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Association of SNP-SNP Interactions Between RANKL, OPG, CHI3L1, and VDR Genes With Breast Cancer Risk in Egyptian Women
Olfat G. Shaker,1 Mahmoud A. Senousy2
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 geneegene 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 geneegene interactions (epistasis) contributes to BC risk. Genetic
variants in receptor activator of nuclear factor kB ligand (RANKL), osteoprotegerin (OPG), chitinase-3elike 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 ¼ 8.33; 95% confidence interval, 1.32-52.46; P ¼ .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