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.

Figure 1.

A schematic view of the structure and association results in the UBC-associated region on chromosome 18q12.3. (A) Estimated recombination rates (saRR) in cM/Mb from the HapMap (release 22) Phase II data. (B) Location of known genes in the region. (C) Schematic view of the association with bladder cancer for all SNPs tested in the region for the initial scan (Iceland and the Netherlands). The y-axis indicates the –log 10 P-value. Red dots indicate SNPs directly genotyped in both discovery series; blue dots indicate SNPs imputed in both discovery series; green dots indicate SNPs directly genotyped in the Icelandic series but imputed in the Dutch series.