Author:
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Selinski, Silvia; Blaszkewicz, Meinolf; Ickstadt, Katja; Gerullis, Holger; Otto, Thomas; Roth, Emanuel; Volkert, Frank; Ovsiannikov, Daniel; Moormann, Oliver; Banfi, Gergely; Nyirady, Peter; Vermeulen, Sita H.; Garcia-Closas, Montserrat; Figueroa, Jonine D.; Johnson, Alison; Karagas, Margaret R.; Kogevinas, Manolis; Malats, Núria; Schwenn, Molly; Silverman, Debra T.; Koutros, Stella; Rothman, Nathaniel; Kiemeney, Lambertus A.; Hengstler, Jan G.; Golka, Klaus
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Abstract:
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Little is known whether genetic variants identified in
genome-wide association studies interact to increase bladder
cancer risk. Recently, we identified two- and three-variant
combinations associated with a particular increase of bladder
cancer risk in a urinary bladder cancer case-control series
(IfADo, 1501 cases, 1565 controls). In an independent
case-control series (Nijmegen Bladder Cancer Study, NBCS, 1468
cases, 1720 controls) we confirmed these two- and three-variant
combinations. Pooled analysis of the two studies as discovery
group (IfADo-NBCS) resulted in sufficient statistical power to
test up to four-variant combinations by a logistic regression
approach. The New England and Spanish Bladder Cancer Studies
(2080 cases and 2167 controls) were used as a replication
series. Twelve previously identified risk variants were
considered.The strongest four-variant combination was obtained
in never smokers. The combination of rs1014971[AA] near APOBEC3A
and CBX6, SLC14A1 exon SNP rs1058396[AG,GG], UGT1A intron SNP
rs11892031[AA], and rs8102137[CC,CT] near CCNE resulted in an
unadjusted odds ratio of 2.59 (95% CI = 1.93-3.47; P =
1.87x10-10), while the individual variant odds ratios ranged
only between 1.11-1.30. The combination replicated in the New
England and Spanish bladder Cancer Studies (ORunadjusted=1.60,
95% CI = 1.10-2.33; P = 0.013). The four-variant combination is
relatively frequent, with 25% in never smoking cases and 11% in
never smoking controls (total study group: 19% cases, 14%
controls). In conclusion, we show that four high risk variants
can statistically interact to confer increased bladder cancer
risk particularly in never smokers. |