Trends in the Contribution of Genetic Susceptibility Loci to Hyperuricemia and Gout and Associated Novel Mechanisms

Abstract

Hyperuricemia and gout are complex diseases mediated by genetic, epigenetic, and environmental exposure interactions. The incidence and medical burden of gout, an inflammatory arthritis caused by hyperuricemia, increase every year, significantly increasing the disease burden. Genetic factors play an essential role in the development of hyperuricemia and gout. Currently, the search on disease-associated genetic variants through large-scale genome-wide scans has primarily improved our understanding of this disease. However, most genome-wide association studies (GWASs) still focus on the basic level, whereas the biological mechanisms underlying the association between genetic variants and the disease are still far from well understood. Therefore, we summarized the latest hyperuricemia- and gout-associated genetic loci identified in the Global Biobank Meta-analysis Initiative (GBMI) and elucidated the comprehensive potential molecular mechanisms underlying the effects of these gene variants in hyperuricemia and gout based on genetic perspectives, in terms of mechanisms affecting uric acid excretion and reabsorption, lipid metabolism, glucose metabolism, and nod-like receptor pyrin domain 3 (NLRP3) inflammasome and inflammatory pathways. Finally, we summarized the potential effect of genetic variants on disease prognosis and drug efficacy. In conclusion, we expect that this summary will increase our understanding of the pathogenesis of hyperuricemia and gout, provide a theoretical basis for the innovative development of new clinical treatment options, and enhance the capabilities of precision medicine for hyperuricemia and gout treatment.

Keywords: genetic susceptibility loci; gout; hyperuricemia; inflammation introduction; novel mechanism.

FIGURE 1

Relationship between gene variants and reabsorption and excretion of uric acid in hyperuricemia and gout. Uric acid is reabsorbed and secreted into the proximal tubules of the kidneys. URAT1, GLUT9 (also known as GLUT9L), OAT4, and OAT10 are responsible for its reabsorption. ABCG2, ABCC4, NPT1, and NPT4 mediate uric acid excretion. The balance between reabsorption and secretion is related to uric acid homeostasis. In addition, SMCT1/2 proteins can regulate ion concentrations both inside and outside the cell. Different gene variants have different effects on these processes.

FIGURE 2

Potential relationship between gene variants and glucolipid metabolism and NLRP3 inflammasome-mediated inflammatory pathways in hyperuricemia and gout. The ingestion of fructose increases uric acid formation via the gluconeogenic pathway. In addition, triglycerides are also produced, increasing free fatty acid contents via the lipid metabolic pathway. Free fatty acids and monosodium urate crystals together stimulate downstream TLR2/4 and NLRP3 inflammasome formation, facilitate the of release IL-1β, and inhibit P62-mediated activation of autophagy and NETosis, ultimately promoting inflammation. Gene variants have different effects on different processes.