A genome-wide association study of bladder cancer identifies a new susceptibility locus within SLC14A1, a urea transporter gene on chromosome 18q12.3

Abstract

Genome-wide and candidate-gene association studies of bladder cancer have identified 10 susceptibility loci thus far. We conducted a meta-analysis of two previously published genome-wide scans (4501 cases and 6076 controls of European background) and followed up the most significant association signals [17 single nucleotide polymorphisms (SNPs) in 10 genomic regions] in 1382 cases and 2201 controls from four studies. A combined analysis adjusted for study center, age, sex, and smoking status identified a novel susceptibility locus that mapped to a region of 18q12.3, marked by rs7238033 (P = 8.7 × 10(-9); allelic odds ratio 1.20 with 95% CI: 1.13-1.28) and two highly correlated SNPs, rs10775480/rs10853535 (r(2)= 1.00; P = 8.9 × 10(-9); allelic odds ratio 1.16 with 95% CI: 1.10-1.22). The signal localizes to the solute carrier family 14 member 1 gene, SLC14A1, a urea transporter that regulates cellular osmotic pressure. In the kidney, SLC14A1 regulates urine volume and concentration whereas in erythrocytes it determines the Kidd blood groups. Our findings suggest that genetic variation in SLC14A1 could provide new etiological insights into bladder carcinogenesis.

Figure 1.

Study design of meta-analysis and follow up stages in GWAS of urinary bladder cancer. See Supplementary Material, Table S1 for details of study designs and sample sizes.

Figure 2.

Association results, recombination and linkage disequilibrium plots for chromosome 18q12.3. Association results of stage I (green circles), stage II (blue triangle) and combined data from stages I and II (red diamond) for log-additive models are shown in the top panel with −log10 P values (left y-axis). Overlaid on the top panel is the LR statistics (right y-axis) to estimate putative recombination hotspot across the region based on five sets of 100 randomly selected control samples (connected lines in various colors). Pairwise r² values based on control populations are displayed at the bottom for all SNPs included in the GWAS analysis. Genomic coordinates are based on NCBI Human Genome Build 36.3.