Suggestive evidence of protective haplotype within TGF-B1 gene region in breast density utilizing fine mapping analysis

Introduction and aim: Increased mammographic density is a strong and independent attribute factor for breast carcinoma. The density is associated with epithelial cell proliferation and stromal fibrosis development that is regulated by Transforming Growth Factor-Beta 1 (TGF-beta 1). This study was aimed to fine map the TGF-beta 1 gene cluster in predicting the role of predisposing haplotypes in breast density development using tagging SNPs.Materials and methods: Genotyping was conducted for three tagging TGF-beta 1 SNPs assigned as rs1800469, rs1800470 and rs4803455 in a total of 50 consented female participants as case group which involved BI-RADS 3 and 4, while the control group (n=50) consisted of BI-RADS 1 and 2 who underwent a mammography check-up at The Department of Radiology, Hospital Sultanah Nur Zahirah of Kuala Terengganu. A series of bioinformatics analysis including individual SNP-based association analysis, haplotype-based association analysis and fine mapping analysis was conducted spanning the gene region of 20 kb utilizing Chinese Hans Beijing (CHB) and Japanese (JPT) representing the Asian dataset from the HapMap database.Results: The study demonstrated two tagging SNPs of TGF-beta 1 yielded a significant association (rs1800469, p-value=.034; rs1800470, p-value=.004). However, rs4803455 did not show a significant association with p value of 0.053. We further revealed the susceptible haplotype that was assigned as haplotype GGA with significant P value 0.003 indicated by odd ratio of 3.349 (1.482-7.568). A potential protective haplotype was observed in haplotype AGC with odd ratio 0.585 (0.316-1.080) even though with less significant (p=.085). The fine map revealed four targeted SNPs in which consist of rs12461895, rs10416269, rs7408955 and rs1549934 from Block 2 and five potential SNPs from Block 4 assigned as rs4803457, rs2317130, rs1166933, rs1982072, rs11670143 as another potential genetic variant that might contribute to breast density.Discussion: This fine map study suggests the potential protective haplotype and genetic variants of TGF-beta 1 in predisposing to breast density development which is worth to be genotyped and further investigated.