Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Int J Cancer. 2013 Dec 15;133(12):3008-13. doi: 10.1002/ijc.28325. Epub 2013 Jul 16.
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.
全基因组关联研究（GWAS）鉴定了溶质载体家族 14（尿素转运蛋白）成员 1（SLC14A1）基因内标记物与膀胱癌风险之间的关联。SLC14A1 在红细胞中定义了 Kidd 血型，并且还参与肾脏中尿液的浓缩。我们评估了 SLC14A1 的代表性遗传变异（rs10775480）与在新英格兰膀胱癌研究中招募的 275 名基于人群的对照组的一部分中测量的尿比重（USG）之间的关联。收集过夜尿液样本，并使用折射计测量 USG。使用协方差分析估计与 rs10775480 相关的 USG 的调整最小二乘均值。我们还在一组人类组织中检查了两种尿素转运蛋白，SLC14A1 和 SLC14A2 的 mRNA 表达。随着 rs10775480 风险 T 等位基因的每一个拷贝，USG 降低（p-trend = 0.011），CC 与 TT 基因型之间观察到显著差异（p 值（tukey）= 0.024）。膀胱组织中的 RNA 测序显示 SLC14A1 的高表达和 SLC14A2 的缺失，而这两种转运蛋白在肾脏中均有表达。我们认为，这种 GWAS 发现的分子表型是 SLC14A1 在膀胱组织中的基因型特异性生物学活性。我们的数据表明，SLC14A1 可能是膀胱中一种独特的尿素转运蛋白，具有影响尿液浓缩的能力，并且这种机制可能解释与 rs10775480 相关的膀胱癌易感性增加。
