Περίληψη:
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 (r(2) = 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 x 10(-5)] for rs2294008 and OR = 1.07 (95% CI =
1.02-1.13, P= 9.7 x 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
x 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.
Συγγραφείς:
Fu, Yi-Ping
Kohaar, Indu
Rothman, Nathaniel
Earl, Julie and
Figueroa, Jonine D.
Ye, Yuanqing
Malats, Nuria
Tang, Wei and
Liu, Luyang
Garcia-Closas, Montserrat
Muchmore, Brian and
Chatterjee, Nilanjan
Tarway, McAnthony
Kogevinas, Manolis and
Porter-Gill, Patricia
Baris, Dalsu
Mumy, Adam
Albanes,
Demetrius
Purdue, Mark P.
Hutchinson, Amy
Carrato, Alfredo
and Tardon, Adonina
Serra, Consol
Garcia-Closas, Reina and
Lloreta, Josep
Johnson, Alison
Schwenn, Molly
Karagas,
Margaret R.
Schned, Alan
Diver, W. Ryan
Gapstur, Susan M.
and Thun, Michael J.
Virtamo, Jarmo
Chanock, Stephen J. and
Fraumeni, Jr., Joseph F.
Silverman, Debra T.
Wu, Xifeng and
Real, Francisco X.
Prokunina-Olsson, Ludmila
