Population-level diversity in the association of genetic polymorphisms of one-carbon metabolism with breast cancer risk

Abstract

Aberrations in one-carbon metabolism were reported to increase breast cancer risk by influencing the DNA synthesis and methylation of DNA and catecholamines. However, the results of these association studies remain inconclusive. We have explored the contribution of eight genetic polymorphisms in modulating the susceptibility to breast cancer by performing a meta-analysis of worldwide studies. In total, 62 case-control studies representing 17 different populations involving 18,117 breast cancer cases and 23,573 healthy controls were included in this meta-analysis. Out of the eight polymorphisms analyzed, methylenetetrahydrofolate reductase (MTHFR) C677T exhibited positive association with the breast cancer risk in both fixed effects (OR 1.14, 95 % CI 1.10-1.17) and random effects (OR 1.10, 95 % CI 1.02-1.18) models. Solute carrier family 19 (folate transporter), member 1 (SLC19A1) G80A exhibited positive association (OR 1.16, 95 % CI 1.03-1.31) while MTR A2756G exhibited an inverse association (OR 0.78, 95 % CI 0.75-0.82) with the breast in fixed effect model alone. Significant heterogeneity was observed in the association of MTHFR C677T with breast cancer even between studies from the same geographical area, specifically among Chinese, Indians, and Turks. Subgroup analysis revealed MTHFR C677T-mediated breast cancer risk in post-menopausal women and women with low dietary intake of folate. Geographical area wise segregation of data revealed MTHFR-mediated increased breast cancer risk in populations who consume methionine-rich diet. Altitude-level variations were observed in the association of SHMT1 C1420T with breast cancer. India and Brazil of same altitude showed an inverse association with this polymorphism, while USA and China that share similar altitude showed a null association. MTHFR C677T and SLC19A1 G80A are the two polymorphisms of one-carbon metabolic pathway that increase breast cancer in the worldwide population. Dietary patterns and altitudinal variations are the likely risk modulators that are contributing toward ethnic-and population-level variations in genetic associations.

MassARRAY-based single nucleotide polymorphism analysis in breast cancer of north Indian population

“…Fig. 2 A network analysis of the associated genes using GeneMANIA database worldwide populations [35] including African American women [36]. Our data revealed the variant rs1051266 to be significantly associated with BC risk in the population under study.…”

“…SLC19A1 or Solute Carrier family member protein is a gene implicated in placental carcinomas and pediatrics osteosarcomas. Studies have shown the SLC19A1 gene variants to be associate with BC risk in worldwide populations [ 35 ] including African American women [ 36 ]. Our data revealed the variant rs1051266 to be significantly associated with BC risk in the population under study.…”

Variants of Genes Involved in Metabolism of Folate among Patients with Breast Cancer: Association of TYMS 3R Allele with Susceptibility to Breast Cancer and Metastasis

“…The 5,10-methylene tetra hydrofolate (THF) is the common substrate for two key enzymes of TYMS and methylenetetrahydrofolate reductase (MTHFR). These enzymes catalyze the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) and flavin adenine dinucleotide (FAD)-dependent reduction of 5,10-methylene THF to 5-methyl THF, respectively ( 9 ). The dTMP is necessary for DNA synthesis and repair.…”

Genetic Variants Modifying the Risk of Lung Cancer and Its Subtypes: A Comprehensive Meta-analysis and a Case-control Study

“…In another study conducted, rs1048943 of CYP1A1 showed a signi cant association with lung cancer 31 , while the same variant showed no signi cant association with lung cancer in a different study from the Indian subcontinent 36 . The differences in genetic association across the geographical regions of the Indian subcontinent, comprised of distinct population groups, might be attributed to gene-gene and gene-environment interactions, which could act as potential modulators of lung cancer risk 37 . The contradictory outcomes of the variant between different studies could be due to small sample sizes, clinical heterogeneity between the populations, and racial/ethnic differences 38 within the Indian subcontinent.…”