Sex-specific association of sequence variants in CBS and MTRR with risk for promoter hypermethylation in the lung epithelium of smokers

Abstract

Gene promoter hypermethylation is now regarded as a promising biomarker for the risk and progression of lung cancer. The one-carbon metabolism pathway is postulated to affect deoxyribonucleic acid (DNA) methylation because it is responsible for the generation of S-adenosylmethionine (SAM), the methyl donor for cellular methylation reactions. This study investigated the association of single nucleotide polymorphisms (SNPs) in six one-carbon metabolism-related genes with promoter hypermethylation in sputum DNA from non-Hispanic white smokers in the Lovelace Smokers Cohort (LSC) (n = 907). Logistic regression was used to assess the association of SNPs with hypermethylation using a high/low methylation cutoff. SNPs in the cystathionine beta synthase (CBS) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) genes were significantly associated with high methylation in males [CBS rs2850146 (-8283G > C), OR = 4.9; 95% CI: 1.98, 12.2, P = 0.0006] and low methylation in females [MTRR rs3776467 (7068A > G), OR = 0.57, 95% CI: 0.42, 0.77, P = 0.0003]. The variant allele of rs2850146 was associated with reduced gene expression and increased plasma homocysteine (Hcy) concentrations. Three plasma metabolites, Hcy, methionine and dimethylglycine, were associated with increased risk for gene methylation. These studies suggest that SNPs in CBS and MTRR have sex-specific associations with aberrant methylation in the lung epithelium of smokers that could be mediated by the affected one-carbon metabolism and transsulfuration in the cells.

Dietary Nutrient Intake, Ethnicity, and Epigenetic Silencing of Lung Cancer Genes Detected in Sputum in New Mexican Smokers

“…between methionine and methylation (P ¼ 0.064, Supplementary Table S4), consistent with our previous finding that plasma methionine level was associated with increased methylation in 149 LSC members (32). When total folate intake, vitamin B12, and methionine as independent variables with minimal correlations (Pearson correlation coefficients range from 0.04 to 0.33, not shown) were included in one GEE model, all three nutrients were significantly associated with methylation (Ps 0.043, not shown).…”

Genetic and environmental influences interact with age and sex in shaping the human methylome

“…A study of neonatal MZ twins reported that twin pairs may show trajectories of divergent, convergent or longitudinally stable methylation patterns after birth 33 . Examples of sites where the relationships between age and DNA methylation depends on genotype 34 and sex-specific methylation quantitative trait loci (QTL) 35 have also been reported.…”

Native American Ancestry Affects the Risk for Gene Methylation in the Lungs of Hispanic Smokers from New Mexico

“…The detection of promoter methylation in exfoliated lung cells collected in sputum samples provides an assessment of the extent of field cancerization in the lungs and is a validated biomarker for identifying smokers at higher risk for lung cancer incidence (2,3). Several studies conducted by our group and using the Lovelace Smokers cohort (LSC) identified sex, dietary factors, and variants in genes involved in DNA replication, DNA damage response, and one-carbon metabolism and transsulfuration pathways as important factors affecting this epigenetic alteration in the lungs of smokers (4)(5)(6)(7).…”