Abstract
The α7 neuronal nicotinic acetylcholine receptors (α7nAChRs) are essential for anti-inflammatory responses. The human-specific CHRFAM7A gene and its 2bp deletion polymorphism (Δ2bp variant) encodes a structurally-deficient α7nAChRs that may impact the anti-inflammatory function. We studied 45 spinal cord injury (SCI) patients for up to six weeks post SCI to investigate the role of the Δ2bp variant on multiple circulating inflammatory mediators and two outcome measures (neuropathic pain and risk of pressure ulcers). The patient’s SCI were classified as either severe or mild. Missing values were imputed. Overall genetic effect was conducted with independent sample t-test and corrected with false discovery rate (FDR). Univariate analysis and regression analysis were applied to evaluate the Δ2bp effects on temporal variation of inflammatory mediators post SCI and their interaction with outcome measures. In severe SCI, the Δ2bp carriers showed higher levels of circulating inflammatory mediators than the Δ2bp non-carriers in TNF-α (FDR = 9.6x10-4), IFN-γ (FDR = 1.3x10-3), IL-13 (FDR = 1.6x10-3), CCL11 (FDR = 2.1x10-3), IL-12p70 (FDR = 2.2x10-3), IL-8 (FDR = 2.2x10-3), CXCL10 (FDR = 3.1x10-3), CCL4 (FDR = 5.7x10-3), IL-12p40 (FDR = 7.1x10-3), IL-1b (FDR = 0.014), IL-15 (FDR = 0.024), and IL-2 (FDR = 0.037). IL-8 and CCL2 were negatively associated with days post injury (DPI) for the Δ2bp carriers (P = 2x10-7 and P = 2x10-8, respectively) and IL-5 was positively associated with DPI for the Δ2bp non-carriers (P = 0.015). Neuropathic pain was marginally positively associated with IL-13 for the Δ2bp carriers (P = 0.056). In mild SCI, the Δ2bp carriers had lower circulating levels of IL-15 (FDR = 0.04) than the Δ2bp non-carriers. Temporal variation of inflammatory mediators post SCI was not associated with the Δ2bp variant. For the mild SCI Δ2bp carriers, risk of pressure ulcers was positively associated with circulating levels of IFN-γ, CXCL10, and CCL4 and negatively associated with circulating levels of IL-12p70. These findings support an important role for the human-specific CHRFAM7A Δ2bp gene variant in modifying anti-inflammatory function of α7nAChRs following SCI.
Highlights
Individuals with traumatic spinal cord injury (SCI) are subjected to severe motor and/or sensory dysfunction and have a poorer quality of life outcome
AIS grade A and B injuries were grouped as severe SCI (25 patients) and AIS grade C and D injuries were grouped as mild SCI (20 patients)
In severe SCI, temporal variation of IL-5, IL-8, and CCL2 levels following SCI were associated with the Δ2bp variant, and NP was a function of circulating IL-13 level and the Δ2bp variant
Summary
Individuals with traumatic spinal cord injury (SCI) are subjected to severe motor and/or sensory dysfunction and have a poorer quality of life outcome. Primary damage is caused by the direct mechanical impact to spinal cord tissue immediately after injury. Neutrophils and macrophages release proteases, including matrix metalloprotease 9 (MMP-9), which alters the blood-spinal cord barrier and induces neuronal axon dieback, contributing to further injury. These cells release reactive oxygen intermediates, lysosomal enzymes, and pro-inflammatory cytokines/chemokines to aggravate cellular damage [1, 2]. The complex role of inflammation after injury, providing certain beneficial aspects initially, and causing damages to surrounding tissue, inducing apoptotic cell death, and impairing spontaneous neuron regeneration and functional recovery [3, 4]
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