TY - JOUR
T1 - Common genetic variants in the PSCA gene influence gene expression and bladder cancer risk
AU - Fu, Yi Ping
AU - Kohaar, Indu
AU - Rothman, Nathaniel
AU - Earl, Julie
AU - Figueroa, Jonine D.
AU - Ye, Yuanqing
AU - Malats, Núria
AU - Tang, Wei
AU - Liu, Luyang
AU - Garcia-Closas, Montserrat
AU - Muchmore, Brian
AU - Chatterjee, Nilanjan
AU - Tarway, McAnthony
AU - Kogevinas, Manolis
AU - Porter-Gill, Patricia
AU - Baris, Dalsu
AU - Mumy, Adam
AU - Albanes, Demetrius
AU - Purdue, Mark P.
AU - Hutchinson, Amy
AU - Carrato, Alfredo
AU - Tardón, Adonina
AU - Serra, Consol
AU - García-Closas, Reina
AU - Lloreta, Josep
AU - Johnson, Alison
AU - Schwenn, Molly
AU - Karagas, Margaret R.
AU - Schned, Alan
AU - Diver, W. Ryan
AU - Gapstur, Susan M.
AU - Thun, Michael J.
AU - Virtamo, Jarmo
AU - Chanock, Stephen J.
AU - Fraumeni, Joseph F.
AU - Silverman, Debra T.
AU - Wu, Xifeng
AU - Real, Francisco X.
AU - Prokunina-Olsson, Ludmila
PY - 2012/3/27
Y1 - 2012/3/27
N2 - 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% confi- dence 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 differentmechanisms that influence the control of mRNA expression and interaction with regulatory factors.
AB - 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% confi- dence 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 differentmechanisms that influence the control of mRNA expression and interaction with regulatory factors.
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U2 - 10.1073/pnas.1202189109
DO - 10.1073/pnas.1202189109
M3 - Article
C2 - 22416122
AN - SCOPUS:84859476141
SN - 0027-8424
VL - 109
SP - 4974
EP - 4979
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 13
ER -