Wei Tang

Publications (8)90.63 Total impact

• Article: Common Genetic Polymorphisms Modify the Effect of Smoking on Absolute Risk of Bladder Cancer.

  Montserrat Garcia-Closas, Nathaniel Rothman, Jonine D Figueroa, Ludmila Prokunina-Olsson, Summer S Han, Dalsu Baris, Eric J Jacobs, Nuria Malats, Immaculata De Vivo, Demetrius Albanes, [......], Neil Caporaso, Maria Teresa Landi, Amy Hutchinson, Laurie Burdett, Kevin B Jacobs, Meredith Yeager, Joseph F Fraumeni, Stephen J Chanock, Debra T Silverman, Nilanjan Chatterjee
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  ABSTRACT: Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to assess the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for U.S. males aged 50 years. Six of 12 variants showed significant additive gene-environment interactions, most notably NAT2 (P = 7 × 10(-4)) and UGT1A6 (P = 8 × 10(-4)). The 30-year absolute risk of bladder cancer in U.S. males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile compared with 2,000 cases prevented by a similar effort in the lowest PRS quartile (Padditive = 1 × 10(-4)). Thus, the potential impact of eliminating smoking on the number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made. Cancer Res; 73(7); 1-10. ©2012 AACR.
  Cancer Research 03/2013; · 7.86 Impact Factor
• Article: A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.

  Ludmila Prokunina-Olsson, Brian Muchmore, Wei Tang, Ruth M Pfeiffer, Heiyoung Park, Harold Dickensheets, Dianna Hergott, Patricia Porter-Gill, Adam Mumy, Indu Kohaar, [......], Faruk Sheikh, Jacquie Astemborski, Herbert L Bonkovsky, Brian R Edlin, Charles D Howell, Timothy R Morgan, David L Thomas, Barbara Rehermann, Raymond P Donnelly, Thomas R O'Brien
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  ABSTRACT: Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.
  Nature Genetics 01/2013; · 35.53 Impact Factor
• Article: Genetic Variant as a Selection Marker for Anti-Prostate Stem Cell Antigen Immunotherapy of Bladder Cancer.

  Indu Kohaar, Patricia Porter-Gill, Petra Lenz, Yi-Ping Fu, Adam Mumy, Wei Tang, Andrea B Apolo, Nathaniel Rothman, Dalsu Baris, Alan R Schned, Kris Ylaya, Molly Schwenn, Alison Johnson, Michael Jones, Masatoshi Kida, Debra T Silverman, Stephen M Hewitt, Lee E Moore, Ludmila Prokunina-Olsson
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  ABSTRACT: A monoclonal antibody against prostate stem cell antigen (PSCA) has emerged as a novel cancer therapy currently being tested in clinical trials for prostate and pancreatic cancers, but this treatment is likely to be efficient only in patients with PSCA-expressing tumors. The present study demonstrates that a genetic variant (rs2294008) discovered by bladder cancer genome-wide association studies is a strong predictor of PSCA protein expression in bladder tumors, as measured by two-sided multivariable linear regression (P = 6.46×10(-11); n = 278). The association pattern is similar in non-muscle-invasive tumors, stages Ta (P = 3.10×10(-5); n = 173) and T1 (P = 2.64×10(-5); n = 60), and muscle-invasive tumors, stages T2 (P =.01; n = 23) and T3/4 (P =.03; n = 22). The study suggests that anti-PSCA immunotherapy might be beneficial for bladder cancer patients with high tumor PSCA expression, which is statistically significantly associated with the presence of CT and TT genotypes of a common genetic variant, rs2294008. Future clinical studies will be needed to validate PSCA as a therapeutic target for bladder cancer.
  CancerSpectrum Knowledge Environment 12/2012; · 14.07 Impact Factor
• Article: Common genetic variants in the PSCA gene influence gene expression and bladder cancer risk

  Yi-Ping Fu, Indu Kohaar, Nathaniel Rothman, Julie Earl, Jonine D. Figueroa, Yuanqing Ye, Núria Malats, Wei Tang, Luyang Liu, Montserrat Garcia-Closas, [......], W. Ryan Diver, Susan M. Gapstur, Michael J. Thun, Jarmo Virtamo, Stephen J. Chanock, Jr. Joseph F. Fraumeni, Debra T. Silverman, Xifeng Wu, Francisco X. Real, Ludmila Prokunina-Olsson
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  ABSTRACT: Genome-wide association studies have identified a SNP, rs2294008, on 8q24.3 within the prostate stem cell antigen (PSCA) gene, as a risk factor for bladder cancer. To fine-map this region, we imputed 642 SNPs within 100 Kb of rs2294008 in addition to 33 markers genotyped in one of the reported genome-wide association study in 8,652 subjects. A multivariable logistic regression model adjusted for rs2294008 revealed a unique signal, rs2978974 (r2 = 0.02, D′ = 0.19 with rs2294008). In the combined analysis of 5,393 cases and 7,324 controls, we detected a per-allele odds ratio (OR) = 1.11 [95% confidence interval (CI) = 1.06–1.17, P = 5.8 × 10−5] for rs2294008 and OR = 1.07 (95% CI = 1.02–1.13, P = 9.7 × 10−3) for rs2978974. The effect was stronger in carriers of both risk variants (OR = 1.24, 95% CI = 1.08–1.41, P = 1.8 × 10−3) and there was a significant multiplicative interaction (P = 0.035) between these two SNPs, which requires replication in future studies. The T risk allele of rs2294008 was associated with increased PSCA mRNA expression in two sets of bladder tumor samples (n = 36, P = 0.0007 and n = 34, P = 0.0054) and in normal bladder samples (n = 35, P = 0.0155), but rs2978974 was not associated with PSCA expression. SNP rs2978974 is located 10 Kb upstream of rs2294008, within an alternative untranslated first exon of PSCA. The non-risk allele G of rs2978974 showed strong interaction with nuclear proteins from five cell lines tested, implying a regulatory function. In conclusion, a joint effect of two PSCA SNPs, rs2294008 and rs2978974, suggests that both variants may be important for bladder cancer susceptibility, possibly through different mechanisms that influence the control of mRNA expression and interaction with regulatory factors.
  Proceedings of the National Academy of Sciences 03/2012; 109(13):4974-4979. · 9.68 Impact Factor
• Article: Mapping of the UGT1A locus identifies an uncommon coding variant that affects mRNA expression and protects from bladder cancer.

  Wei Tang, Yi-Ping Fu, Jonine D Figueroa, Núria Malats, Montserrat Garcia-Closas, Nilanjan Chatterjee, Manolis Kogevinas, Dalsu Baris, Michael Thun, Jennifer L Hall, [......], Eric J Jacobs, W Ryan Diver, Susan M Gapstur, Jarmo Virtamo, David J Hunter, Joseph F Fraumeni, Stephen J Chanock, Debra T Silverman, Nathaniel Rothman, Ludmila Prokunina-Olsson
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  ABSTRACT: A recent genome-wide association study of bladder cancer identified the UGT1A gene cluster on chromosome 2q37.1 as a novel susceptibility locus. The UGT1A cluster encodes a family of UDP-glucuronosyltransferases (UGTs), which facilitate cellular detoxification and removal of aromatic amines. Bioactivated forms of aromatic amines found in tobacco smoke and industrial chemicals are the main risk factors for bladder cancer. The association within the UGT1A locus was detected by a single nucleotide polymorphism (SNP) rs11892031. Now, we performed detailed resequencing, imputation and genotyping in this region. We clarified the original genetic association detected by rs11892031 and identified an uncommon SNP rs17863783 that explained and strengthened the association in this region (allele frequency 0.014 in 4035 cases and 0.025 in 5284 controls, OR = 0.55, 95%CI = 0.44-0.69, P = 3.3 × 10(-7)). Rs17863783 is a synonymous coding variant Val209Val within the functional UGT1A6.1 splicing form, strongly expressed in the liver, kidney and bladder. We found the protective T allele of rs17863783 to be associated with increased mRNA expression of UGT1A6.1 in in-vitro exontrap assays and in human liver tissue samples. We suggest that rs17863783 may protect from bladder cancer by increasing the removal of carcinogens from bladder epithelium by the UGT1A6.1 protein. Our study shows an example of genetic and functional role of an uncommon protective genetic variant in a complex human disease, such as bladder cancer.
  Human Molecular Genetics 01/2012; 21(8):1918-30. · 7.64 Impact Factor
• Article: Large-scale pathway-based analysis of bladder cancer genome-wide association data from five studies of European background.

  Idan Menashe, Jonine D Figueroa, Montserrat Garcia-Closas, Nilanjan Chatterjee, Nuria Malats, Antoni Picornell, Dennis Maeder, Qi Yang, Ludmila Prokunina-Olsson, Zhaoming Wang, [......], Ryan W Diver, Susan M Gapstur, Stephanie J Weinstein, Jarmo Virtamo, Neil E Caporaso, Maria Teresa Landi, Joseph F Fraumeni, Stephen J Chanock, Debra T Silverman, Nathaniel Rothman
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  ABSTRACT: Pathway analysis of genome-wide association studies (GWAS) offer a unique opportunity to collectively evaluate genetic variants with effects that are too small to be detected individually. We applied a pathway analysis to a bladder cancer GWAS containing data from 3,532 cases and 5,120 controls of European background (n = 5 studies). Thirteen hundred and ninety-nine pathways were drawn from five publicly available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome), and we constructed 22 additional candidate pathways previously hypothesized to be related to bladder cancer. In total, 1421 pathways, 5647 genes and ∼90,000 SNPs were included in our study. Logistic regression model adjusting for age, sex, study, DNA source, and smoking status was used to assess the marginal trend effect of SNPs on bladder cancer risk. Two complementary pathway-based methods (gene-set enrichment analysis [GSEA], and adapted rank-truncated product [ARTP]) were used to assess the enrichment of association signals within each pathway. Eighteen pathways were detected by either GSEA or ARTP at P≤0.01. To minimize false positives, we used the I(2) statistic to identify SNPs displaying heterogeneous effects across the five studies. After removing these SNPs, seven pathways ('Aromatic amine metabolism' [P(GSEA) = 0.0100, P(ARTP) = 0.0020], 'NAD biosynthesis' [P(GSEA) = 0.0018, P(ARTP) = 0.0086], 'NAD salvage' [P(ARTP) = 0.0068], 'Clathrin derived vesicle budding' [P(ARTP) = 0.0018], 'Lysosome vesicle biogenesis' [P(GSEA) = 0.0023, P(ARTP)<0.00012], 'Retrograde neurotrophin signaling' [P(GSEA) = 0.00840], and 'Mitotic metaphase/anaphase transition' [P(GSEA) = 0.0040]) remained. These pathways seem to belong to three fundamental cellular processes (metabolic detoxification, mitosis, and clathrin-mediated vesicles). Identification of the aromatic amine metabolism pathway provides support for the ability of this approach to identify pathways with established relevance to bladder carcinogenesis.
  PLoS ONE 01/2012; 7(1):e29396. · 4.09 Impact Factor
• Article: A genome-wide association study of bladder cancer identifies a new susceptibility locus within SLC14A1, a urea transporter gene on chromosome 18q12.3.

  Montserrat Garcia-Closas, Yuanqing Ye, Nathaniel Rothman, Jonine D Figueroa, Núria Malats, Colin P Dinney, Nilanjan Chatterjee, Ludmila Prokunina-Olsson, Zhaoming Wang, Jie Lin, [......], Susan M Gapstur, Stephanie J Weinstein, Jarmo Virtamo, David J Hunter, Neil Caporaso, Maria Teresa Landi, Joseph F Fraumeni, Debra T Silverman, Stephen J Chanock, Xifeng Wu
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  ABSTRACT: Genome-wide and candidate-gene association studies of bladder cancer have identified 10 susceptibility loci thus far. We conducted a meta-analysis of two previously published genome-wide scans (4501 cases and 6076 controls of European background) and followed up the most significant association signals [17 single nucleotide polymorphisms (SNPs) in 10 genomic regions] in 1382 cases and 2201 controls from four studies. A combined analysis adjusted for study center, age, sex, and smoking status identified a novel susceptibility locus that mapped to a region of 18q12.3, marked by rs7238033 (P = 8.7 × 10(-9); allelic odds ratio 1.20 with 95% CI: 1.13-1.28) and two highly correlated SNPs, rs10775480/rs10853535 (r(2)= 1.00; P = 8.9 × 10(-9); allelic odds ratio 1.16 with 95% CI: 1.10-1.22). The signal localizes to the solute carrier family 14 member 1 gene, SLC14A1, a urea transporter that regulates cellular osmotic pressure. In the kidney, SLC14A1 regulates urine volume and concentration whereas in erythrocytes it determines the Kidd blood groups. Our findings suggest that genetic variation in SLC14A1 could provide new etiological insights into bladder carcinogenesis.
  Human Molecular Genetics 08/2011; 20(21):4282-9. · 7.64 Impact Factor
• Article: Refining the prostate cancer genetic association within the JAZF1 gene on chromosome 7p15.2.

  Ludmila Prokunina-Olsson, Yi-Ping Fu, Wei Tang, Kevin B Jacobs, Richard B Hayes, Peter Kraft, Sonja I Berndt, Sholom Wacholder, Kai Yu, Amy Hutchinson, [......], Kristian Hveem, Merethe Kumle, Margaret Tucker, Robert N Hoover, Joseph F Fraumeni, David J Hunter, Gilles Thomas, Nilanjan Chatterjee, Stephen J Chanock, Meredith Yeager
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  ABSTRACT: Genome-wide association studies have identified multiple genetic variants associated with susceptibility to prostate cancer (PrCa). In the two-stage Cancer Genetic Markers of Susceptibility prostate cancer scan, a single-nucleotide polymorphism (SNP), rs10486567, located within intron 2 of JAZF1 gene on chromosome 7p15.2, showed a promising association with PrCa overall (P=2.14x10(-6)), with a suggestion of stronger association with aggressive disease (P=1.2x10(-7)). In the third stage of genome-wide association studies, we genotyped 106 JAZF1 SNPs in 10,286 PrCa cases and 9,135 controls of European ancestry. The strongest association was observed with the initial marker rs10486567, which now achieves genome-wide significance [P=7.79x10(-11); ORHET, 1.19 (95% confidence interval, 1.12-1.27); ORHOM, 1.37 (95% confidence interval, 1.20-1.56)]. We did not confirm a previous suggestion of a stronger association of rs10486567 with aggressive disease (P=1.60x10(-4) for aggressive cancer, n=4,597; P=3.25x10(-8) for nonaggressive cancer, n=4,514). Based on a multilocus model with adjustment for rs10486567, no additional independent signals were observed at chromosome 7p15.2. There was no association between PrCa risk and SNPs in JAZF1 previously associated with height (rs849140; P=0.587), body stature (rs849141, tagged by rs849136; P=0.171), and risk of type 2 diabetes and systemic lupus erythematosus (rs864745, tagged by rs849142; P=0.657). rs10486567 remains the most significant marker for PrCa risk within JAZF1 in individuals of European ancestry. Future studies should identify all variants in high linkage disequilibrium with rs10486567 and evaluate their functional significance for PrCa.
  Cancer Epidemiology Biomarkers &amp Prevention 05/2010; 19(5):1349-55. · 4.12 Impact Factor