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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CHRFAM7A Δ2bp 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 变体）编码可能影响抗炎功能的结构缺陷 α7nAChR。我们研究了 45 名脊髓损伤 (SCI) 患者在 SCI 后长达六周的时间，以研究 Δ2bp 变体对多种循环炎症介质和两种结果指标（神经性疼痛和压疮风险）的作用。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样本 t 检验进行，并用错误发现率 (FDR) 进行校正。应用单变量分析和回归分析来评估 Δ2bp 对 SCI 后炎症介质时间变化的影响及其与结果测量的相互作用。在严重的 SCI 中，Δ2bp 携带者比 Δ2bp 非携带者在 TNF-α (FDR = 9.6x10-4)、IFN-γ (FDR = 1.3x10-3)、IL-13 (FDR) 中表现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 非携带者的 DPI 呈正相关（ P = 0.015）。对于 Δ2bp 携带者，神经性疼痛与 IL-13 呈轻微正相关（P = 0.056）。在轻度 SCI 中，Δ2bp 携带者的 IL-15 循环水平（FDR = 0.04）低于 Δ2bp 非携带者。SCI 后炎症介质的时间变化与 Δ2bp 变异无关。对于轻度 SCI Δ2bp 携带者，压疮风险与 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。这些发现支持人类特异性 CHRFAM7A Δ2bp 基因变体在改变 SCI 后 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 SCI Δ2bp 携带者，压疮风险与 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。这些发现支持人类特异性 CHRFAM7A Δ2bp 基因变体在改变 SCI 后 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 SCI Δ2bp 携带者，压疮风险与 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。这些发现支持人类特异性 CHRFAM7A Δ2bp 基因变体在改变 SCI 后 α7nAChRs 的抗炎功能中的重要作用。