title: Genetic variants of PPAR-gamma coactivator 1B augment NLRP3-mediated inflammation in gouty arthritis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.affiliation: Institute of Pharmacology, Program in Molecular Medicine, School of Medicine, National Yang-Ming University, Taipei.
authors.forename: Wan-Chun
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Keelung.
authors.forename: Yeong-Jian
authors.initials: YJ
authors.lastname: Jan Wu
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taipei.
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Chung
authors.affiliation: Department of Biotechnology, Ming Chuan University, Taoyuan.
authors.forename: Yun-Shien
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Institute of Pharmacology, Program in Molecular Medicine, School of Medicine, National Yang-Ming University, Taipei.|Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taipei.
authors.forename: See-Wen
authors.initials: SW
authors.lastname: Chin
authors.affiliation: Institute of Pharmacology, Program in Molecular Medicine, School of Medicine, National Yang-Ming University, Taipei.|Department of Dermatology, Wan Fang Hospital, Taipei Medical University, Taipei.
authors.forename: Ting-Jui
authors.initials: TJ
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Molecular Medicine Research Center, School of Medicine, Chang Gung University, Taoyuan.
authors.forename: Yu-Sun
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Department of Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Der-Yuan
authors.initials: DY
authors.lastname: Chen
authors.affiliation: Institute of Pharmacology, Program in Molecular Medicine, School of Medicine, National Yang-Ming University, Taipei.
authors.forename: Shuen-Iu
authors.initials: SI
authors.lastname: Hung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015210:Arthritis, Gouty / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D020170:Caspase 1 / Q000235:genetics*; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D055785:Gene Knockdown Techniques; D014644:Genetic Variation; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D020125:Mutation, Missense; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics*; D016017:Odds Ratio; D047495:PPAR gamma / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D060888:Real-Time Polymerase Chain Reaction; D000070918:Synoviocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C508585:IL1B protein, human; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D047495:PPAR gamma; C486497:PPARGC1A protein, human; C455622:PPARGC1B protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D020170:Caspase 1
keywords: NLRP3 inflammasome; PPAR-gamma coactivator 1B; gout