Common genetic variants of the human uromodulin gene regulate transcription and predict plasma uric acid levels.

Uromodulin (UMOD) genetic variants cause familial juvenile hyperuricemic nephropathy, characterized by hyperuricemia, decreased renal excretion of UMOD and uric acid; such findings suggest a role for UMOD in the regulation of plasma uric acid. We screened common variants across the UMOD locus in two populations, one from a community-based Chinese population, the other from California twins and siblings. Transcriptional activity of promoter variants was estimated in luciferase reporter plasmids transfected into HEK293 cells and mlMCD3 cells. By variance components in twin pairs, uric acid concentration and excretion were heritable traits. In the primary population from Beijing, we identified that carriers of haplotype GCC displayed higher plasma uric acid, and 3 UMOD promoter variants associated with plasma uric acid. UMOD promoter variants displayed reciprocal effects on urine uric acid excretion and plasma uric acid concentration, suggesting a primary effect on renal tubular handling of urate. These UMOD genetic marker-on-trait associations for uric acid were replicated in an independent American population sample. Site-directed mutagenesis at trait-associated UMOD promoter variants altered promoter activity in transfected luciferase reporter plasmids. These results suggest that UMOD promoter variants seem to initiate a cascade of transcriptional and biochemical changes influencing UMOD secretion, eventuating in elevation of plasma uric acid.

尿调节素（UMOD）基因变异导致家族性青少年高尿酸血症肾病，其特征为高尿酸血症、尿调节素和尿酸的肾排泄减少；这些发现表明尿调节素在血浆尿酸的调节中起作用。我们在两个人群中筛查了整个尿调节素基因座的常见变异，一个来自基于社区的中国人群，另一个来自加利福尼亚的双胞胎和兄弟姐妹。通过将启动子变异体转染到HEK293细胞和mlMCD3细胞中的荧光素酶报告质粒来评估其转录活性。通过双胞胎对的方差成分分析，尿酸浓度和排泄是可遗传的性状。在北京的原始人群中，我们发现单倍型GCC的携带者血浆尿酸水平较高，并且有3个尿调节素启动子变异体与血浆尿酸相关。尿调节素启动子变异体对尿尿酸排泄和血浆尿酸浓度表现出相互作用，表明其对肾小管尿酸处理有主要影响。这些尿调节素基因标记 - 尿酸性状的关联在一个独立的美国人群样本中得到了重复。在与性状相关的尿调节素启动子变异体处进行定点诱变改变了转染的荧光素酶报告质粒中的启动子活性。这些结果表明，尿调节素启动子变异体似乎引发了一系列影响尿调节素分泌的转录和生化变化，最终导致血浆尿酸升高。