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.

Exploring metabolic changes in gout – Insights from a genetic study

“…These observations, combined with the observed genetic correlations with several measures of lipid metabolism, suggest a shared genetic basis between gout and abnormalities in blood lipid and glucose levels. Variations in both genes, GCKR and MLXIPL , have been found to increase the glycolytic flux, which can lead to increased urate production via the pentose-phosphate pathway and simultaneously reduce fatty acid oxidation and increase lipogenesis 47,49 .…”

Purine Metabolism Dysfunctions: Experimental Methods of Detection and Diagnostic Potential

“…Attention should also be paid to the interconnection between hyperuricemia/gout and other diseases, such as metabolic syndrome and cardiovascular disease, as well as the role of genetic factors in these diseases. Elucidation of these genetic aspects will contribute to improved clinical outcomes and precision medicine [ 49 ].…”

Palladium-Catalyzed Carbonylative Synthesis of Diaryl Ketones from Arenes and Arylboronic Acids through C(sp2)–H Thianthrenation

“…Diaryl ketones are important chemical intermediates that are frequently present in chemical products, pharmaceutical molecules, and organic electroluminescent devices, and they also have broad applications in the chemical industry . Taking pharmaceutical applications as an example, benzbromarone has the function of strong uric acid removal, it can effectively inhibit the production of uric acid, and it is also able to reduce the concentration of uric acid in the blood . Fenofibrate can be used alone or in combination with statins to treat hypercholesterolemia and hypertriglyceridemia .…”

“…1 Taking pharmaceutical applications as an example, benzbromarone has the function of strong uric acid removal, it can effectively inhibit the production of uric acid, and it is also able to reduce the concentration of uric acid in the blood. 2 Fenofibrate can be used alone or in combination with statins to treat hypercholesterolemia and hypertriglyceridemia. 3 Mebendazole is a broad-spectrum intestinal worm repellent, mainly used to treat ascariasis, and has a significant advantage of killing larvae and inhibiting the development of eggs of taenia solium.…”