European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene

Abstract

Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.

Cumulative effect of genome‐wide association study‐identified genetic variants for bladder cancer

“…3 Then additional predisposing loci, 5p15.33 (rs2736098 and rs401681), 4p16.3 (rs798766), 22q13.1 (rs1014971), 19q12 (rs8102137), 2q37.1 (rs11892031), 18q12.3 (rs17674580, rs7238033, rs10775480 and rs10853535), 3q26.2 (rs10936599) and 11p15.5 (rs907611), were identified by other GWAS in Caucasian, respectively. [4][5][6][7][8][9] Further, large candidate gene and metaanalysis studies revealed NAT2 slow acetylation and GSTM1 null genotypes as susceptibility loci for bladder cancer. 10,11 Although the aforementioned loci associated with bladder cancer risk have been successfully performed in the populations of European ancestry, the individual effect of these risk variants in other populations is as yet unknown.…”

“…[2][3][4][5][6][7][8][9] The SNPs rs9642880 at 8q24.21 and rs710521 at 3q28 were the first to be identified as common susceptibility loci for bladder cancer in nine study groups of European ancestry.…”

“…1 Several significant GWAS of bladder cancer have provided strong evidence for over 10 independent loci and single-nucleotide polymorphisms (SNPs) that reach the statistical genome-wide significance. [2][3][4][5][6][7][8][9] The SNPs rs9642880 at 8q24.21 and rs710521 at 3q28 were the first to be identified as common susceptibility loci for bladder cancer in nine study groups of European ancestry. 2 The second SNP rs2294008 at 8q24.3 harboring PSCA, an adjunct marker for the detection of urothelial transitional cell carcinoma, has subsequently been identified by a GWAS in US and European populations.…”

Genetic Variation in PSCA is Associated with Bladder Cancer Susceptibility in a Korean Population

“…Recently, genomewide association studies (GWAS) have permitted the identification of novel susceptibility loci in the human genome associated with many complex diseases, including cancer (Dudek et al, 2013). To date, three GWAS for bladder cancer risk have been conducted, and eight single nucleotide polymorphisms (SNPs) were identified near the following genes: MYC (8q24), TP63 (3q28), PSCA (8q24), FGFR3/TACC3 (4p16), CBX6/ APOBEC3A (22q13), CCNE1 (19q12), UGT1A (2q37), and SLC14A1 (18q12) (Kiemeney et al, 2008;Wu et al, 2009;Kiemeney et al, 2010;Rothman et al, 2010;Rafnar et al, 2011).…”

Combined presence of four individually weak genetic variants strongly increases cancer risk

“…Recently, large efforts have been invested into genome-wide association studies to identify genetic variants that confer urinary bladder cancer risk (Rothman et al 2010;Selinski 2014C;Rafnar et al 2014Rafnar et al , 2011Rafnar et al , 2009Kiemeney et al 2008Kiemeney et al , 2010Garcia-Closas et al 2011;Figueroa et al 2016Figueroa et al , 2014. Usually, the odds ratios of individual variants are low and do not exceed 1.4 (Selinski 2012(Selinski , 2014aGolka et al 2011;Schwender et al 2012).…”