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.

Abstract

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. The participants were patients with T1D and islet autoantibody-negative control subjects from the Phenome and Genome of Diabetes Autoimmunity study. Thirteen cytokines and chemokines were measured in serum of 4424 subjects using multiplex immunoassays. 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. IL8, IL-1Ra, MCP-1, and MIP-1β are significantly lower in patients with T1D than controls.