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

Shaik Mohammad Naushad; Chandrasekhar Divya; M Janaki Ramaiah; Tajamul Hussain; Salman A Alrokayan; Vijay Kumar Kutala

doi:10.1007/s12687-016-0277-1

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

J Community Genet. 2016 Oct;7(4):279-290. doi: 10.1007/s12687-016-0277-1. Epub 2016 Aug 19.

Authors

Shaik Mohammad Naushad^{1

2}, Chandrasekhar Divya³, M Janaki Ramaiah³, Tajamul Hussain⁴, Salman A Alrokayan⁵, Vijay Kumar Kutala⁶

Affiliations

¹ Biochemical Genetics, Sandor Life Sciences Pvt Ltd, Banjara Hills, Road No. 3, Hyderabad, 500034, India. naushadsm@gmail.com.
² School of Chemical and Biotechnology, SASTRA University, Tirumalaisamudram, Thanjavur, 613401, India. naushadsm@gmail.com.
³ School of Chemical and Biotechnology, SASTRA University, Tirumalaisamudram, Thanjavur, 613401, India.
⁴ Center of Excellence in Biotechnology Research, King Saud University, PO Box 2455, Riyadh, 11451, Saudi Arabia.
⁵ Department of Biochemistry, College of Science, King Saud University, PO Box 2455, Riyadh, 11451, Saudi Arabia.
⁶ Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, 500082, India.

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.

Keywords: Altitude; Breast cancer; One-carbon metabolism; Polymorphisms.