Browsing by Author "Hwang, Shelley"
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Item Open Access Association of genetic variants of FBXO32 and FOXO6 in the FOXO pathway with breast cancer risk.(Molecular carcinogenesis, 2021-07) Wang, Haijiao; Liu, Hongliang; Zhao, Lingling; Luo, Sheng; Akinyemiju, Tomi; Hwang, Shelley; Yue, Ying; Wei, QingyiForkhead box class O (FOXO) transcription factors play a pivotal role in regulating a variety of biological processes, including organismal development, cell signaling, cell metabolism, and tumorigenesis. Therefore, we hypothesize that genetic variants in FOXO pathway genes are associated with breast cancer (BC) risk. To test this hypothesis, we conducted a large meta-analysis using 14 published genome-wide association study (GWAS) data sets in the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study. We assessed associations between 5214 (365 genotyped in DRIVE and 4849 imputed) common single-nucleotide polymorphisms (SNPs) in 55 FOXO pathway genes and BC risk. After multiple comparison corrections by the Bayesian false-discovery probability method, we found five SNPs to be significantly associated with BC risk. In stepwise multivariate logistic regression analysis with adjustment for age, principal components, and previously published SNPs in the same data set, three independent SNPs (i.e., FBXO32 rs10093411 A>G, FOXO6 rs61229336 C>T, and FBXO32 rs62521280 C>T) remained to be significantly associated with BC risk (p = 0.0008, 0.0011, and 0.0017, respectively). Additional expression quantitative trait loci analysis revealed that the FBXO32 rs62521280 T allele was associated with decreased messenger RNA (mRNA) expression levels in breast tissue, while the FOXO6 rs61229336 T allele was found to be associated with decreased mRNA expression levels in the whole blood cells. Once replicated by other investigators, these genetic variants may serve as new biomarkers for BC risk.Item Open Access 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.(International journal of cancer, 2019-09) Ge, Jie; Liu, Hongliang; Qian, Danwen; Wang, Xiaomeng; Moorman, Patricia G; Luo, Sheng; Hwang, Shelley; Wei, QingyiA 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.Item Open Access Variants in SNAI1, AMDHD1 and CUBN in vitamin D pathway genes are associated with breast cancer risk: a large-scale analysis of 14 GWASs in the DRIVE study.(American journal of cancer research, 2020-01) Wang, Haijiao; Zhao, Lingling; Liu, Hongliang; Luo, Sheng; Akinyemiju, Tomi; Hwang, Shelley; Wei, QingyiVitamin D has a potential anticarcinogenic role, possibly through regulation of cell proliferation and differentiation, stimulation of apoptosis, immune modulation and regulation of estrogen receptor levels. Because breast cancer (BC) risk varies among individuals exposed to similar risk factors, we hypothesize that genetic variants in the vitamin D pathway genes are associated with BC risk. To test this hypothesis, we performed a larger meta-analysis using 14 published GWAS datasets in the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Study. We assessed associations between 2,994 (237 genotyped in the DRIVE study and 2,757 imputed from the 1000 Genomes Project) single nucleotide polymorphisms (SNPs) in 33 vitamin D pathway genes and BC risk. In unconditional logistic regression analysis, we found 11 noteworthy SNPs to be associated with BC risk after multiple comparison correction by the Bayesian false-discovery probability method (<0.80). In stepwise logistic regression analysis, with adjustment for age, principal components and previously published SNPs in the same study populations, we identified three independent SNPs (SNAI1 rs1047920 C>T, AMDHD1 rs11826 C>T and CUBN rs3914238 C>T) to be associated with BC risk (P = 0.0014, 0.0020 and 0.0022, respectively). Additional expression quantitative trait loci analysis revealed that the rs73276407 A allele, in a high LD with the rs1047920 T allele, was associated with decreased SNAI1 mRNA expression levels, while the rs11826 T allele was significantly associated with elevated AMDHD1 mRNA expression levels. Once replicated by other investigators and additional mechanistic studies, these genetic variants may serve as new biomarkers for susceptibility to BC.