Large-Scale Discovery and Validation Studies Demonstrate Significant Reductions in Circulating Levels of IL8, IL-1Ra, MCP-1, and MIP-1β in Patients With Type 1 Diabetes

• Published in: The journal of clinical endocrinology and metabolism Vol. 100; no. 9; pp. E1179 - E1187
• Main Authors: Purohit, Sharad, Sharma, Ashok, Hopkins, Diane, Steed, Leigh, Bode, Bruce, Anderson, Stephen W., Reed, John Chip, Steed, R. Dennis, Yang, Tao, She, Jin-Xiong
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.09.2015; Endocrine Society
• Subjects: Adolescent; Adult; Aged; Autoantibodies; Autoimmunity; Chemokine CCL2 - blood; Chemokine CCL4 - blood; Chemokines; Child; Child, Preschool; Cytokines; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - blood; Female; Hot Topics in Translational Endocrinology; Humans; Interleukin 1 receptor antagonist; Interleukin 1 Receptor Antagonist Protein - blood; Interleukin 1 receptors; Interleukin-8 - blood; Male; Middle Aged; Monocyte chemoattractant protein 1; Proteins; Risk groups; Serum levels; Serum proteins; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/JC.2015-1388

Context:Previous studies have attempted to elucidate the potential role of various cytokines and chemokines in human type 1 diabetes (T1D); however, the precise role of these serum proteins in T1D is still controversial and undetermined primarily due to the small sample sizes of the previous studies. We profiled a panel of serum cytokines and chemokines using a large-scale, two-stage study design for the discovery and validation of the serum proteins associated with T1D.Participants:The participants were patients with T1D and islet autoantibody–negative control subjects from the Phenome and Genome of Diabetes Autoimmunity study.Main Outcome Measures:Thirteen cytokines and chemokines were measured in serum of 4424 subjects using multiplex immunoassays.Results:Using 1378 samples in Stage 1, we found that four of the 13 proteins are significantly lower in patients with T1D than controls (IL8: odds ratio [OR] = 0.40; P = 5.7 × 10−19; IL-1Ra: OR = 0.42; P = 1.1 × 10−13; MCP-1: OR = 0.60; P = 6.7 × 10−9; and MIP-1β: OR = 0.63; P = 4.2 × 10−7). Our confirmation data with 3046 samples in Stage 2 further confirmed the significant negative associations of these four proteins with T1D (IL8: OR = 0.43; P = 8.9 × 10−32; IL-1Ra: OR = 0.56, P = 3.7 × 10−27; MCP-1: OR = 0.61, P = 4.3 × 10−17; and MIP-1β: OR = 0.69, P = 2.4 × 10−13). Quartile analyses also suggested that significantly more T1D cases have protein levels in the bottom quartile than in the top quartile for all four proteins: IL8 (OR = 0.09), IL-1Ra (OR = 0.18), MCP-1 (OR = 0.38), and MIP-1β (OR = 0.44). Furthermore, the negative associations between T1D and serum levels of all four proteins are stronger in genetically high-risk groups compared with the moderate and low-risk groups.Conclusions:IL8, IL-1Ra, MCP-1, and MIP-1β are significantly lower in patients with T1D than controls.