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Genetic variants of genes in the NER pathway associated with risk of breast cancer: A large-scale analysis of 14 published GWAS datasets in the DRIVE study.

dc.contributor.author Wei, Qingyi
dc.contributor.author Luo, Sheng
dc.contributor.author Moorman, Patricia
dc.contributor.author Ge, Jie
dc.contributor.author Liu, Hongliang
dc.contributor.author Qian, Danwen
dc.contributor.author Wang, Xiaomeng
dc.contributor.author Hwang, Shelley
dc.date.accessioned 2019-08-01T21:14:03Z
dc.date.available 2019-08-01T21:14:03Z
dc.date.issued 2019-09
dc.identifier.issn 0020-7136
dc.identifier.issn 1097-0215
dc.identifier.uri https://hdl.handle.net/10161/19156
dc.description.abstract A recent hypothesis-free pathway-level analysis of genome-wide association study (GWAS) datasets suggested that the overall genetic variation measured by single nucleotide polymorphisms (SNPs) in the nucleotide excision repair (NER) pathway genes was associated with breast cancer (BC) risk, but no detailed SNP information was provided. To substantiate this finding, we performed a larger meta-analysis of 14 previously published GWAS datasets in the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) study with 53,107 subjects of European descent. Using a hypothesis-driven approach, we selected 138 candidate genes from the NER pathway using the "Molecular Signatures Database (MsigDB)" and "PathCards". All SNPs were imputed using IMPUTE2 with the 1000 Genomes Project Phase 3. Logistic regression was used to estimate BC risk, and pooled ORs for each SNP were obtained from the meta-analysis using the false discovery rate for multiple test correction. RegulomeDB, HaploReg, SNPinfo and expression quantitative trait loci (eQTL) analysis were used to assess the SNP functionality. We identified four independent SNPs associated with BC risk, BIVM-ERCC5 rs1323697_C (OR = 1.06, 95% CI = 1.03-1.10), GTF2H4 rs1264308_T (OR = 0.93, 95% CI = 0.89-0.97), COPS2 rs141308737_C deletion (OR = 1.06, 95% CI = 1.03-1.09) and ELL rs1469412_C (OR = 0.93, 95% CI = 0.90-0.96). Their combined genetic score was also associated with BC risk (OR = 1.12, 95% CI = 1.08-1.16, ptrend < 0.0001). The eQTL analysis revealed that BIVM-ERCC5 rs1323697 C and ELL rs1469412 C alleles were correlated with increased mRNA expression levels of their genes in 373 lymphoblastoid cell lines (p = 0.022 and 2.67 × 10-22 , respectively). These SNPs might have roles in the BC etiology, likely through modulating their corresponding gene expression.
dc.language eng
dc.publisher Wiley
dc.relation.ispartof International journal of cancer
dc.relation.isversionof 10.1002/ijc.32371
dc.subject DNA repair
dc.subject breast cancer susceptibility
dc.subject expression quantitative trait loci analysis
dc.subject single nucleotide polymorphism
dc.title Genetic variants of genes in the NER pathway associated with risk of breast cancer: A large-scale analysis of 14 published GWAS datasets in the DRIVE study.
dc.type Journal article
duke.contributor.id Wei, Qingyi|0632334
duke.contributor.id Luo, Sheng|0796693
duke.contributor.id Moorman, Patricia|0118714
dc.date.updated 2019-08-01T21:13:58Z
pubs.begin-page 1270
pubs.end-page 1279
pubs.issue 5
pubs.organisational-group School of Medicine
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Population Health Sciences
pubs.organisational-group Basic Science Departments
pubs.organisational-group Medicine, Medical Oncology
pubs.organisational-group Medicine
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke Clinical Research Institute
pubs.organisational-group Biostatistics & Bioinformatics
pubs.organisational-group Family Medicine and Community Health, Prevention Research
pubs.organisational-group Family Medicine and Community Health
pubs.publication-status Accepted
pubs.volume 145
duke.contributor.orcid Wei, Qingyi|0000-0002-3845-9445
duke.contributor.orcid Luo, Sheng|0000-0003-4214-5809


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