title: Differential urinary specific gravity as a molecular phenotype of the bladder cancer genetic association in the urea transporter gene, SLC14A1.
abstract: Genome-wide association studies (GWAS) identified associations between markers within the solute carrier family 14 (urea transporter), member 1 (SLC14A1) gene and risk of bladder cancer. SLC14A1 defines the Kidd blood groups in erythrocytes and is also involved in concentration of the urine in the kidney. We evaluated the association between a representative genetic variant (rs10775480) of SLC14A1 and urine concentration, as measured by urinary specific gravity (USG), in a subset of 275 population-based controls enrolled in the New England Bladder Cancer Study. Overnight urine samples were collected, and USG was measured using refractometry. Analysis of covariance was used to estimate adjusted least square means for USG in relation to rs10775480. We also examined the mRNA expression of both urea transporters, SLC14A1 and SLC14A2, in a panel of human tissues. USG was decreased with each copy of the rs10775480 risk T allele (p-trend = 0.011) with a significant difference observed for CC vs. TT genotypes (p-value(tukey) = 0.024). RNA-sequencing in the bladder tissue showed high expression of SLC14A1 and the absence of SLC14A2, while both transporters were expressed in the kidney. We suggest that the molecular phenotype of this GWAS finding is the genotype-specific biological activity of SLC14A1 in the bladder tissue. Our data suggest that SLC14A1 could be a unique urea transporter in the bladder that has the ability to influence urine concentration and that this mechanism might explain the increased bladder cancer susceptibility associated with rs10775480.
authors.affiliation: Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Stella
authors.initials: S
authors.lastname: Koutros
authors.forename: Dalsu
authors.initials: D
authors.lastname: Baris
authors.forename: Alexander
authors.initials: A
authors.lastname: Fischer
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Karagas
authors.forename: Molly
authors.initials: M
authors.lastname: Schwenn
authors.forename: Alison
authors.initials: A
authors.lastname: Johnson
authors.forename: Jonine
authors.initials: J
authors.lastname: Figueroa
authors.forename: Richard
authors.initials: R
authors.lastname: Waddell
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prokunina-Olsson
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.forename: Debra T
authors.initials: DT
authors.lastname: Silverman
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D013046:Specific Gravity; D001749:Urinary Bladder Neoplasms / Q000209:etiology / Q000235:genetics* / Q000652:urine; D000096982:Urea Transporters
chemical_list: D026901:Membrane Transport Proteins; D000096982:Urea Transporters
keywords: bladder cancer; epidemiology; genome-wide association study; urinary specific gravity