Independent and Combined Associations of 677C/T and 1298A/C Polymorphisms in the MTHFR gene with Breast Cancers in a South-Asian Population

MTHFR is a pivotal enzyme in the folic acid cycle. Two functional SNPs (677C/T and 1298A/C), which affect the function of the MTHFR, are associated with different cancers. In the present study, these SNPs were investigated in breast cancer patients from the Pakistani population. The pilot study includes 187 participants with 124 breast cancer patients and 63 medically confirmed healthy individuals as controls. PCR-RFLP methods validated by Sanger sequencing were used for the polymorphic investigations. Here, we report the significant and unique associations of these polymorphisms with breast cancers in a South-Asian population for the first time in the literature. The case-control analysis showed that in case of 1298A/C polymorphism, a significant protective effect of homozygous C genotype was observed in recessive [CC vs AA+AC; OR: 0.320 (95% CI: 0.259 - 0.397)] and homozygous co-dominant [CC vs AA; OR 0.379 (95% CI: 0.273 - 0.527)] models. In the case of 677C/T analysis, no significant association was observed with the risk of breast cancers. However, homozygous T genotype was more frequent in the advanced age group (>35 years) patients as compared to the young age-group (<35 years) i.e. 6.7% vs 0%. The combined genotype analysis at two loci revealed that 677CC+1298AC [OR: 2.688 (95% CI: 1.247-5.795)] and 677CT+1298AA [OR.:20.91 (95% CI: 1.156-378.2)] increased risk of breast cancers, significantly. The latter association (677T*1298A) was also observed in a semi-parametric haplotype analysis (p-value: 0.03). The study indicates translational applications of these polymorphisms against breast cancers in the studied population.