Genetic variants in the HLA region contribute to the risk of cerebral palsy

Ye Cheng; Yiran Xu; Hongwei Li; Yimeng Qiao; Yangong Wang; Yu Su; Jin Zhang; Xiaoyang Wang; Lili Song; Jian Ding; Dan Wang; Changlian Zhu; Qinghe Xing

doi:10.1016/j.bbadis.2023.167008

Genetic variants in the HLA region contribute to the risk of cerebral palsy

Biochim Biophys Acta Mol Basis Dis. 2024 Mar;1870(3):167008. doi: 10.1016/j.bbadis.2023.167008. Epub 2023 Dec 30.

Authors

Ye Cheng¹, Yiran Xu², Hongwei Li², Yimeng Qiao², Yangong Wang³, Yu Su³, Jin Zhang³, Xiaoyang Wang⁴, Lili Song³, Jian Ding³, Dan Wang³, Changlian Zhu⁵, Qinghe Xing⁶

Affiliations

¹ 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.
² 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.
³ Children's Hospital of Fudan University, and Institutes of Biomedical Sciences of Fudan University, Shanghai 201102, China.
⁴ 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.
⁵ 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, Göteborg 40530, Sweden. Electronic address: [email protected].
⁶ 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: [email protected].

PMID: 38163449
DOI: 10.1016/j.bbadis.2023.167008

Abstract

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.

Keywords: Cerebral palsy; GWAS; Genetics; HLA; Immunogenetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cerebral Palsy* / complications
Cerebral Palsy* / genetics
Child
Female
Genotype
HLA-B Antigens / genetics
Humans
Infant, Low Birth Weight
Infant, Newborn
Pregnancy
Pregnancy Complications*

Substances

HLA-B Antigens