Dataset Information

Strong impact of TGF-?1 gene polymorphisms on breast cancer risk in Indian women: a case-control and population-based study.

ABSTRACT:

Introduction

TGF-?1 is a multi-functional cytokine that plays an important role in breast carcinogenesis. Critical role of TGF-?1 signaling in breast cancer progression is well documented. Some TGF-?1 polymorphisms influence its expression; however, their impact on breast cancer risk is not clear.

Methods

We analyzed 1222 samples in a candidate gene-based genetic association study on two distantly located and ethnically divergent case-control groups of Indian women, followed by a population-based genetic epidemiology study analyzing these polymorphisms in other Indian populations. The c.29C>T (Pro10Leu, rs1982073 or rs1800470) and c.74G>C (Arg25Pro, rs1800471) polymorphisms in the TGF-?1 gene were analyzed using direct DNA sequencing, and peripheral level of TGF-?1 were measured by ELISA.

Results

c.29C>T substitution increased breast cancer risk, irrespective of ethnicity and menopausal status. On the other hand, c.74G>C substitution reduced breast cancer risk significantly in the north Indian group (p?=?0.0005) and only in the pre-menopausal women. The protective effect of c.74G>C polymorphism may be ethnicity-specific, as no association was seen in south Indian group. The polymorphic status of c.29C>T was comparable among Indo-Europeans, Dravidians, and Tibeto-Burmans. Interestingly, we found that Tibeto-Burmans lack polymorphism at c.74G>C locus as true for the Chinese populations. However, the Brahmins of Nepal (Indo-Europeans) showed polymorphism in 2.08% of alleles. Mean TGF-?1 was significantly elevated in patients in comparison to controls (p<0.001).

Conclusion

c.29C>T and c.74G>C polymorphisms in the TGF-?1 gene significantly affect breast cancer risk, which correlates with elevated TGF-?1 level in the patients. The c.29C>T locus is polymorphic across ethnically different populations, but c.74G>C locus is monomorphic in Tibeto-Burmans and polymorphic in other Indian populations.

SUBMITTER: Pooja S

PROVIDER: S-EPMC3798290 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Strong impact of TGF-β1 gene polymorphisms on breast cancer risk in Indian women: a case-control and population-based study.

Pooja Singh S Francis Amirtharaj A Rajender Singh S Tamang Rakesh R Rajkumar Raja R Saini Karan Singh KS Megu Kaling K Goel Madhu Mati MM Surekha Daminani D Rao Digumarthi Raghunatha DR Rao Lakshmi L Ramachandra Lingadakai L Kumar Sandeep S Kumar Surender S Vishnupriya Satti S Satyamoorthy Kapaettu K Negi Mahendra Pal Singh MP Thangaraj Kumarasamy K Konwar Rituraj R

PloS one 20131017 10

<h4>Introduction</h4>TGF-β1 is a multi-functional cytokine that plays an important role in breast carcinogenesis. Critical role of TGF-β1 signaling in breast cancer progression is well documented. Some TGF-β1 polymorphisms influence its expression; however, their impact on breast cancer risk is not clear.<h4>Methods</h4>We analyzed 1222 samples in a candidate gene-based genetic association study on two distantly located and ethnically divergent case-control groups of Indian women, followed by a ...[more]

PMID: 24146803

Similar Datasets

Project description:BACKGROUND: Epidemiological studies have provided enough evidence that genetic factors have an important role in determining susceptibility to IBD. The most significant finding in the IBD research has been identification of mutations in the gene that encodes Nod2 (nucleotide-binding oligomerization domain 2) protein in a subgroup of patients with Crohn's disease. However, a very similar gene encoding Nod1 protein still has not been well documented for its association with ulcerative colitis patients. Detection of polymorphism in NOD1 gene using SNP analysis has been attempted in the present study. We evaluated frequency and significance of mutations present in the nucleotide-binding domain (NBD) of NOD1 gene in context to Indian population. METHODS: A total of 95 patients with ulcerative colitis and 102 controls enrolled in the Gastroenterology department of All India Institute of Medical Sciences, New Delhi were screened for SNPs by DHPLC and RFLP techniques. Exon 6 locus in the NBD domain of NOD1 gene was amplified and sequenced. Genotype and allele frequencies of the patients and controls were calculated by the Pearson's chi2 test, Fisher's exact test and ANOVA with Bonferroni's correction using SPSS software version 12. RESULTS: We have demonstrated DHPLC screening technique to show the presence of SNPs in Exon 6 locus of NBD domain of NOD1 gene. The DHPLC analysis has proven suitable for rapid detection of base pair changes. The data was validated by sequencing of clones and subsequently by RFLP analysis. Analyses of SNP data revealed 3 significant mutations (W219R, p = 0.002; L349P, p = 0.002 and L370R, p = 0.039) out of 5 in the Exon 6 locus of NBD domain of the gene that encompasses ATP and Mg2+binding sites. No significant association was observed within different sub phenotypes. CONCLUSION: We propose that the location of mutations in the Exon 6 spanning the ATP and Mg2+ binding site of NBD in NOD1 gene may affect the process of oligomerization and subsequent function of the LRR domain. Further studies are been conducted at the protein level to prove this possibility.

Project description:BACKGROUND:MicroRNAs (miRNAs) regulate gene expression and influence cancer. Primary transcripts of miRNAs (pri-miRNAs) are poorly annotated and little is known about the role of germline variation in miRNA genes and breast cancer (BC). We sought to identify germline miRNA variants associated with BC risk and tumor subtype among African-American (AA) women. METHODS:Under the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, genotyping and imputed data from four studies on BC in AA women were combined into a final dataset containing 224,188 miRNA gene single nucleotide polymorphisms (SNPs) for 8350 women: 3663 cases and 4687 controls. The primary miRNA sequence was identified for 566 miRNA genes expressed in Encyclopedia of DNA Elements (ENCODE) Tier 1 cell types and human pancreatic islets. Association analysis was conducted using logistic regression for BC status overall and by tumor subtype. RESULTS:A novel BC signal was localized to an 8.6-kb region of 17q25.3 by four SNPs (rs9913477, rs1428882938, rs28585511, and rs7502931) and remained statistically significant after multiple test correction (odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.26-1.65; p =?3.15?×?10-7; false discovery rate (FDR)?=?0.03). These SNPs reside in a genomic location that includes both the predicted primary transcript of the noncoding miRNA gene MIR3065 and the first intron of the gene for brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2). Furthermore, miRNA-associated SNPs on chromosomes 1p32.3, 5q32, and 3p25.1 were the strongest signals for hormone receptor, luminal versus basal-like, and HER2 enrichment status, respectively. A second phase of genotyping (1397 BC cases, 2418 controls) that included two SNPs in the 8.6-kb region was used for validation and meta-analysis. While neither rs4969239 nor rs9913477 was validated, when meta-analyzed with the original dataset their association with BC remained directionally consistent (OR =?1.29, 95% CI = 1.16-1.44 (p?=?4.18?×?10-6) and OR?=?1.33, 95% CI = 1.17-1.51 (p?=?1.6?×?10-5), respectively). CONCLUSION:Germline genetic variation indicates that MIR3065 may play an important role in BC development and heterogeneity among AA women. Further investigation to determine the potential functional effects of these SNPs is warranted. This study contributes to our understanding of BC risk in AA women and highlights the complexity in evaluating variation in gene-dense regions of the human genome.