The addition of genetic factors to prognostic models of neurobehavioral recovery following pediatric traumatic brain injury (TBI) may account for unexplained heterogeneity in outcomes. The present study examined the cumulative influence of candidate genes involved in the inflammatory response on long-term neurobehavioral recovery in children with early childhood TBI relative to children with orthopedic injuries (OI). Participants were drawn from a prospective, longitudinal study evaluating outcomes of children who sustained TBI (n = 67) or OI (n = 68) between the ages of 3 and 7 years. Parents completed ratings of child executive function and behavior at an average of 6.8 years after injury. Exploratory unweighted and weighted polygenic risk scores (PRS) were constructed from single nucleotide polymorphisms (SNPs) across candidate inflammatory response genes (i.e., angiotensin converting enzyme [ACE], brain-derived neurotrophic factor [BDNF], interleukin-1 receptor antagonist [IL1RN], and 5’-ectonucleotidase [NT5E]) that showed nominal (p ≤ 0.20) associations with outcomes in the TBI group. Linear regression models tested the PRS × injury group (TBI vs. OI) interaction term and post-hoc analyses examined the effect of PRS within each injury group. Higher inflammatory response PRS were associated with more executive dysfunction and behavior problems in children with TBI but not in children with OI. The cumulative influence of inflammatory response genes as measured by PRS explained additional variance in long-term neurobehavioral outcomes, over and above well-established predictors and single candidate SNPs tested individually. The results suggest that some of the unexplained heterogeneity in long-term neurobehavioral outcomes following pediatric TBI may be attributable to a child's genetic predisposition to a greater or lesser inflammatory response to TBI.

中文翻译：

---

相对于骨科损伤，炎症反应遗传变异对小儿创伤性脑损伤后长期神经行为结果的累积影响：探索性多基因风险评分。

在儿科创伤性脑损伤（TBI）后神经行为恢复的预后模型中添加遗传因素可能会导致结果中无法解释的异质性。本研究探讨了与骨科损伤 (OI) 儿童相比，参与炎症反应的候选基因对儿童早期 TBI 儿童长期神经行为恢复的累积影响。参与者来自一项前瞻性纵向研究，该研究评估了 3 至 7 岁之间患有 TBI（ n  = 67）或 OI（n = 68）的儿童的结局。父母平均在受伤后 6.8 年完成对儿童执行功能和行为的评级。根据候选炎症反应基因（即血管紧张素转换酶 [ACE]、脑源性神经营养因子 [BDNF]、白细胞介素 1 受体拮抗剂 [IL1RN] 的单核苷酸多态性 (SNP) 构建探索性未加权和加权多基因风险评分 (PRS) ] 和 5'-核酸外切酶 [NT5E]），显示出 与 TBI 组结果的名义相关性( p ≤ 0.20)。线性回归模型测试了 PRS × 损伤组（TBI 与 OI）交互项，事后分析检查了 PRS 在每个损伤组内的影响。PRS 较高的炎症反应与 TBI 儿童更多的执行功能障碍和行为问题相关，但与 OI 儿童无关。PRS 测量的炎症反应基因的累积影响解释了长期神经行为结果的额外差异，超出了公认的预测因子和单独测试的单个候选 SNP。结果表明，儿童 TBI 后长期神经行为结果中一些无法解释的异质性可能归因于儿童对 TBI 的炎症反应或多或少的遗传倾向。