Genetic variants in the HLA region contribute to the risk of cerebral palsy
Genetic variants in the HLA region contribute to the risk of cerebral palsy
复制标题
DOI：
10.1016/j.bbadis.2023.167008
复制
发表时间：
2024-01-03
影响因子：
6.2
通讯作者：
Xing，Qinghe
中科院分区：
文献类型：
--
作者：
Cheng，Ye;Xu，Yiran;Xing，Qinghe
脑瘫是儿童期最常见的肢体残疾，遗传因素在其发病机制中起重要作用。然而，遗传的贡献仍然不完全阐明。在这里，我们对1090例CP病例和1100名健康对照者进行了全外显子组测序后的两阶段关联研究。采用多变量logistic回归进一步分析人白细胞抗原（HLA）等位基因在总CP和亚组中的易感性。我们发现在6号染色体的HLA区域，rs3131787与CP的关联最为显著（P= 2.05 × 10−14,OR = 2.22）。与对照组相比，CP患儿HLA-B*13:02的携带者频率显著升高（对照组为9.82%，CP为19.27%，P= 1.03 × 10−4,OR = 2.17）。此外，HLA-B*13:02对CP风险增加的影响主要存在于未暴露于早产、低出生体重、出生窒息或室周白质软化的隐源性CP。本研究表明HLA变异与CP有很强的相关性，这意味着由免疫遗传变异引起的免疫失调可能是CP发病机制的基础。我们的研究结果提供了遗传学证据，表明免疫调节剂可能通过恢复神经炎症止血，作为CP患者有希望的治疗干预措施。
Cerebral palsy (CP) is the most common physical disability in childhood, and genetic factors play an important role in its pathogenesis. However, the genetic contributions remain incompletely elucidated. Here, we conducted a two-stage association study between 1090 CP cases and 1100 healthy controls after whole exome sequencing. The human leukocyte antigen (HLA) allelic predispositions were further analyzed in overall CP and subgroups using multivariate logistic regression. We found a strong signal in the HLA region on chromosome 6, where rs3131787 harbored the most significant association with CP (P= 2.05 × 10−14, OR = 2.22). In comparison to controls, the carrier frequencies of HLA-B*13:02 were significantly higher in children with CP (9.82 % in control vs 19.27 % in CP,P= 1.03 × 10−4, OR = 2.17). Furthermore, the effect of HLA-B*13:02 on increasing the risk of CP mainly existed in cryptogenic CP without exposure to premature birth, low birth weight, birth asphyxia, or periventricular leukomalacia. This study indicated a strong association of HLA variants with CP, which implied that immune dysregulation resulting from immunogenetic variants might underlie the pathogenesis of CP. Our findings provide genetic evidence that an immunomodulator may serve as a promising therapeutic intervention for patients with CP by reinstating the neuroinflammation hemostasis.