TY - JOUR
T1 - Effect of CHRFAM7A Δ2bp gene variant on secondary inflammation after spinal cord injury
AU - Lin, Mingkuan
AU - Huang, Wan
AU - Kabbani, Nadine
AU - Theiss, Mark M.
AU - Hamilton, John F.
AU - Ecklund, James M.
AU - Conley, Yvette P.
AU - Vodovotz, Yoram
AU - Brienza, David
AU - Wagner, Amy K.
AU - Robbins, Emily
AU - Sowa, Gwendolyn A.
AU - Lipsky, Robert H.
N1 - Publisher Copyright:
© 2021 Lin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2021/5
Y1 - 2021/5
N2 - 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 antiinflammatory 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 = 9.6×10-4), IFN-γ (FDR = 1.3×10-3), IL-13 (FDR = 1.6×10-3), CCL11 (FDR = 2.1×10-3), IL-12p70 (FDR = 2.2×10-3), IL-8 (FDR = 2.2×10-3), CXCL10 (FDR = 3.1×10-3), CCL4 (FDR = 5.7×10-3), IL-12p40 (FDR = 7.1×10-3), 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 = 2×10-7 and P = 2×10-8, 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.
AB - 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 antiinflammatory 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 = 9.6×10-4), IFN-γ (FDR = 1.3×10-3), IL-13 (FDR = 1.6×10-3), CCL11 (FDR = 2.1×10-3), IL-12p70 (FDR = 2.2×10-3), IL-8 (FDR = 2.2×10-3), CXCL10 (FDR = 3.1×10-3), CCL4 (FDR = 5.7×10-3), IL-12p40 (FDR = 7.1×10-3), 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 = 2×10-7 and P = 2×10-8, 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.
UR - http://www.scopus.com/inward/record.url?scp=85105489313&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0251110
DO - 10.1371/journal.pone.0251110
M3 - Article
C2 - 33956875
AN - SCOPUS:85105489313
SN - 1932-6203
VL - 16
JO - PLoS ONE
JF - PLoS ONE
IS - 5 May
M1 - e0251110
ER -