Wan-Chun Chang1, Yeong-Jian Jan Wu2, Wen-Hung Chung3, Yun-Shien Lee4, See-Wen Chin1,3, Ting-Jui Chen1,5, Yu-Sun Chang6, Der-Yuan Chen7, Shuen-Iu Hung1. 1. Institute of Pharmacology, Program in Molecular Medicine, School of Medicine, National Yang-Ming University, Taipei. 2. Department of Medicine, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Keelung. 3. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taipei. 4. Department of Biotechnology, Ming Chuan University, Taoyuan. 5. Department of Dermatology, Wan Fang Hospital, Taipei Medical University, Taipei. 6. Institute of Biomedical Sciences, Molecular Medicine Research Center, School of Medicine, Chang Gung University, Taoyuan. 7. Department of Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.
Abstract
Objective: Gout is characterized by recurrent attacks of arthritis with hyperuricaemia and urate crystal-induced inflammation. Although urate transporters are known as risk factors, the immunogenetics of gouty inflammation remains unclear. This study aimed to investigate the genetic association between immune/metabolism regulators and gout. Methods: We enrolled 448 gout patients and 943 population controls from Taiwan; all were Han Chinese. We screened association between gout and 22 variants of candidate genes, including NLRP3 , caspase 1, peroxisome proliferator-activated receptor-γ, proliferator-activated receptor-γ coactivator 1α ( PPARGC1A ) and 1β ( PPARGC1B ). The association was validated by replication and combined-sample analyses. Functional assays were performed by quantitative PCR, ELISA, siRNA knockdown and transfection using THP-1 cells, peripheral blood mononuclear cells and synovial cells from patients. Results: Gouty arthritis exhibited significant association with variants of peroxisome PPARGC1B , which included a missense single nucleotide polymorphism, rs45520937 [P = 6.66 × 10 -9 ; odds ratio (95% CI): 1.85 (1.51, 2.28)]. Expression of PPARGC1B and NLRP3 was induced in urate crystal-activated THP-1, peripheral blood mononuclear cells and synovial cells from gout patients in acute stage. siRNA knockdown of PPARGC1B upregulated NLRP3 in urate crystal-activated macrophages. Compared with the wild-type carriers, patients with the risk A allele of rs45520937 showed statistically increased NLRP3 (P = 0.044) and plasma IL-1β (P = 0.006). Transfection of PPARGC1B cDNA with rs45520937 A allele to macrophages significantly augmented the expression of NLRP3 and IL-1β. Conclusion: Genetic variants of PPARGC1B are significantly associated with gout, and a missense single nucleotide polymorphism, rs45520937, augments NLRP3 and IL-1β expression. These data suggest that variants of PPARGC1B , a regulator of metabolism and inflammation, contribute to the pathogenesis of gouty arthritis.
Objective: Gout is characterized by recurrent attacks of arthritis with hyperuricaemia and urate crystal-induced inflammation. Although urate transporters are known as risk factors, the immunogenetics of gouty inflammation remains unclear. This study aimed to investigate the genetic association between immune/metabolism regulators and gout. Methods: We enrolled 448 goutpatients and 943 population controls from Taiwan; all were Han Chinese. We screened association between gout and 22 variants of candidate genes, including NLRP3 , caspase 1, peroxisome proliferator-activated receptor-γ, proliferator-activated receptor-γ coactivator 1α ( PPARGC1A ) and 1β ( PPARGC1B ). The association was validated by replication and combined-sample analyses. Functional assays were performed by quantitative PCR, ELISA, siRNA knockdown and transfection using THP-1 cells, peripheral blood mononuclear cells and synovial cells from patients. Results:Gouty arthritis exhibited significant association with variants of peroxisome PPARGC1B , which included a missense single nucleotide polymorphism, rs45520937 [P = 6.66 × 10 -9 ; odds ratio (95% CI): 1.85 (1.51, 2.28)]. Expression of PPARGC1B and NLRP3 was induced in urate crystal-activated THP-1, peripheral blood mononuclear cells and synovial cells from goutpatients in acute stage. siRNA knockdown of PPARGC1B upregulated NLRP3 in urate crystal-activated macrophages. Compared with the wild-type carriers, patients with the risk A allele of rs45520937 showed statistically increased NLRP3 (P = 0.044) and plasma IL-1β (P = 0.006). Transfection of PPARGC1B cDNA with rs45520937 A allele to macrophages significantly augmented the expression of NLRP3 and IL-1β. Conclusion: Genetic variants of PPARGC1B are significantly associated with gout, and a missense single nucleotide polymorphism, rs45520937, augments NLRP3 and IL-1β expression. These data suggest that variants of PPARGC1B , a regulator of metabolism and inflammation, contribute to the pathogenesis of gouty arthritis.
Authors: Hannah Guak; Ryan D Sheldon; Ian Beddows; Alexandra Vander Ark; Matthew J Weiland; Hui Shen; Russell G Jones; Julie St-Pierre; Eric H Ma; Connie M Krawczyk Journal: Sci Rep Date: 2022-09-26 Impact factor: 4.996
Authors: Kenji W Ruiz-Miyazawa; Larissa Staurengo-Ferrari; Felipe A Pinho-Ribeiro; Victor Fattori; Tiago H Zaninelli; Stephanie Badaro-Garcia; Sergio M Borghi; Ketlem C Andrade; Juliana T Clemente-Napimoga; Jose C Alves-Filho; Thiago M Cunha; Leonardo F Fraceto; Fernando Q Cunha; Marcelo H Napimoga; Rubia Casagrande; Waldiceu A Verri Journal: Sci Rep Date: 2018-09-18 Impact factor: 4.379