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]).

CONCLUSION:

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: Laura B E Kienhorst, Ellen van Lochem, Wietske Kievit, Nicola Dalbeth, Marilyn E Merriman, Amanda Phipps-Green, Arnoud Loof, Waander van Heerde, Sita Vermeulen, Lisa K Stamp, Elly van Koolwijk, Jacqueline de Graaf, Dirk Holzinger, Johannes Roth, Hein J E M Janssens, Tony R Merriman, Jasper C A Broen, Matthijs Janssen, Timothy R D J Radstake
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 67 Issue 12 Pg. 3303-13 (Dec 2015) ISSN: 2326-5205 [Electronic] United States
• PMID: 26248007 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015, American College of Rheumatology.

Chemical References

• CXCL8 protein, human
• Calgranulin A
• Calgranulin B
• IL10 protein, human
• IL1B protein, human
• IL6 protein, human
• Interleukin-1beta
• Interleukin-6
• Interleukin-8
• Proteome
• TNF protein, human
• Tumor Necrosis Factor-alpha
• Interleukin-10
• Interleukin-12

Topics

• Adult
• Aged
• Calgranulin A (immunology, metabolism)
• Calgranulin B (immunology, metabolism)
• Cardiovascular Diseases (immunology, metabolism)
• Diabetes Mellitus (immunology, metabolism)
• Female
• Gout (immunology, metabolism)
• Humans
• Interleukin-10 (immunology, metabolism)
• Interleukin-12 (immunology, metabolism)
• Interleukin-1beta (immunology, metabolism)
• Interleukin-6 (immunology, metabolism)
• Interleukin-8 (immunology, metabolism)
• Male
• Middle Aged
• Proteome (immunology, metabolism)
• Tumor Necrosis Factor-alpha (immunology, metabolism)