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  • br We further carried out functional annotation analysis to

    2020-08-06


    We further carried out functional annotation analysis to explore possible biological insights into the observed SNP-SNP interactions. We observed that the SNP-SNP interactions in the studied genes
    SNP-SNP Interactions
    SNP6 A G G A
    a
    a
    SNP5 T T T T
    a a a a
    Cancer Risk
    SNP4 C C C C
    Breast
    SNP3
    With
    T T T T
    a a a a
    AssociationofHaplotypesTable5
    Haplotype
    SNP1SNP2 T T T CC
    G G a a
    C
    a a a
    software using odds ratio; SNP
    online ¼OR
    Adjustedbyageandfamilyhistoryinmultiple logistic regression by SNPStats e¼ ¼ fiAbbreviations:CHI3L1chitinase-3likeprotein1;CIcondence interval;¼¼SNP5VDRFokI-rs2228570(C/T);SNP6VDRBsmI-rs1544410(A/G).P Risk alleles. Statistically signi 
    were complemented by common involvement in biological pro-cesses, including immune response, regulation of mitogen-activated protein kinase (MAPK), protein kinase B signaling, tumor necrosis factor (TNF) signaling, cytokineecytokine receptor interaction, angiogenesis, and apoptosis (Table 1); observed/predicted direct or indirect interactions among proteins encoded by participating genes or with other proteins linked to carcinogenesis; and protein/tran-scription factoregene interactions. Our bioinformatic analysis of protein interactions revealed 6 significant predicted proteins/tran-scription factors (STAT5B, STAT, STAT1, SRY, BACH2, and IK3) that were in common interaction with RANKL, OPG, CHI3L1, and VDR genes; the most significant was STAT5B. STAT5 signaling mediated mesenchymal phenotypes of basal-type BC cells.40 PR and STAT5 signaling cross-talk through RANKL in mammary epithelial cells.41 OPG interacts with and inhibits TRAIL; TRAIL induces RANKL expression through a STAT6-dependent transcriptional regulatory mechanism in bone marrow stromal/preosteoblast cells.42 The robust cytokine-driven expression of YKL-40 requires both STAT3 and nuclear factor kappaelight-chain enhancer of activated CL 316243 (NF-kB; RelB/p50 complex) binding elements of the CHI3L1 promoter.43 RANKL/RANK binding activates NF-kB, and downstream pathways and can acti-vate a noncanonical NF-kB pathway with translocation of RelB/52 heterodimers to the nucleus44 and thus could induce YKL-40 expression. The 1,25(OH)2D3/VDR signaling regulates the expression of RANKL and OPG.45 The 1,25(OH)2D3 down-regulated RANKL expression and inhibited osteoclastogenesis through inhibiting JAK2/STAT3 and p38 MAPK/NF-kB signal-ling.46 The 1,25(OH)2D3 through VDR also suppressed RANKL expression in Th17 cells via suppressing NF-kBp65 nuclear trans-location.47 Vitamin D/VDR signaling may reprogram T cells to decrease essential STAT activation and proinflammatory cytokine output.48 Together, these findings explore that the impact of the observed SNP-SNP interactions on BC susceptibility could be through direct or indirect cross-talk between their encoded proteins through a complex interaction network that could affect the tumor microenvironment.
    More specifically, our study revealed that the epistatic interaction between RANKL-rs9533156 and OPG-rs2073618 carrying one or two C risk alleles was a candidate risk factor for BC. These results may in part be attributed to a functionally altered RANKL/OPG ratio by the combined genotypes, with a high RANKL/OPG ratio supposedly predisposing to BC risk as well as BC-associated bone metastasis.49-51 Carriers of the OPG-rs2073618 CC genotype were more likely to have a lower OPG level and a higher RANKL/OPG ratio than carriers of the GG genotype.30,49 Similarly, a trend of elevation of serum OPG level in OPG-rs2073618 GG genotype than GC or CC genotypes, and a slightly higher serum RANKL in RANKL-rs9533156 TT than TC genotype carriers was observed in Egyptian women with BC; however, results were statistically nonsignificant.23 Although the exact mechanism of RANKL-rs9533156 is not known, carriers of a nearby RANKL-rs7984870 promoter SNP was associated with higher RANKL level as well as higher RANKL/OPG ratio.49
    In contrast to OPG-rs2073618, the presence of RANKL-rs9533156 heterozygosity with OPG-rs2073617 carrying one or two nonrisk C alleles was protective against BC risk in our study.
    Table 6 Correlation of Haplotypes With ER/PR Status, Bone Metastasis, and Tumor Size in Breast Cancer Group
    Haplotype
    Frequency
    Total Negative ER/PR Positive ER/PR Adjusted OR
    Global
    Without Metastasis With Metastasis
    Olfat G. Shaker, Mahmoud A. Senousy
    SNP-SNP Interactions
    Table 7 Protein Interaction With 4 Studied Genes (RANKL, OPG, VDR, and CHI3L1)