Association between the <i>Bsm</i>I Polymorphism in the Vitamin D Receptor Gene and Breast Cancer Risk: Results from a Pakistani Case-Control Study

<div><p>Background</p><p>Vitamin D is postulated to decrease the risk of breast cancer by inhibiting cell proliferation via the vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNPs) in the <i>VDR</i> gene, rs1544410 (<i>Bsm</i>I) and rs2228570 (<i>Fok</i>I), are inconsistently associated with breast cancer risk in Caucasian populations, while data for Asians are scarce. Here, we investigated the possible contribution of these SNPs to breast cancer risk in Pakistani breast cancer patients and in controls participating in a hospital-based breast cancer case-control study (PAK-BCCC).</p><p>Methods</p><p>Genotyping of the <i>Bsm</i>I and <i>Fok</i>I SNPs was performed by PCR-based restriction fragment length polymorphism (RFLP) analysis of 463 genetically enriched female breast cancer cases with known <i>BRCA1/2</i> status and in 1,012 controls from Pakistan. The association between SNP genotypes and breast cancer risk was investigated by logistic regression adjusted for potential breast cancer risk factors and stratified by <i>BRCA1/2</i> status and family history. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported.</p><p>Results</p><p>The b allele of the <i>Bsm</i>I was associated with an increased breast cancer risk (per b allele OR 1.28, 95% CI 1.09–1.49, <i>P</i> = 0.003). Subgroup analysis revealed that this effect was restricted to <i>BRCA1/2</i> non-carriers (per b allele OR 1.33, 95% CI 1.11–1.59, <i>P</i> = 0.002) and was stronger in those who reported a positive family history of breast and/or ovarian cancer (per b allele OR 1.64, 95% CI 1.20–2.22, <i>P</i> = 0.002). No association with breast cancer risk was detected for the <i>Fok</i>I SNP.</p><p>Conclusions</p><p>The <i>Bsm</i>I polymorphism in the <i>VDR</i> gene may be associated with an increased breast cancer risk in Pakistani women negative for <i>BRCA1/2</i> germline mutations.</p></div

Additional file 3: Figure S2. of A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients

Meta-analysis across BCAC studies of PARP2 and breast cancer prognosis. Forest plot of the combined hazard ratios and 95 % confidence intervals for PARP2 rs878156 in the discovery MARIE study and the replication studies in Breast Cancer Association Consortium (BCAC) using fixed effect models, according to treatment, i.e. no chemotherapy (A), any type of chemotherapy (B), and anthracycline-based chemotherapy (C). The combined effects for the BCAC studies were also based on fixed effect models. (DOCX 996 kb

Additional file 5: Table S2. of A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients

Associations between SNP and breast cancer-specific mortality by radiotherapy for interactions showing p <0.1 (LRT)$ in the MARIE study and results of replication in BCAC studies. (DOCX 20 kb

Meta-analysis of the association between genetically predicted BMI and breast cancer risk in the BCAC.

<p>The summary OR was calculated by combining individual analysis results from each study in BCAC (<i>p</i> for heterogeneity = 0.06).</p

Two independent association signals at the 1p11.2 locus: Association results for breast cancer risk among European women in BCAC, by tumor characteristic.

<p>Two independent association signals at the 1p11.2 locus: Association results for breast cancer risk among European women in BCAC, by tumor characteristic.</p

Sensitivity analyses using pooled data for associations between genetically predicted BMI and breast cancer risk in the BCAC.

<p>(A) Adjusted for age, study sites, and the first eight principal components. (b) Adjusted for age, study sites, the first eight principal components, and additional breast cancer risk factors: age at menarche, parity, use of contraceptive, use of hormone replacement therapy, breast feeding, and smoking status. Weighted: the BMI-GS was constructed using the additive model weighted by external beta reported from previous literatures. Unweighted: the BMI-GS was constructed using the additive model without any weight.</p

Regional plots of breast cancer association in 1p12-11.2.

<p>Regional plot of association result, recombination hotspots and linkage disequilibrium for the 1p12-11.2:120,505,799–121,481,132 breast cancer susceptibility loci. Association result from a trend test in—log10<i>P</i>values (y axis, left; red diamond, the top ranked breast cancer associated locus in the region; blue diamond, best conditioned analysis results conditioned on rs11249433; black diamonds, genotyped SNPs; gray diamonds, imputed SNPs) of the SNPs are shown according to their chromosomal positions (x axis). Linkage disequilibrium structure based on the 1000 Genomes CEU data (n = 85) was visualized by snp.plotter software. The line graph shows likelihood ratio statistics (y axis, right) for recombination hotspot by SequenceLDhot software based on the background recombination rates inferred by PHASE v2.1. Physical locations are based on hg19. Gene annotation was based on the NCBI RefSeq genes from the UCSC Genome Browser.</p

Associations of the weighted BMI-GSs with BMI and traditional breast cancer risk factors.

<p>Associations of the weighted BMI-GSs with BMI and traditional breast cancer risk factors.</p

Associations between genetically predicted BMI and breast cancer risk.

<p>Associations between genetically predicted BMI and breast cancer risk.</p

Significant associations detected at <i>p</i> < 0.05 between breast cancer risk and BMI-related SNPs.

<p>Significant associations detected at <i>p</i> < 0.05 between breast cancer risk and BMI-related SNPs.</p