LAUSR

Micro‐Abstract Genetic susceptibility for breast cancer (BC) is still poorly understood. We investigated the association of single nucleotide polymorphism (SNP)‐SNP interactions of 6 SNPs in RANKL, OPG, CHI3L1, and VDR genes with BC risk in 115 BC patients and 120 controls using logistic regression models. A stronger combined effect of SNPs via gene–gene interaction may predict BC risk. Our data have implications in genetic counseling, BC screening, and prognosis. Background: Genetic susceptibility for breast cancer (BC) is still poorly understood. A combination of multiple low‐penetrant alleles of cancer‐related genes and gene–gene interactions (epistasis) contributes to BC risk. Genetic variants in receptor activator of nuclear factor &kgr;B ligand (RANKL), osteoprotegerin (OPG), chitinase‐3–like protein 1 (CHI3L1), and vitamin D receptor (VDR) genes are implicated in breast carcinogenesis; however, the influence of their epistatic effects on BC susceptibility has not yet been studied. We investigated the association of single nucleotide polymorphism (SNP)‐SNP interactions and haplotypes of 6 SNPs in these 4 genes with the genetic predisposition of BC in Egyptian women. Patients and Methods: Data of 115 BC patients and 120 cancer‐free controls were studied. Association tests were conducted using logistic regression models. Results: Individual SNPs showed weak statistical significance with BC susceptibility. The interactions between RANKL‐rs9533156 and OPG‐rs2073618; OPG‐rs2073618 with CHI3L1‐rs4950928, VDR‐rs2228570 and VDR‐rs1544410; OPG‐rs2073617 and VDR‐rs1544410; VDR‐rs2228570 and VDR‐rs1544410 were strongly associated with increased BC risk after adjustment for multiple comparisons. No SNPs were in strong linkage disequilibrium. The TCTCTG‐rs9533156‐rs2073618‐rs2073617‐rs4950928‐rs2228570‐rs1544410 haplotype was significantly associated with increased BC risk (adjusted odds ratio = 8.33; 95% confidence interval, 1.32‐52.46; P = .025) compared with controls. TCCCTG haplotype stratified BC patients according to estrogen receptor/progesterone receptor status. TCTCTA was positively associated, and TCTCTG and TGTCTG haplotypes inversely correlated with bone metastasis. Bioinformatic analysis revealed 13 proteins commonly interacting with our 4 genes; the most significant was signal transducer and activator of transcription 5B. Conclusion: Our results suggested that a stronger combined effect of SNPs in RANKL, OPG, CHI3L1, and VDR genes via gene–gene interaction may help predict BC risk and prognosis.