Leask Megan P, Sumpter Nicholas A, Lupi Alexa S, Vazquez Ana I, Reynolds Richard J, Mount David B, Merriman Tony R
Department of Biochemistry, University of Otago, Dunedin, New Zealand; Division of Clinical Immunology and Rheumatology, University of Alabama Birmingham, Birmingham, AL.
Division of Clinical Immunology and Rheumatology, University of Alabama Birmingham, Birmingham, AL.
Semin Nephrol. 2020 Nov;40(6):586-599. doi: 10.1016/j.semnephrol.2020.12.002.
Increased urate levels and gout correlate with chronic kidney disease with consensus that the primary driver of this relationship is reduced kidney function. However, a comparison of results of genome-wide association studies in serum urate levels and kidney function indicate a more complex situation. Approximately 20% of loci are shared-comprised of those in which the urate-raising allele associates with reduced kidney function, the vice versa situation, and those in which the signals/alleles are different. Although there is very little known regarding the molecular basis of the shared genetic relationship, it is clear that there is no major role for urate transporters and associated transportasome machinery. Some loci, however, do provide clues. The ATXN2 locus, with a shared signal, is one of only a small number of master regulators of expression by chromatin interaction, regulating expression of genes relevant for cholesterol and blood pressure. This suggests a role for systemic metabolic alteration. At HNF4A there is genetic heterogeneity with different genetic variants conferring risk to hyperuricemia and chronic kidney disease, suggesting different pathways. Interestingly, the shared loci congregate in the olfactory receptor pathway. The genome-wide association studies have generated a range of experimentally testable hypotheses that should provide insights into the shared pathogenesis of hyperuricemia/gout and chronic kidney disease.
尿酸水平升高和痛风与慢性肾脏病相关，人们普遍认为这种关系的主要驱动因素是肾功能下降。然而，对血清尿酸水平和肾功能的全基因组关联研究结果进行比较后发现情况更为复杂。大约20%的基因座是共享的，包括尿酸升高等位基因与肾功能下降相关的基因座、反之亦然的情况，以及信号/等位基因不同的基因座。尽管对于这种共享遗传关系的分子基础知之甚少，但很明显尿酸转运蛋白和相关转运体机制没有起主要作用。然而，一些基因座确实提供了线索。具有共享信号的ATXN2基因座是少数通过染色质相互作用调控表达的主调控因子之一，调控与胆固醇和血压相关基因的表达。这表明全身代谢改变起了作用。在肝细胞核因子4α（HNF4A）基因座存在遗传异质性，不同的基因变异赋予高尿酸血症和慢性肾脏病风险，提示存在不同的途径。有趣的是，共享基因座聚集在嗅觉受体途径中。全基因组关联研究产生了一系列可通过实验验证的假设，这些假设应该能为高尿酸血症/痛风和慢性肾脏病的共同发病机制提供见解。
