Identification of 377 gout-associated loci through analysis of 2.62 million people across four racial groups

A research group led by Professor Hirotaka Matsuo of the National Defense Medical College and Assistant Professor Yuya Shirai and Professor Yukinori Okada of Osaka University, in international joint research with the University of Alabama in the United States, has announced that they successfully identified 377 gout-associated loci through genetic analysis in 2.62 million people from 4 racial groups. The genes at these loci included those encoding proteins for intracellular and extracellular uric acid transport across cell membranes and several other molecules involved in developing gout, including those involved in immune responses. The findings are expected to contribute to the clarification of the molecular mechanism of gout and the development of antipodagric agents. The results were published in the international journal Nature Genetics on October 15.

Gout is a lifestyle-related disease known for sudden attacks of severe pain, affecting estimated 1.35 million patients in Japan. Gout is caused by an inflammatory response of the immune system to deposited intra-articular uric acid crystals in the setting of persistent hyperuricemia, a condition characterized by high serum uric acid levels. Gout and hyperuricemia can cause chronic kidney disease and cerebrovascular disease. It has become clear that middle-aged and older obese men who drink heavily are particularly prone to gout and that genetic factors also have a strong effect.

Previously, Matsuo and his research group had reported multiple novel urate transporter genes and gout-associated loci identified by genome-wide association analysis (GWAS) in gout patients. In the present study, the research group led an international collaborative genetic analysis of 2.62 million people from 4 racial groups. Approximately 120,000 patients with gout (the gout group) and approximately 2.5 million control individuals without gout (the non-gout control group) were included in this study.

The racial groups were as follows: (1) European group: approximately 100,000 patients with gout and approximately 2.11 million individuals without gout; (2) East Asian group: approximately 11,000 patients with gout and 82,000 individuals without gout; (3) Latino group: approximately 6,000 patients with gout and 236,000 individuals without gout; and (4) African group: approximately 3,000 patients with gout and 78,000 individuals without gout. After a GWAS in each group was performed, a meta-analysis of the combined results from the 4 groups identified 377 gout-associated loci. Of these, 149 were novel loci. The genes at these loci included genes encoding conventionally known proteins for transporting intracellular and extracellular uric acid across cell membranes. The other genes at the novel loci include those encoding proteins involved in the regulation of immune responses, such as the regulation of NLRP3 inflammasome activity, cell osmolarity, and epigenetic remodeling.

Matsuo said, "The identified genes included genes involved in the inflammatory response in gout, being expected to contribute to the elucidation of the pathogenic mechanism of gout and the development of new antipodagric agents. Research on gout and uric acid in Japan is leading the globe. The participation of Japanese researchers as key members in this international joint research paper is of great significance for future research in this field. Meanwhile, we will continue genetic research in an increased number of patients with gout in Asia, including Japan."

Journal Information
Publication: Nature Genetics
Title: A genome-wide association analysis reveals new pathogenic pathways in gout
DOI: 10.1038/s41588-024-01921-5