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.

中文翻译：

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CHRFAM7AΔ2bp基因变异对脊髓损伤后继发性炎症的影响。

α7神经元烟碱乙酰胆碱受体（α7nAChRs）对于抗炎反应至关重要。人类特异性CHRFAM7A基因及其2bp缺失多态性（Δ2bp变异）编码可能影响抗炎功能的结构缺陷性α7nAChRs。我们研究了45名脊髓损伤（SCI）患者，在脊髓损伤后长达6周，以研究Δ2bp变异体在多种循环炎症介质中的作用和两种预后指标（神经性疼痛和压疮风险）。患者的SCI分为严重或轻度。缺失值被估算。总体遗传效应通过独立的样本t检验进行，并通过错误发现率（FDR）进行校正。应用单因素分析和回归分析评估Δ2bp对SCI后炎症介质的时间变化及其与结局指标的相互作用的影响。在严重SCI中，与TNF-α（FDR = 9.6x10-4），IFN-γ（FDR = 1.3x10-3），IL-13（FDR）的Δ2bp非载体相比，Δ2bp载体显示出更高水平的循环炎症介质。 = 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）和IL-2（FDR = 0.037） 。IL-8和CCL2与Δ2bp携带者的伤后天数（DPI）呈负相关（分别为P = 2x10-7和P = 2x10-8），而IL-5与Δ2bp携带者的DPI正相关（ P = 0.015）。对于Δ2bp携带者，神经性疼痛与IL-13呈正相关（P = 0.056）。在轻度SCI中，与Δ2bp非携带者相比，Δ2bp携带者的IL-15循环水平较低（FDR = 0.04）。SCI后炎症介质的时间变化与Δ2bp变异无关。对于轻度SCIΔ2bp携带者，压力性溃疡的风险与IFN-γ，CXCL10和CCL4的循环水平呈正相关，与IL-12p70的循环水平呈负相关。这些发现支持人特异性CHRFAM7AΔ2bp基因变异在SCI后修饰α7nAChRs的抗炎功能中的重要作用。SCI后炎症介质的时间变化与Δ2bp变异无关。对于轻度SCIΔ2bp携带者，压力性溃疡的风险与IFN-γ，CXCL10和CCL4的循环水平呈正相关，与IL-12p70的循环水平呈负相关。这些发现支持人特异性CHRFAM7AΔ2bp基因变异在SCI后修饰α7nAChRs的抗炎功能中的重要作用。SCI后炎症介质的时间变化与Δ2bp变异无关。对于轻度SCIΔ2bp携带者，压力性溃疡的风险与IFN-γ，CXCL10和CCL4的循环水平呈正相关，与IL-12p70的循环水平呈负相关。这些发现支持人特异性CHRFAM7AΔ2bp基因变异在SCI后修饰α7nAChRs的抗炎功能中的重要作用。