Effect of CHRFAM7A Delta 2bp gene variant on secondary inflammation after spinal cord injury

The alpha 7 neuronal nicotinic acetylcholine receptors (alpha 7nAChRs) are essential for anti-inflammatory responses. The human-specific CHRFAM7A gene and its 2bp deletion polymorphism (Delta 2bp variant) encodes a structurally-deficient alpha 7nAChRs 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 Delta 2bp 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 Delta 2bp effects on temporal variation of inflammatory mediators post SCI and their interaction with outcome measures. In severe SCI, the Delta 2bp carriers showed higher levels of circulating inflammatory mediators than the Delta 2bp non-carriers in TNF-alpha (FDR = 9.6x10(-4)), IFN-gamma (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 Delta 2bp carriers (P = 2x10(-7) and P = 2x10(-8), respectively) and IL-5 was positively associated with DPI for the Delta 2bp non-carriers (P = 0.015). Neuropathic pain was marginally positively associated with IL-13 for the Delta 2bp carriers (P = 0.056). In mild SCI, the Delta 2bp carriers had lower circulating levels of IL-15 (FDR = 0.04) than the Delta 2bp non-carriers. Temporal variation of inflammatory mediators post SCI was not associated with the Delta 2bp variant. For the mild SCI Delta 2bp carriers, risk of pressure ulcers was positively associated with circulating levels of IFN-gamma, CXCL10, and CCL4 and negatively associated with circulating levels of IL-12p70. These findings support an important role for the human-specific CHRFAM7A Delta 2bp gene variant in modifying anti-inflammatory function of alpha 7nAChRs following SCI.