title: Gout Is a Chronic Inflammatory Disease in Which High Levels of Interleukin-8 (CXCL8), Myeloid-Related Protein 8/Myeloid-Related Protein 14 Complex, and an Altered Proteome Are Associated With Diabetes Mellitus and Cardiovascular Disease.
abstract: OBJECTIVE
  The frequent association of gout with metabolic syndrome and cardiovascular disease (CVD) suggests that it has a systemic component. Our objective was to study whether circulating proinflammatory cytokines are associated with comorbidities in gout patients.
  
  
  METHODS
  We studied 330 gout patients from 3 independent cohorts and compared them with 144 healthy individuals and 276 disease controls. We measured circulating levels of interleukin-8 (IL-8)/CXCL8, IL-1β, IL-6, IL-10, IL-12, and tumor necrosis factor, after which we performed proteome-wide analysis in a selection of samples to identify proteins that were possibly prognostic for the development of comorbidities. Replication analysis was performed specifically for myeloid-related protein 8 (MRP-8)/MRP-14 complex.
  
  
  RESULTS
  Compared to healthy controls and disease control patients, patients with gouty arthritis (n = 48) had significantly higher mean levels of CXCL8 (P < 0.001), while other cytokines were almost undetectable. Similarly, patients with intercritical gout showed high levels of CXCL8. CXCL8 was independently associated with diabetes mellitus in patients with intercritical gout (P < 0.0001). Proteome-wide analysis in gouty arthritis (n = 18) and intercritical gout (n = 39) revealed MRP-8 and MRP-14 as the proteins with the greatest differential expression between low and high levels of CXCL8 and also showed a positive correlation of MRP8/MRP14 complex with CXCL8 levels (R(2)  = 0.49, P < 0.001). These findings were replicated in an independent cohort. The proteome of gout patients with high levels of CXCL8 was associated with diabetes mellitus (odds ratio 16.5 [95% confidence interval 2.8-96.6]) and CVD (odds ratio 3.9 [95% confidence interval 1.0-15.3]).
  
  
  CONCLUSIONS
  Circulating levels of CXCL8 are increased during both the acute and intercritical phases of gout, and they coincide with a specific circulating proteome that is associated with risk of diabetes mellitus and CVD. Further research focused on the roles of CXCL8 and MRP8/MRP14 complex in patients with gout is warranted.
authors.affiliation: Rijnstate Hospital, Arnhem, The Netherlands.
authors.forename: Laura B E
authors.initials: LB
authors.lastname: Kienhorst
authors.affiliation: Rijnstate Hospital, Arnhem, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: van Lochem
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Wietske
authors.initials: W
authors.lastname: Kievit
authors.affiliation: University of Auckland, Auckland, New Zealand.
authors.forename: Nicola
authors.initials: N
authors.lastname: Dalbeth
authors.affiliation: University of Otago, Dunedin, New Zealand.
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Merriman
authors.affiliation: University of Otago, Dunedin, New Zealand.
authors.forename: Amanda
authors.initials: A
authors.lastname: Phipps-Green
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Arnoud
authors.initials: A
authors.lastname: Loof
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Waander
authors.initials: W
authors.lastname: van Heerde
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Sita
authors.initials: S
authors.lastname: Vermeulen
authors.affiliation: University of Otago, Christchurch, New Zealand.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Stamp
authors.affiliation: Rijnstate Hospital, Arnhem, The Netherlands.
authors.forename: Elly
authors.initials: E
authors.lastname: van Koolwijk
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Graaf
authors.affiliation: University Hospital Muenster, Muenster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Holzinger
authors.affiliation: University Hospital Muenster, Muenster, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands, and Rijnstate Hospital, Arnhem, The Netherlands.
authors.forename: Hein J E M
authors.initials: HJ
authors.lastname: Janssens
authors.affiliation: University of Otago, Dunedin, New Zealand.
authors.forename: Tony R
authors.initials: TR
authors.lastname: Merriman
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jasper C A
authors.initials: JC
authors.lastname: Broen
authors.affiliation: Rijnstate Hospital, Arnhem, The Netherlands.
authors.forename: Matthijs
authors.initials: M
authors.lastname: Janssen
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
mesh_terms: D000328:Adult; D000368:Aged; D040501:Calgranulin A / Q000276:immunology* / Q000378:metabolism; D040502:Calgranulin B / Q000276:immunology* / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000276:immunology* / Q000378:metabolism; D003920:Diabetes Mellitus / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006073:Gout / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020543:Proteome / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; D040501:Calgranulin A; D040502:Calgranulin B; C508609:IL10 protein, human; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D020543:Proteome; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12