Investigating Multiple Candidate Genes and Nutrients in the Folate Metabolism Pathway to Detect Genetic and Nutritional Risk Factors for Lung Cancer

Purpose: Folate metabolism, with its importance to DNA repair, provides a promising region for genetic investigation of lung cancer risk. This project investigates genes (MTHFR, MTR, MTRR, CBS, SHMT1, TYMS), folate metabolism related nutrients (B vitamins, methionine, choline, and betaine) and their gene-nutrient interactions. Methods: We analyzed 115 tag single nucleotide polymorphisms (SNPs) and 15 nutrients from 1239 and 1692 non-Hispanic white, histologically-confirmed lung cancer cases and controls, respectively, using stochastic search variable selection (a Bayesian model averaging approach). Analyses were stratified by current, former, and never smoking status. Results: Rs6893114 in MTRR (odds ratio [OR] = 2.10; 95% credible interval [CI]: 1.20–3.48) and alcohol (drinkers vs. non-drinkers, OR = 0.48; 95% CI: 0.26–0.84) were associated with lung cancer risk in current smokers. Rs13170530 in MTRR (OR = 1.70; 95% CI: 1.10–2.87) and two SNP*nutrient interactions [betaine*rs2658161 (OR = 0.42; 95% CI: 0.19–0.88) and betaine*rs16948305 (OR = 0.54; 95% CI: 0.30–0.91)] were associated with lung cancer risk in former smokers. SNPs in MTRR (rs13162612; OR = 0.25; 95% CI: 0.11–0.58; rs10512948; OR = 0.61; 95% CI: 0.41–0.90; rs2924471; OR = 3.31; 95% CI: 1.66–6.59), and MTHFR (rs9651118; OR = 0.63; 95% CI: 0.43–0.95) and three SNP*nutrient interactions (choline*rs10475407; OR = 1.62; 95% CI: 1.11–2.42; choline*rs11134290; OR = 0.51; 95% CI: 0.27–0.92; and riboflavin*rs8767412; OR = 0.40; 95% CI: 0.15–0.95) were associated with lung cancer risk in never smokers. Conclusions: This study identified possible nutrient and genetic factors related to folate metabolism associated with lung cancer risk, which could potentially lead to nutritional interventions tailored by smoking status to reduce lung cancer risk

Choline and Betaine Metabolism.

<p>Abbreviations: PC – phosphatidylcholine; PE – phosphatidylethanolamine; AdoMet – S-adenosylmethionine; AdoHcy – S-adenosylhomocysteine; THF – tetrahydrofolate; mTHF –5-methyltetrahydrofolate; Met – methionine; Hcy – homocysteine; DMG – dimethylglycine; MS – methionine synthase; BHMT – betaine-homocysteine S-methyltransferase; CBS – cystathionine β-synthase; B6– vitamin B6; B12– vitamin B12.</p

Summary Statistics for Energy-adjusted intake by smoking status.

*<p>p-value, test for linear trend.</p

Comparison of demographic and other characteristics between cases and controls (n = 5744).

a<p>Total 12.9% missing. ^b Total 13% missing. ^c Total 32.8% missing. ^d Smokers only. ^e Former smokers only.</p>*<p>p-value, two-sided chi-square test. ** p-value, Student’s t-test.</p

Association between quartiles of choline intake and lung cancer risk.

a<p>Adjusted for sex, race/ethnicity, age (continuous), smoking status, total caloric intake.</p>b<p>Adjusted for sex, race/ethnicity, age, pack-years, total caloric intake, family cancer history, dust exposure, second-hand smoke, emphysema, hay fever, smoking status, asthma, addiction index, alcohol, time since smoking cessation.</p>c<p>Adjusted for sex, race/ethnicity, age (continuous), total caloric intake.</p>d<p>Adjusted for sex, race/ethnicity, age, pack-years, total caloric intake, family cancer history, dust exposure, second-hand smoke, emphysema, hay fever, asthma, addiction index, alcohol, time since smoking cessation.</p>*<p>p-value, chi-square test using quartiles of choline intake as categorical variable.</p>**<p>p-value, test for linear trend using quartiles of choline intake as continuous variable.</p

Analysis Flow Chart.

<p>This figure depicts the flow of analysis. We analyzed SNPs and nutrients in parallel, using stochastic search methodology in stage 2. Then the most important SNPs and nutrients were jointly investigated along with the gene-nutrient interactions in stage 3, again using stochastic search methodology.</p

Further Examination of Alcohol from the Final Model for Current Smokers (263 Cases/314 Controls).

a<p>Odds ratios adjusted for age, sex, family history, pack years, and <i>MTRR</i> mutants.</p

Final Model Stratified by Smoking Status.

a<p>SNPs located within 500 kb of given gene.</p>b<p>Odds ratios for current smokers adjusted for sex, age, family history of smoking-related cancers, and pack years smoked; odds ratios for former smokers adjusted for sex, age, family history, and age at smoking cessation; odds ratios for never smokers adjusted for sex, age, family history, and exposure to secondhand tobacco smoke.</p>c<p>Bayes factor greater than or equal to 3; included in the final model.</p