Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Department of Medicine, University of Auckland, Auckland, New Zealand.
Nat Rev Rheumatol. 2018 Jun;14(6):341-353. doi: 10.1038/s41584-018-0004-x.
A central aspect of the pathogenesis of gout is elevated urate concentrations, which lead to the formation of monosodium urate crystals. The clinical features of gout result from an individual's immune response to these deposited crystals. Genome-wide association studies (GWAS) have confirmed the importance of urate excretion in the control of serum urate levels and the risk of gout and have identified the kidneys, the gut and the liver as sites of urate regulation. The genetic contribution to the progression from hyperuricaemia to gout remains relatively poorly understood, although genes encoding proteins that are involved in the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome pathway play a part. Genome-wide and targeted sequencing is beginning to identify uncommon population-specific variants that are associated with urate levels and gout. Mendelian randomization studies using urate-associated genetic variants as unconfounded surrogates for lifelong urate exposure have not supported claims that urate is causal for metabolic conditions that are comorbidities of hyperuricaemia and gout. Genetic studies have also identified genetic variants that predict responsiveness to therapies (for example, urate-lowering drugs) for treatment of hyperuricaemia. Future research should focus on large GWAS (that include asymptomatic hyperuricaemic individuals) and on increasing the use of whole-genome sequencing data to identify uncommon genetic variants with increased penetrance that might provide opportunities for clinical translation.
痛风发病机制的一个核心方面是尿酸浓度升高，这导致单钠尿酸盐晶体的形成。痛风的临床特征源自个体对这些沉积晶体的免疫反应。全基因组关联研究（GWAS）已经证实了尿酸排泄在控制血清尿酸水平和痛风风险中的重要性，并确定了肾脏、肠道和肝脏是尿酸调节的部位。从高尿酸血症进展到痛风的遗传贡献仍然相对了解较少，尽管编码参与 NLRP3（NOD、LRR 和 pyrin 结构域包含 3）炎性小体途径的蛋白质的基因起了一定的作用。全基因组和靶向测序开始识别与尿酸水平和痛风相关的罕见人群特异性变异。使用尿酸相关遗传变异作为终生尿酸暴露的无偏替代物的孟德尔随机化研究并未支持尿酸是与高尿酸血症和痛风并存的代谢疾病的因果关系的说法。遗传研究还确定了可预测对治疗（例如，降低尿酸药物）反应的遗传变异，以治疗高尿酸血症。未来的研究应集中在大型 GWAS（包括无症状高尿酸血症个体）上，并增加全基因组测序数据的使用，以识别具有更高外显率的罕见遗传变异，这可能为临床转化提供机会。
