PMID- 38163449 OWN - NLM STAT- MEDLINE DCOM- 20240220 LR - 20240227 IS - 1879-260X (Electronic) IS - 0925-4439 (Linking) VI - 1870 IP - 3 DP - 2024 Mar TI - Genetic variants in the HLA region contribute to the risk of cerebral palsy. PG - 167008 LID - S0925-4439(23)00374-5 [pii] LID - 10.1016/j.bbadis.2023.167008 [doi] AB - 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 x 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 x 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. CI - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Cheng, Ye AU - Cheng Y AD - Children's Hospital of Fudan University, and Institutes of Biomedical Sciences of Fudan University, Shanghai 201102, China; Shanghai Center for Women and Children's Health, Shanghai 200062, China. FAU - Xu, Yiran AU - Xu Y AD - Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou 450052, China. FAU - Li, Hongwei AU - Li H AD - Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou 450052, China. FAU - Qiao, Yimeng AU - Qiao Y AD - Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou 450052, China. FAU - Wang, Yangong AU - Wang Y AD - Children's Hospital of Fudan University, and Institutes of Biomedical Sciences of Fudan University, Shanghai 201102, China. FAU - Su, Yu AU - Su Y AD - Children's Hospital of Fudan University, and Institutes of Biomedical Sciences of Fudan University, Shanghai 201102, China. FAU - Zhang, Jin AU - Zhang J AD - Children's Hospital of Fudan University, and Institutes of Biomedical Sciences of Fudan University, Shanghai 201102, China. FAU - Wang, Xiaoyang AU - Wang X AD - Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou 450052, China; Centre of Perinatal Medicine and Health, Institute of Clinical Science, University of Gothenburg, 40530 Gothenburg, Sweden. FAU - Song, Lili AU - Song L AD - Children's Hospital of Fudan University, and Institutes of Biomedical Sciences of Fudan University, Shanghai 201102, China. FAU - Ding, Jian AU - Ding J AD - Children's Hospital of Fudan University, and Institutes of Biomedical Sciences of Fudan University, Shanghai 201102, China. FAU - Wang, Dan AU - Wang D AD - Children's Hospital of Fudan University, and Institutes of Biomedical Sciences of Fudan University, Shanghai 201102, China. FAU - Zhu, Changlian AU - Zhu C AD - Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou 450052, China; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Goteborg 40530, Sweden. Electronic address: changlian.zhu@neuro.gu.se. FAU - Xing, Qinghe AU - Xing Q AD - Children's Hospital of Fudan University, and Institutes of Biomedical Sciences of Fudan University, Shanghai 201102, China; Shanghai Center for Women and Children's Health, Shanghai 200062, China. Electronic address: qhxing@fudan.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20231230 PL - Netherlands TA - Biochim Biophys Acta Mol Basis Dis JT - Biochimica et biophysica acta. Molecular basis of disease JID - 101731730 RN - 0 (HLA-B Antigens) SB - IM MH - Infant, Newborn MH - Child MH - Pregnancy MH - Female MH - Humans MH - *Cerebral Palsy/genetics/complications MH - Infant, Low Birth Weight MH - *Pregnancy Complications MH - Genotype MH - HLA-B Antigens/genetics OTO - NOTNLM OT - Cerebral palsy OT - GWAS OT - Genetics OT - HLA OT - Immunogenetics COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2024/01/02 11:46 MHDA- 2024/02/20 11:50 CRDT- 2024/01/01 19:11 PHST- 2023/09/26 00:00 [received] PHST- 2023/12/22 00:00 [revised] PHST- 2023/12/22 00:00 [accepted] PHST- 2024/02/20 11:50 [medline] PHST- 2024/01/02 11:46 [pubmed] PHST- 2024/01/01 19:11 [entrez] AID - S0925-4439(23)00374-5 [pii] AID - 10.1016/j.bbadis.2023.167008 [doi] PST - ppublish SO - Biochim Biophys Acta Mol Basis Dis. 2024 Mar;1870(3):167008. doi: 10.1016/j.bbadis.2023.167008. Epub 2023 Dec 30.