.7 × 10−7, respectively) (Supplemental Table 1). SNP rs12292921 and rs12805061 were not independently associated with 3-y circulating α-tocopherol concentrations based on a general linear regression model conditioned on rs964184, suggesting that these 3 variants represent an association signal derived from a common source. The quantile-quantile plot is provided as supplemental information (Supplemental Fig. 1). There was no evidence of overall systematic bias (genomic inflation factor, λ = 1.00).

FIGURE 1.

FIGURE 1

Open in a new tab

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.

SNP rs964184 (11q23.3:116648917, hg19, P = 2.6 × 10−12) is located between the BUD13 homolog (Saccharomyces cerevisiae) and zinc finger protein 259 (ZNF259) and only 359 bp 3′ to ZNF259. Rs12292921 is located between LOC100128347 and BUD13. SNP rs2108622 (19p13.12:15990431, hg19, P = 2.2 × 10−7) is a missense mutation [V(Val) to M (Met)] in the region of CYP4F2 (cytochrome P450, family 4, subfamily F, polypeptide 2). SNP rs7834588 (8q12.3:63883593, hg19, P = 6.2 × 10−7) is located in an intron of Na+/K+ Transporting ATPase Interacting Protein 3 (NKAIN3). The magnitudes of the estimated βs ranged from 0.03 to 0.07 (Table 2). Combined, the 3 independent SNP accounted for 3.4% of the variance in log-transformed serum α-tocopherol concentrations after 3 y of vitamin E supplementation.

TABLE 2.

Serum α-tocopherol concentrations by genotype for SNP independently associated in GWAS with serum α-tocopherol response to 3 y of vitamin E supplementation in men (ATBC Study)1

Minor alleles, n
SNP Chr Location Gene MAF P value β SE 0 1 2
Serumα-tocopherol,2mg/L
rs964184 11 116154127 BUD13/ZNF259/APOA5 0.15 (G) 2.6 x 10−12 0.07 0.01 17.5 19.2 21.2
rs2108622 19 15851431 CYP4F2 0.19 (T) 2.2 x 10−7 0.04 0.01 17.8 18.6 19.3
rs7834588 8 64046147 NKAIN3 0.41 (T) 6.2 x 10−7 0.03 0.01 17.5 18.2 18.8
Open in a new tab
1

Mean 3-y serum levels are reported for 0 to 2 copies of the minor alleles for the 2112 individuals. The regression beta and standard error were based on logarithmic scale. Models were adjusted for age, BMI, non-HDL cholesterol concentrations, and cancer case status. ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; Chr, chromosome; GWAS, genome-wide association study; MAF, minor allele frequency; SNP, single nucleotide polymorphism.

2

To convert serum tocopherol values from mg/L to mol/L, multiply by 2.322.

Because of the significant associations between both rs964184 and rs2108622 and unsupplemented circulating α-tocopherol, the recombination hotspot plots for in these SNP regions were previously reported (19). For SNP rs7834588, a novel SNP for serum response to supplementation with α-tocopherol, a total of 5 recombination hotspots were inferred within the ~268-kb region analyzed (Fig. 1B). The top SNP, rs7834588, is located in an intron of NKAIN3 and within an inferred recombination hotspot interval (chr8:63882649–63884649, hg19). This hotspot corresponds to a HapMap estimated hotspot (ch8:63881447–63884447, hg19) (31).

A subgroup analysis of men whose baseline concentrations of serum α-tocopherol were above the median value of 11.5 mg/L (26.7 μmol/L) confirmed our findings for the association of rs964184 with the 3-y supplemented α-tocopherol concentrations (P = 4.8 × 10−10, β = 0.08). No SNP reached genome-wide significant associations when analysis was restricted to men who had baseline serum α-tocopherol concentrations below the median (data not shown). To explore whether different SNP were associated with nonresponse to vitamin E supplementation, we performed an additional subgroup GWAS analysis on men whose 3-y serum α-tocopherol concentrations were below the median value; one SNP located in the discs, large homolog 1 (DLG1) gene, approached genome-wide significance (rs9861063, P = 9.6 × 10−7). DLG1 is an essential, multi-domain scaffolding protein that may play a role in signal transduction and cell proliferation. Our main SNP signal, rs964184, was significant only among men with 3-y concentrations above the median serum α-tocopherol value (P = 1.9 × 10−11, β = 0.06). We additionally tested whether the association of our top SNP differed between time points (i.e., baseline and 3-y follow-up) by including a cross-product term for the interaction between time point and SNP in a repeated-measures regression model. We found that the association of SNP with serum α-tocopherol differed between baseline and following 3 y of supplementation for rs964184 (P = 0.01) and rs7834588 (P = 0.001) but was not significant for rs2108622 (P = 0.16), albeit the effect sizes (i.e., βs) were only slightly larger after 3 y of vitamin E supplementation compared with baseline. A sensitivity analysis that examined change in serum α-tocopherol concentrations from baseline to 3 y confirmed findings for the association with rs964184 (P = 3.6 × 10−7) at the genome-wide significance concentration (Table 3) but not for the other 2 top SNP (rs2108622 and rs7834588) (Supplemental Table 2). The associations of rs11057830 in scavenger receptor class B member 1 (SCARB1) on 12p24.31, which was highly significantly related to the baseline unsupplemented α-tocopherol concentrations (P = 2.0 × 10−8), was weakly associated with circulating α-tocopherol after supplementation and unrelated to change in α-tocopherol concentrations (Table 3).

TABLE 3.

Associations of SNP rs964184, rs2108622, rs7834588, and rs11057830 with serum α-tocopherol concentration at baseline and 3 y, and with change in serum α-tocopherol after 3 y of vitamin E supplementation in men (ATBC Study)1

SNP Baseline (n = 4014) 3 y (n = 2112) Change in α-tocopherol2 (n = 2112)
rs964184
 β 0.04 0.07 0.88
 SE 0.01 0.01 0.17
 P value 2.7 x 10−10 2.6 x 10−12 3.6 x 10−7
rs2108622
 β 0.04 0.04 0.51
 SE 0.01 0.01 0.16
 P value 1.7 x 10−8 2.2 x 10−7 1.4 x 10−3
rs7834588
 β 0.01 0.03 0.47
 SE 0.01 0.01 0.13
 P value 6.7 x 10−2 6.2 x 10−7 1.9 x 10−4
rs11057830
 β 0.04 0.03 0.03
 SE 0.01 0.01 0.18
 P value 2.0 x 10−8 2.9 x 10−3 8.5 x 10−1
Open in a new tab
1

The regression β and SE were based on logarithmic scale for 3-y α-tocopherol. Models were adjusted for age, BMI, non-HDL cholesterol concentrations, and cancer case status. ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; SNP, single nucleotide polymorphism.

2

Change in α-tocopherol concentrations from baseline to 3 y.

Genes encoding proteins involved in vitamin E transport and metabolism include α-tocopherol transfer protein (TTPA), SEC14-like protein 2 (SEC14L2), cytochrome p450, family 3, subfamily A (CYP3A), cholesteryl ester transfer protein (CETP), and cluster of the differentiation (CD36) (32–34). In the present GWAS analysis, gene variants in SEC14L2, CYP3A, CETP, and CD36 did not reach genome-wide significance, although 2 SNP in TTPA and one SNP in a separate cluster of the differentiation gene (CD4) were associated with a high level of significance (i.e., rs6472073, P = 2.1 × 10−5 and rs1031551, P = 2.9 × 10−5 in TTPA, and rs3741920 in CD4, P = 4.2 × 10−6). These findings represent promising signals for these candidate genes that should be examined in other studies (32, 33).

Discussion

In our GWAS, we found that 5 SNP, including 3 independent loci (rs964184, rs12272004, rs7834588), were associated with serum response to long-term α-tocopherol (vitamin E) supplementation. Two of the 3 SNP localize to candidate genes that have a strong biological basis in vitamin E transport and metabolism (i.e., BUD13 and CYP4F2), and the third SNP was located in NKAIN3, the gene encoding a Na+/K+ transport membrane protein. Our findings identify common variants that can partially explain how much genetic variation contributes to the variability of vitamin-E status in a supplemented state, with the 3 SNP together explaining 3.4% of the variance in the log-transformed serum α-tocopherol concentrations among vitamin E-supplemented individuals. That 3.4% of the variance of response to a standard 50-mg daily dose is in line with GWAS of other micronutrients, including vitamins A and D, points to the inter-individual variation in response to supplementation.

Two previous GWAS studies examined circulating α-tocopherol concentrations (19, 35), but neither investigated vitamin E concentrations in response to long-term daily supplementation. Consistent with the prior findings, we observed significant and near genome-wide significant markers in the region of BUD13/ZNF259/APOA5 (rs964184, P = 2.6 × 10−12 and rs12272004, P = 2.2 × 10−6). Although the rs12272004 SNP was previously reported to be associated with serum α-tocopherol concentrations (P = 3.9 × 10−7) (35), it was not highly correlated with the SNP most significantly associated with α-tocopherol concentrations (rs964184; linkage disequilibrium r2 = 0.20). The minor allele in the same SNP, rs964184, has also been reported to be associated with lower HDL cholesterol and higher TG concentrations according to the results of recent meta-analyses (36–39) and the APOA gene has been reported to predispose carriers to elevated concentrations of TG and vitamin E (40, 41). Rs2108622 in CYP4F2 has been reported to be associated with altered fatty acid metabolism (42) but not with TG (P values ranging from 0.39 to 0.97) in meta-analyses (37–39), supporting a potential nonlipid transport function for CYP4F2 in vitamin E metabolism, i.e., by catalyzing tocopherol phytyl side-chain oxidation. With regard to our signal in the region of NKAIN3, the observed association with serum α-tocopherol in the supplemented state may be partly explained by the role vitamin E plays in preventing loss of Na/K-ATPase activity (a plasma membrane-bound enzyme essential for the maintenance of cell viability) and lipid peroxidation (43, 44). It is clear that the biological actions and potential benefits of vitamin E supplementation may function at multiple levels, including chain-breaking protection against oxidative damage and inhibition of free radical-mediated lipid peroxidation within lipid-rich regions of the cell, including the plasma, nuclear, and mitochondrial membranes. Alternatively, vitamin E may also modify the signal transduction cascade of proinflammatory cytokines by inhibiting, e.g., NF-κβ activation (45).

Our study is largely confirmatory of previous findings, mainly that SNP in 2 independent loci (rs964184 in BUD13/ZNF259/APOA5 and rs2108622 in CYP4F2) are statistically related to serum α-tocopherol. An additional variant (rs7834588 in NKAIN3) was also identified, whereas other loci identified in previous studies (e.g., TTPA and SEC14L2) were not associated or did not meet the extremely high requirements of a GWAS. It is of note that the variant in NKAIN3, rs7834588, was not associated with lipids in recent GWAS meta-analyses (P values ranging from 0.23 to 0.81) (37–39). Why other biologically relevant genes appear to be less significantly associated with on-supplementation α-tocopherol concentrations compared with BUD13, CYP4F2, and NKAIN3 remains to be determined, although variation in the blood carriage capacity (i.e., BUD13), metabolism (i.e., CYP4F2), and plasma membrane regulation (i.e., NKAIN3) may be more important than hepatic tocopherol transfer from chylomicrons to lipoproteins (i.e., TTPA).

Strengths of the present study include the controlled and long-term nature of the vitamin E supplementation within an intervention trial, the large sample size, and the availability of α-tocopherol concentrations measured in fasting serum from 2 time points 3 y apart. To our knowledge, no study has examined the association between genetic variants and serum concentrations after vitamin E supplementation and few large trials of vitamin supplementation have repeated measures of on-study serum nutrient concentrations. Our investigation is limited in that TG concentrations were not measured and we were therefore unable to directly adjust for them, although we did adjust for serum total cholesterol and non-HDL cholesterol concentrations, which did not alter the findings. Previous meta-analyses have not reported a significant association for the CYP4F2 SNP and TG concentrations (37–39), however, and the relation between TG and rs7834588 (NKAIN3) is not known. Another potential limitation is that all participants in our genome-wide scan were male smokers and it has been reported that smoking-associated free radicals deplete vitamin E and other antioxidants (46). The possible modifying effects of smoking status on the observed associations with response to vitamin supplementation therefore cannot be excluded. Arguing against a substantial role for smoking in the associations we observed here, however, is the fact that 2 of the 3 SNP (rs964184 and rs2108622) were associated with unsupplemented serum α-tocopherol in a population of women primarily comprosed of individuals who never smoked (19), thus making both smoking-related and gender-based heterogeneity in the vitamin E-genetic associations unlikely.

Insights gained from this nutrigenomic study of serologic response to vitamin E supplementation, following replication of the findings in other populations, may have potential application to more personalized regimens for vitamin E supplementation. The findings also have implications for the investigation of complex diseases such as cardiovascular disease, diabetes, and cancer and indicate that the genetic variants identified in the present study can be examined in human studies to test vitamin E-risk associations. Further investigation of the biological mechanisms underlying some of the associations observed here (e.g., for NKAIN3) is needed.

Acknowledgments

D.A., J.M.M., S.J.W., and S.C. designed the research project; D.A. and J.V. designed the ATBC Study; J.V., M.Y., C.C.C., W.W., and K.S. conducted the research; J.M.M. and K.Y. analyzed the data; J.M.M. wrote the paper; K.Y., S.C., C.C.C., S.J.W., M.Y., M.E.W., and J.V. performed a major critical review; and D.A. had primary responsibility for final content. All authors read and approved the final manuscript.

Footnotes

1

Supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, the research was supported by Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C) from the National Cancer Institute, Department of Health and Human Services.

3

This trial was registered at clinicaltrials.gov as NCT00342992.

4

Supplemental Tables 1 and 2 and Supplemental Figure 1 are available from the “Online Supporting Material” link in the online posting of the article and from the same link in the online table of contents at http://jn.nutrition.org.

10

Abbreviations used: ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; GWAS, genome-wide association study; SNP, single nucleotide polymorphism.

Literature Cited

  • 1.Aggarwal BB, Sundaram C, Prasad S, Kannappan R. Tocotrienols, the vitamin E of the 21(st) century: it's potential against cancer and other chronic diseases. Biochem Pharmacol. 2010;80:1613–31 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, Parnes HL, Minasian LM, Gaziano JM, Hartline JA, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009;301:39–51 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Mayer-Davis EJ, Costacou T, King I, Zaccaro DJ, Bell RA. Plasma and dietary vitamin E in relation to incidence of type 2 diabetes: The Insulin Resistance and Atherosclerosis Study (IRAS). Diabetes Care. 2002;25:2172–7 [DOI] [PubMed] [Google Scholar]
  • 4.Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, Ross C, Arnold A, Sleight P, Probstfield J, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293:1338–47 [DOI] [PubMed] [Google Scholar]
  • 5.Marchioli R, Schweiger C, Levantesi G, Tavazzi L, Valagussa F. Antioxidant vitamins and prevention of cardiovascular disease: epidemiological and clinical trial data. Lipids. 2001;36 Suppl:S53–63 [DOI] [PubMed] [Google Scholar]
  • 6.Shklar G, Schwartz JL. Vitamin E inhibits experimental carcinogenesis and tumour angiogenesis. Eur J Cancer B Oral Oncol. 1996;32B:114–9 [DOI] [PubMed] [Google Scholar]
  • 7.Sigounas G, Anagnostou A, Steiner M. dl-alpha-Tocopherol induces apoptosis in erythroleukemia, prostate, and breast cancer cells. Nutr Cancer. 1997;28:30–5 [DOI] [PubMed] [Google Scholar]
  • 8.Meydani SN, Beharka AA. Recent developments in vitamin E and immune response. Nutr Rev. 1998;56:S49–58 [DOI] [PubMed] [Google Scholar]
  • 9.Bostick RM, Potter JD, McKenzie DR, Sellers TA, Kushi LH, Steinmetz KA, Folsom AR. Reduced risk of colon cancer with high intake of vitamin E: the Iowa Women's Health Study. Cancer Res. 1993;53:4230–7 [PubMed] [Google Scholar]
  • 10.Albanes D, Malila N, Taylor PR, Huttunen JK, Virtamo J, Edwards BK, Rautalahti M, Hartman AM, Barrett MJ, Pietinen P, et al. Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: results from a controlled trial (Finland). Cancer Causes Control. 2000;11:197–205 [DOI] [PubMed] [Google Scholar]
  • 11.Weinstein SJ, Wright ME, Pietinen P, King I, Tan C, Taylor PR, Virtamo J, Albanes D. Serum alpha-tocopherol and gamma-tocopherol in relation to prostate cancer risk in a prospective study. J Natl Cancer Inst. 2005;97:396–9 [DOI] [PubMed] [Google Scholar]
  • 12.Klein EA, Thompson IM, Jr, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, Minasian LM, Ford LG, Parnes HL, Gaziano JM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306:1549–56 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Rodriguez C, Jacobs EJ, Mondul AM, Calle EE, McCullough ML, Thun MJ. Vitamin E supplements and risk of prostate cancer in U.S. men. Cancer Epidemiol Biomarkers Prev. 2004;13:378–82 [PubMed] [Google Scholar]
  • 14.Stratton J, Godwin M. The effect of supplemental vitamins and minerals on the development of prostate cancer: a systematic review and meta-analysis. Fam Pract. 2011;28:243–52 [DOI] [PubMed] [Google Scholar]
  • 15.Arain MA, Abdul Qadeer A. Systematic review on "vitamin E and prevention of colorectal cancer". Pak J Pharm Sci. 2010;23:125–30 [PubMed] [Google Scholar]
  • 16.Mondul AM, Yu K, Wheeler W, Zhang H, Weinstein SJ, Major JM, Cornelis MC, Mannisto S, Hazra A, Hsing A, et al. doi: 10.1093/hmg/ddr387. Genome-wide association study of circulating retinol levels. Hum Mol Genet. Epub 2011 Aug 30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Hazra A, Kraft P, Selhub J, Giovannucci EL, Thomas G, Hoover RN, Chanock SJ, Hunter DJ. Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat Genet. 2008;40:1160–2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, Jacobs EJ, Ascherio A, Helzlsouer K, Jacobs KB, et al. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet. 2010;19:2739–45 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Major JM, Yu K, Wheeler W, Zhang H, Cornelis MC, Wright ME, Yeager M, Snyder K, Weinstein SJ, Mondul AM, et al. Genome-wide association study identifies common variants associated with circulating vitamin E levels. Hum Mol Genet. 2011;20:3876–83 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Zingg JM, Azzi A, Meydani M. Genetic polymorphisms as determinants for disease-preventive effects of vitamin E. Nutr Rev. 2008;66:406–14 [DOI] [PubMed] [Google Scholar]
  • 21.The ATBC Cancer Prevention Study Group The alpha-tocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics, and compliance. The ATBC Cancer Prevention Study Group. Ann Epidemiol. 1994;4:1–10 [DOI] [PubMed] [Google Scholar]
  • 22.Milne DB, Botnen J. Retinol, alpha-tocopherol, lycopene, and alpha- and beta-carotene simultaneously determined in plasma by isocratic liquid chromatography. Clin Chem. 1986;32:874–6 [PubMed] [Google Scholar]
  • 23.Kattermann R, Jaworek D, Moller G, Assmann G, Bjorkhem I, Svensson L, Borner K, Boerma G, Leijnse B, Desager JP, et al. Multicentre study of a new enzymatic method of cholesterol determination. J Clin Chem Clin Biochem. 1984;22:245–51 [DOI] [PubMed] [Google Scholar]
  • 24.Fearnhead P. SequenceLDhot: detecting recombination hotspots. Bioinformatics. 2006;22:3061–6 [DOI] [PubMed] [Google Scholar]
  • 25.Fearnhead P, Donnelly P. Approximate likelihood methods for estimating local recombination rates. J R Stat Soc Ser A Stat Soc. 2002;64:657–80 [Google Scholar]
  • 26.The 1000 Genomes Project Consortium A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061–73 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Crawford DC, Bhangale T, Li N, Hellenthal G, Rieder MJ, Nickerson DA, Stephens M. Evidence for substantial fine-scale variation in recombination rates across the human genome. Nat Genet. 2004;36:700–6 [DOI] [PubMed] [Google Scholar]
  • 28.Li N, Stephens M. Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data. Genetics. 2003;165:2213–33 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Luna A, Nicodemus KK. snp.plotter: an R-based SNP/haplotype association and linkage disequilibrium plotting package. Bioinformatics. 2007;23:774–6 [DOI] [PubMed] [Google Scholar]
  • 30.R Development Core Team R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2008 [Google Scholar]
  • 31.McVean GA, Myers SR, Hunt S, Deloukas P, Bentley DR, Donnelly P. The fine-scale structure of recombination rate variation in the human genome. Science. 2004;304:581–4 [DOI] [PubMed] [Google Scholar]
  • 32.Wright ME, Peters U, Gunter MJ, Moore SC, Lawson KA, Yeager M, Weinstein SJ, Snyder K, Virtamo J, Albanes D. Association of variants in two vitamin e transport genes with circulating vitamin e concentrations and prostate cancer risk. Cancer Res. 2009;69:1429–38 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Lecompte S, Szabo de Edelenyi F, Goumidi L, Maiani G, Moschonis G, Widhalm K, Molnar D, Kafatos A, Spinneker A, Breidenassel C, et al. Polymorphisms in the CD36/FAT gene are associated with plasma vitamin E concentrations in humans. Am J Clin Nutr. 2011;93:644–51 [DOI] [PubMed] [Google Scholar]
  • 34.Döring F, Rimbach G, Lodge JK. In silico search for single nucleotide polymorphisms in genes important in vitamin E homeostasis. IUBMB Life. 2004;56:615–20 [DOI] [PubMed] [Google Scholar]
  • 35.Ferrucci L, Perry JR, Matteini A, Perola M, Tanaka T, Silander K, Rice N, Melzer D, Murray A, Cluett C, et al. Common variation in the beta-carotene 15,15'-monooxygenase 1 gene affects circulating levels of carotenoids: a genome-wide association study. Am J Hum Genet. 2009;84:123–33 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Weissglas-Volkov D, Aguilar-Salinas CA, Sinsheimer JS, Riba L, Huertas-Vazquez A, Ordonez-Sanchez ML, Rodriguez-Guillen R, Cantor RM, Tusie-Luna T, Pajukanta P. Investigation of variants identified in Caucasian genome-wide association studies for plasma high-density lipoprotein cholesterol and triglycerides levels in Mexican dyslipidemic study samples. Circ Cardiovasc Genet. 2010;3:31–8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, Kaplan L, Bennett D, Li Y, Tanaka T, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009;41:56–65 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, Heath SC, Timpson NJ, Najjar SS, Stringham HM, et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008;40:161–9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707–13 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Guardiola M, Ribalta J, Gomez-Coronado D, Lasuncion MA, de Oya M, Garces C. The apolipoprotein A5 (APOA5) gene predisposes Caucasian children to elevated triglycerides and vitamin E (Four Provinces Study). Atherosclerosis. 2010;212:543–7 [DOI] [PubMed] [Google Scholar]
  • 41.Sundl I, Guardiola M, Khoschsorur G, Sola R, Vallve JC, Godas G, Masana L, Maritschnegg M, Meinitzer A, Cardinault N, et al. Increased concentrations of circulating vitamin E in carriers of the apolipoprotein A5 gene - 1131T>C variant and associations with plasma lipids and lipid peroxidation. J Lipid Res. 2007;48:2506–13 [DOI] [PubMed] [Google Scholar]
  • 42.Hardwick JP. Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases. Biochem Pharmacol. 2008;75:2263–75 [DOI] [PubMed] [Google Scholar]
  • 43.Swarts HG, Schuurmans Stekhoven FM, De Pont JJ. Binding of unsaturated fatty acids to Na+, K(+)-ATPase leading to inhibition and inactivation. Biochim Biophys Acta. 1990;1024:32–40 [DOI] [PubMed] [Google Scholar]
  • 44.Thomas CE, Reed DJ. Radical-induced inactivation of kidney Na+,K(+)-ATPase: sensitivity to membrane lipid peroxidation and the protective effect of vitamin E. Arch Biochem Biophys. 1990;281:96–105 [DOI] [PubMed] [Google Scholar]
  • 45.Nakamura T, Goto M, Matsumoto A, Tanaka I. Inhibition of NF-kappa B transcriptional activity by alpha-tocopheryl succinate. Biofactors. 1998;7:21–30 [DOI] [PubMed] [Google Scholar]
  • 46.Kharb S, Singh GP. Effect of smoking on lipid profile, lipid peroxidation and antioxidant status in normal subjects and in patients during and after acute myocardial infarction. Clin Chim Acta. 2000;302:213–9 [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Nutrition are provided here courtesy of American Society for Nutrition

RESOURCES