Lin, Mingkuan;
Huang, Wan;
Kabbani, Nadine;
Theiss, Mark M.;
Hamilton, John F.;
Ecklund, James M.;
Conley, Yvette P.;
Vodovotz, Yoram;
Brienza, David;
Wagner, Amy K.;
Robbins, Emily;
Sowa, Gwendolyn A.;
Lipsky, Robert H.
Effect of CHRFAM7A Δ2bp gene variant on secondary inflammation after spinal cord injury
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Medientyp:
E-Artikel
Titel:
Effect of CHRFAM7A Δ2bp gene variant on secondary inflammation after spinal cord injury
Beteiligte:
Lin, Mingkuan;
Huang, Wan;
Kabbani, Nadine;
Theiss, Mark M.;
Hamilton, John F.;
Ecklund, James M.;
Conley, Yvette P.;
Vodovotz, Yoram;
Brienza, David;
Wagner, Amy K.;
Robbins, Emily;
Sowa, Gwendolyn A.;
Lipsky, Robert H.
Erschienen:
Public Library of Science (PLoS), 2021
Beschreibung:
<jats:p>The α7 neuronal nicotinic acetylcholine receptors (α7nAChRs) are essential for anti-inflammatory responses. The human-specific <jats:italic>CHRFAM7A</jats:italic> gene and its 2bp deletion polymorphism (<jats:italic>Δ2bp</jats:italic> 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 <jats:italic>Δ2bp</jats:italic> 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 <jats:italic>Δ2bp</jats:italic> effects on temporal variation of inflammatory mediators post SCI and their interaction with outcome measures. In severe SCI, the <jats:italic>Δ2bp</jats:italic> carriers showed higher levels of circulating inflammatory mediators than the <jats:italic>Δ2bp</jats:italic> non-carriers in TNF-α (FDR = 9.6x10<jats:sup>-4</jats:sup>), IFN-γ (FDR = 1.3x10<jats:sup>-3</jats:sup>), IL-13 (FDR = 1.6x10<jats:sup>-3</jats:sup>), CCL11 (FDR = 2.1x10<jats:sup>-3</jats:sup>), IL-12p70 (FDR = 2.2x10<jats:sup>-3</jats:sup>), IL-8 (FDR = 2.2x10<jats:sup>-3</jats:sup>), CXCL10 (FDR = 3.1x10<jats:sup>-3</jats:sup>), CCL4 (FDR = 5.7x10<jats:sup>-3</jats:sup>), IL-12p40 (FDR = 7.1x10<jats:sup>-3</jats:sup>), 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 <jats:italic>Δ2bp</jats:italic> carriers (P = 2x10<jats:sup>-7</jats:sup> and P = 2x10<jats:sup>-8</jats:sup>, respectively) and IL-5 was positively associated with DPI for the <jats:italic>Δ2bp</jats:italic> non-carriers (P = 0.015). Neuropathic pain was marginally positively associated with IL-13 for the <jats:italic>Δ2bp</jats:italic> carriers (P = 0.056). In mild SCI, the <jats:italic>Δ2bp</jats:italic> carriers had lower circulating levels of IL-15 (FDR = 0.04) than the <jats:italic>Δ2bp</jats:italic> non-carriers. Temporal variation of inflammatory mediators post SCI was not associated with the <jats:italic>Δ2bp</jats:italic> variant. For the mild SCI <jats:italic>Δ2bp</jats:italic> 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 <jats:italic>CHRFAM7A Δ2bp</jats:italic> gene variant in modifying anti-inflammatory function of α7nAChRs following SCI.</jats:p>