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A survey of microRNA single nucleotide polymorphisms identifies novel breast cancer susceptibility loci in a case-control, population-based study of African-American women.

ABSTRACT: 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.

SUBMITTER: Bensen JT

PROVIDER: S-EPMC5989404 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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A survey of microRNA single nucleotide polymorphisms identifies novel breast cancer susceptibility loci in a case-control, population-based study of African-American women.

Bensen Jeannette T JT Graff Mariaelisa M Young Kristin L KL Sethupathy Praveen P Parker Joel J Pecot Chad V CV Currin Kevin K Haddad Stephen A SA Ruiz-Narváez Edward A EA Haiman Christopher A CA Hong Chi-Chen CC Sucheston-Campbell Lara E LE Zhu Qianqian Q Liu Song S Yao Song S Bandera Elisa V EV Rosenberg Lynn L Lunetta Kathryn L KL Ambrosone Christine B CB Palmer Julie R JR Troester Melissa A MA Olshan Andrew F AF

Breast cancer research : BCR 20180605 1

<h4>Background</h4>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.<h4>Methods</h4>Under the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, genotyping and imputed data from f ...[more]

PMID: 29871690

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Project description:BackgroundSmoking is a leading cause of preventable death. Early studies based on samples of twins have linked the lifetime smoking practices to genetic predisposition. The flavin-containing monooxygenase (FMO) protein family consists of a group of enzymes that metabolize drugs and xenobiotics. Both FMO1 and FMO3 were potentially susceptible genes for nicotine metabolism process.MethodsIn this study, we investigated the potential of FMO genes to confer risk of nicotine dependence via deep targeted sequencing in 2,820 study subjects comprising 1,583 nicotine dependents and 1,237 controls from European American and African American. Specifically, we focused on the two genomic segments including FMO1,FMO3, and pseudo gene FMO6P, and aimed to investigate the potential association between FMO genes and nicotine dependence. Both common and low-frequency/rare variants were analyzed using different algorithms. The potential functional significance of SNPs with association signal was investigated with relevant bioinformatics tools.ResultsWe identified different clusters of significant common variants in European (with most significant SNP rs6674596, p = .0004, OR = 0.67, MAF_EA = 0.14, FMO1) and African Americans (with the most significant SNP rs6608453, p = .001, OR = 0.64, MAF_AA = 0.1, FMO6P). No significant signals were identified through haplotype-based analyses. Gene network investigation indicated that both FMO1 and FMO3 have a strong relation with a variety of genes belonging to CYP gene families (with combined score greater than 0.9). Most of the significant variants identified were SNPs located within intron regions or with unknown functional significance, indicating a need for future work to understand the underlying functional significance of these signals.ConclusionsOur findings indicated significant association between FMO genes and nicotine dependence. Replications of our findings in other ethnic groups were needed in the future. Most of the significant variants identified were SNPs located within intronic regions or with unknown functional significance, indicating a need for future work to understand the underlying functional significance of these signals.

Dataset Information

A survey of microRNA single nucleotide polymorphisms identifies novel breast cancer susceptibility loci in a case-control, population-based study of African-American women.

Publications

A survey of microRNA single nucleotide polymorphisms identifies novel breast cancer susceptibility loci in a case-control, population-based study of African-American women.

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