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Single nucleotide polymorphisms of one-carbon metabolism and cancers of the esophagus, stomach, and liver in a Chinese population.

Chang SC, Chang PY, Butler B, Goldstein BY, Mu L, Cai L, You NC, Baecker A, Yu SZ, Heber D, Lu QY, Li L, Greenland S, Zhang ZF - PLoS ONE (2014)

Bottom Line: To account for multiple comparisons and reduce the chances of false reports, we employed semi-Bayes (SB) shrinkage analysis.There was an inverse association between DNMT1 rs2228612 and esophageal cancer (any G versus A/A, SBOR: 0.60, 95% posterior limits: 0.39, 0.94).Our results suggest that genetic polymorphisms related to one-carbon metabolism may be associated with cancers of the esophagus, stomach, and liver.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, University of California Los Angeles Fielding School of Public Health, Los Angeles, CA, United States of America.

ABSTRACT
One-carbon metabolism (folate metabolism) is considered important in carcinogenesis because of its involvement in DNA synthesis and biological methylation reactions. We investigated the associations of single nucleotide polymorphisms (SNPs) in folate metabolic pathway and the risk of three GI cancers in a population-based case-control study in Taixing City, China, with 218 esophageal cancer cases, 206 stomach cancer cases, 204 liver cancer cases, and 415 healthy population controls. Study participants were interviewed with a standardized questionnaire, and blood samples were collected after the interviews. We genotyped SNPs of the MTHFR, MTR, MTRR, DNMT1, and ALDH2 genes, using PCR-RFLP, SNPlex, or TaqMan assays. To account for multiple comparisons and reduce the chances of false reports, we employed semi-Bayes (SB) shrinkage analysis. After shrinkage and adjusting for potential confounding factors, we found positive associations between MTHFR rs1801133 and stomach cancer (any T versus C/C, SB odds-ratio [SBOR]: 1.79, 95% posterior limits: 1.18, 2.71) and liver cancer (SBOR: 1.51, 95% posterior limits: 0.98, 2.32). There was an inverse association between DNMT1 rs2228612 and esophageal cancer (any G versus A/A, SBOR: 0.60, 95% posterior limits: 0.39, 0.94). In addition, we detected potential heterogeneity across alcohol drinking status for ORs relating MTRR rs1801394 to esophageal (posterior homogeneity P = 0.005) and stomach cancer (posterior homogeneity P = 0.004), and ORs relating MTR rs1805087 to liver cancer (posterior homogeneity P = 0.021). Among non-alcohol drinkers, the variant allele (allele G) of these two SNPs was inversely associated with the risk of these cancers; while a positive association was observed among ever-alcohol drinkers. Our results suggest that genetic polymorphisms related to one-carbon metabolism may be associated with cancers of the esophagus, stomach, and liver. Heterogeneity across alcohol consumption status of the associations between MTR/MTRR polymorphisms and these cancers indicates potential interactions between alcohol drinking and one-carbon metabolic pathway.

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Selected semi-Bayes stratum-specific associations.Selected semi-Bayes stratum-specific associations between SNPs in MTHFR, MTR, MTRR, DNMT1, ALDH2, and upper GI cancer susceptibility, by plasma levels of micronutrients (folate, vitamin B12, and homocysteine) and environmental factors (smoking, alcohol drinking, H. pylori CagA status, HBsAg status, and plasma AFB1-albumin adduct levels). Semi-Bayes adjusted ORs (SBOR) and 95% posterior limits were under dominant genetic models, except for the SBOR relating ALDH2 rs671to esophageal cancer, where recessive genetic model was used. P* denotes P-value for homogeneity test.
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pone-0109235-g001: Selected semi-Bayes stratum-specific associations.Selected semi-Bayes stratum-specific associations between SNPs in MTHFR, MTR, MTRR, DNMT1, ALDH2, and upper GI cancer susceptibility, by plasma levels of micronutrients (folate, vitamin B12, and homocysteine) and environmental factors (smoking, alcohol drinking, H. pylori CagA status, HBsAg status, and plasma AFB1-albumin adduct levels). Semi-Bayes adjusted ORs (SBOR) and 95% posterior limits were under dominant genetic models, except for the SBOR relating ALDH2 rs671to esophageal cancer, where recessive genetic model was used. P* denotes P-value for homogeneity test.

Mentions: Table 2 presents the SB odds-ratio estimates (SBOR) for each SNP-cancer association of the eight SNPs; Table S1, S2, S3, S4, S5, S6 shows stratified associations and Figure 1 summarizes selected results. Genotype distributions among controls appeared compatible with Hardy-Weinberg equilibrium, except possibly for DNMT1 rs2228612, which had P = 0.010, below the traditional alpha level of 0.05, but larger than the Bonferroni-adjusted alpha level of 0.05/8 = 0.006 (testing all eight SNPs). However, we note that matching may bias controls away from equilibrium if the matching factors are associated with both the SNPs and cancer.


Single nucleotide polymorphisms of one-carbon metabolism and cancers of the esophagus, stomach, and liver in a Chinese population.

Chang SC, Chang PY, Butler B, Goldstein BY, Mu L, Cai L, You NC, Baecker A, Yu SZ, Heber D, Lu QY, Li L, Greenland S, Zhang ZF - PLoS ONE (2014)

Selected semi-Bayes stratum-specific associations.Selected semi-Bayes stratum-specific associations between SNPs in MTHFR, MTR, MTRR, DNMT1, ALDH2, and upper GI cancer susceptibility, by plasma levels of micronutrients (folate, vitamin B12, and homocysteine) and environmental factors (smoking, alcohol drinking, H. pylori CagA status, HBsAg status, and plasma AFB1-albumin adduct levels). Semi-Bayes adjusted ORs (SBOR) and 95% posterior limits were under dominant genetic models, except for the SBOR relating ALDH2 rs671to esophageal cancer, where recessive genetic model was used. P* denotes P-value for homogeneity test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4206280&req=5

pone-0109235-g001: Selected semi-Bayes stratum-specific associations.Selected semi-Bayes stratum-specific associations between SNPs in MTHFR, MTR, MTRR, DNMT1, ALDH2, and upper GI cancer susceptibility, by plasma levels of micronutrients (folate, vitamin B12, and homocysteine) and environmental factors (smoking, alcohol drinking, H. pylori CagA status, HBsAg status, and plasma AFB1-albumin adduct levels). Semi-Bayes adjusted ORs (SBOR) and 95% posterior limits were under dominant genetic models, except for the SBOR relating ALDH2 rs671to esophageal cancer, where recessive genetic model was used. P* denotes P-value for homogeneity test.
Mentions: Table 2 presents the SB odds-ratio estimates (SBOR) for each SNP-cancer association of the eight SNPs; Table S1, S2, S3, S4, S5, S6 shows stratified associations and Figure 1 summarizes selected results. Genotype distributions among controls appeared compatible with Hardy-Weinberg equilibrium, except possibly for DNMT1 rs2228612, which had P = 0.010, below the traditional alpha level of 0.05, but larger than the Bonferroni-adjusted alpha level of 0.05/8 = 0.006 (testing all eight SNPs). However, we note that matching may bias controls away from equilibrium if the matching factors are associated with both the SNPs and cancer.

Bottom Line: To account for multiple comparisons and reduce the chances of false reports, we employed semi-Bayes (SB) shrinkage analysis.There was an inverse association between DNMT1 rs2228612 and esophageal cancer (any G versus A/A, SBOR: 0.60, 95% posterior limits: 0.39, 0.94).Our results suggest that genetic polymorphisms related to one-carbon metabolism may be associated with cancers of the esophagus, stomach, and liver.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, University of California Los Angeles Fielding School of Public Health, Los Angeles, CA, United States of America.

ABSTRACT
One-carbon metabolism (folate metabolism) is considered important in carcinogenesis because of its involvement in DNA synthesis and biological methylation reactions. We investigated the associations of single nucleotide polymorphisms (SNPs) in folate metabolic pathway and the risk of three GI cancers in a population-based case-control study in Taixing City, China, with 218 esophageal cancer cases, 206 stomach cancer cases, 204 liver cancer cases, and 415 healthy population controls. Study participants were interviewed with a standardized questionnaire, and blood samples were collected after the interviews. We genotyped SNPs of the MTHFR, MTR, MTRR, DNMT1, and ALDH2 genes, using PCR-RFLP, SNPlex, or TaqMan assays. To account for multiple comparisons and reduce the chances of false reports, we employed semi-Bayes (SB) shrinkage analysis. After shrinkage and adjusting for potential confounding factors, we found positive associations between MTHFR rs1801133 and stomach cancer (any T versus C/C, SB odds-ratio [SBOR]: 1.79, 95% posterior limits: 1.18, 2.71) and liver cancer (SBOR: 1.51, 95% posterior limits: 0.98, 2.32). There was an inverse association between DNMT1 rs2228612 and esophageal cancer (any G versus A/A, SBOR: 0.60, 95% posterior limits: 0.39, 0.94). In addition, we detected potential heterogeneity across alcohol drinking status for ORs relating MTRR rs1801394 to esophageal (posterior homogeneity P = 0.005) and stomach cancer (posterior homogeneity P = 0.004), and ORs relating MTR rs1805087 to liver cancer (posterior homogeneity P = 0.021). Among non-alcohol drinkers, the variant allele (allele G) of these two SNPs was inversely associated with the risk of these cancers; while a positive association was observed among ever-alcohol drinkers. Our results suggest that genetic polymorphisms related to one-carbon metabolism may be associated with cancers of the esophagus, stomach, and liver. Heterogeneity across alcohol consumption status of the associations between MTR/MTRR polymorphisms and these cancers indicates potential interactions between alcohol drinking and one-carbon metabolic pathway.

Show MeSH
Related in: MedlinePlus