Association of NME1, CXCL12, VDR, DNMT1, CAV1, IL27, and IL33 polymorphisms with breast cancer susceptibility in Bangladeshi women: A case-control and in silico study

Purpose: Breast cancer (BC) remains one of the most common cancers and a leading cause of death among women worldwide. Despite therapeutic advances, identifying genetic factors that influence susceptibility is crucial for populations at high risk. This study aimed to investigate whether polymorphisms in NME1 (rs16949649), CXCL12 (rs2839693, rs1801157), VDR (rs7975232, rs731236, rs2228570), DNMT1 (rs16999593), CAV1 (rs3807987), IL27 (rs181206), and IL33 (rs7044343) are linked to BC in Bangladeshi women, combining case-control data with in-silico analysis. Methods: We analyzed 250 histologically confirmed BC cases and 250 age-matched healthy controls. Genotyping was carried out by PCR-RFLP. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated, and p<0.05 was considered significant. To complement these findings, in-silico predictions of variant impact were performed using GEPIA, UALCAN, SIFT, PolyPhen-2, CADD, PredictSNP, Mutation Assessor, MuPro, and I-Mutant. Results: NME1 rs16949649 showed a significant association with BC (dominant model: OR=2.24, p=0.040; allele model: OR=2.44, p=0.045). CXCL12 rs2839693 also increased risk (dominant model: OR=1.69, p=0.017; allele model: OR=1.67, p=0.008). Among VDR variants, rs7975232 and rs731236 were positively associated with BC, whereas rs2228570 was protective (additive model 2: OR=0.36, p=0.009). No meaningful associations were observed for DNMT1 rs16999593, CAV1 rs3807987, IL27 rs181206, IL33 rs7044343, or CXCL12 rs1801157 in the case-control analysis. Interestingly, in-silico modeling suggested that DNMT1 rs16999593 (H97R) could reduce protein stability, with some predictors indicating possible disease relevance. For IL33 rs7044343 (C>T), the T allele was predicted to increase BC susceptibility, reflecting IL-33's context-dependent roles in tumor biology. Conclusions: This study highlights NME1 rs16949649, CXCL12 rs2839693, and VDR variants (rs7975232, rs731236, rs2228570) as important genetic markers of BC risk in Bangladeshi women. While case-control analysis did not confirm significant effects for DNMT1 and IL33 , computational predictions suggest they may influence protein function and deserve further exploration. Integrating genetic association with in-silico analysis can provide deeper insights into breast cancer susceptibility in underrepresented populations.