Skip to main content

An association study of IL2RA polymorphisms with cerebral palsy in a Chinese population

Abstract

Background

Cerebral palsy (CP), the most common physical disability of childhood, is a nonprogressive movement disorder syndrome. Eighty percent of cases are considered idiopathic without a clear cause. Evidence has shown that cytokine abnormalities are widely thought to contribute to CP.

Methods

An association between 6 SNPs (rs12244380, rs2025345, rs12722561, rs4749926, rs2104286 and rs706778) in IL2RA (interleukin 2 receptor subunit alpha) and CP was investigated using a case–control method based on 782 CP cases and 778 controls. The allele, genotype and haplotype frequencies of SNPs were assessed using the SHEsis program. Subgroup analyses based on complications and clinical subtypes were also conducted.

Results

Globally, no differences in genotype or allele frequencies for any SNPs remained significant after Bonferroni correction between patients and controls, except rs706778, which deviated from Hardy–Weinberg equilibrium and was excluded from further analyses. However, subgroup analysis revealed a significant association of rs2025345 with spastic tetraplegia (P genotype = 0.048 after correction) and rs12722561 with CP accompanied by global developmental delay (P allele = 0.045 after correction), even after Bonferroni correction.

Conclusions

These findings indicated that genetic variations in IL2RA are significantly associated with CP susceptibility in the Chinese Han population, suggesting that IL2RA is likely involved in the pathogenesis of CP. Further investigation with a larger sample size in a multiethnic population is needed to confirm the association.

Peer Review reports

Background

Cerebral palsy (CP) is a nonprogressive movement disorder caused by brain damage occurring in the developing fetus or infant [1, 2]. It is a group of permanent disorders that can affect the development of sports and lead to restricted activities [3]. CP is one of the most common physical disability diseases in children, with an incidence of 1.5–2.5/1,000 live births [4]. Although some studies have pointed out that risk factors, such as intrauterine infection, hypoxic-ischemia insults, and central nervous system infections, can result in CP [5, 6], 80% of cases are considered idiopathic without a clear cause [7]. It has been reported that CP children are prone to have congenital anomalies, the incidence is higher in identical twins than in fraternal twins, and the risk of CP is higher in consanguineous families than nonconsanguineous families [8], suggesting that genetic factors may play an important role in the etiology of CP. Moreover, genes such as NOS1, OLIG2, ATG5, ATG7 and IL-6 have been significantly associated with susceptibility to CP [9,10,11,12].

CP is linked to immune dysfunction, including altered serum and cerebrospinal fluid cytokine profiles and aberrant cell-mediated immune responses [13]. Inflammation is one etiologic component of brain white matter damage acquired during early development that gives rise to CP [14, 15]. In addition, cytokines, such as interleukins and interferons, are a group of small and secreted proteins that can mediate normal and continuous signal transduction between nonimmune tissue cells, including the central nervous system (CNS) [16]. Cytokines are of particular importance during neural development and function at all stages and are associated with CP and other neurodevelopmental disorders (NDDs). Magalhaes et al. analyzed the relationship between inflammatory molecules and neurodevelopment and found that higher circulating levels of IL-1β, IL-6, TNF and CXCL8/IL-8 were associated with neurological abnormalities in CP children [17]. Furthermore, studies have reported that IL-23R, IL-8 and IL-6 gene polymorphisms are related to CP in the Chinese population [18,19,20].

Interleukin-2 (IL-2), the first cytokine to be molecularly cloned, is a typical alpha helix cytokine that binds to and transmits signals through the IL-2 receptor (IL2R) complex, which consists of 3 different subunits, IL2RA (interleukin 2 receptor subunit alpha), IL2RB (interleukin 2 receptor subunit beta), and IL2RG (interleukin 2 receptor subunit gamma) [21, 22]. Previous studies have proven that the IL-2/IL2R complex signaling pathway plays a key role in the proliferation of T cells and the generation of effector and memory cells to promote immune responses. Furthermore, the IL-2/IL2R complex signaling pathway can promote the generation, survival, and functional activity of Treg cells to control immune responses and maintain self-tolerance [23]. Damaging mutations disrupting this pathway can cause severe forms of Mendelian immune dysregulation [22, 23]. IL2RA forms the largest of the three subunit interfaces, which, together with the high abundance of charge-charge interactions, correlates well with the rapid association rate and high-affinity interaction of IL2RA with IL-2 at the cell surface [24, 25]. IL2RA deficiency can result in human immune-mediated diseases [26,27,28].

Based on the above findings, we speculate that IL2RA may be associated with susceptibility to CP. However, it remains unknown whether IL2RA is associated with CP. Therefore, we used a case–control study to explore the possible association of IL2RA with CP, which will provide genetic evidence for the role of IL2RA in the etiology of CP and its related potential mechanisms.

Methods

Participants

In our study, 782 children with CP and 778 healthy controls were recruited from the centers for CP rehabilitation and Child Health Care Departments in the Third Affiliated Hospital of Zhengzhou University, Zhengzhou Children’s Hospital. This study was approved by the Ethics Committee of Zhengzhou University (No: 2017–09) in accordance with the principles of the Declaration of Helsinki. Statements of informed consent were obtained from the guardians of all children after full explanation of the procedure. The case group consisted of 542 males (69.3%) and 240 females (30.7%), and the mean age was 18.5 ± 15.4 months. The control group consisted of 778 healthy children, including 520 males (66.8%) and 258 females (33.2%), and the mean age was 19.3 ± 16.8 months (Table 1).

Table 1 Clinical characteristics of all participants

CP diagnosis, classification and exclusion criteria

In the case group, children diagnosed with congenital metabolic diseases and myopathy as well as children with a family history of nervous system diseases were excluded. Pediatric rehabilitation specialists ensured CP diagnosis using standard criteria related to nonprogressive disorders of movement control and posture [1]. Every participant received a detailed clinical evaluation with comprehensive pretest counseling.

Clinical information, including demographic variables (such as sex, gestational age, mode of delivery, singletons or twins), known risk factors (such as pregnancy-induced hypertension (PIH), perinatal asphyxia, threatened premature labor), CP complications (such as global developmental delay, intellectual disability) and neonatal complications, were all recorded if available.

Quadriplegia, one subtype of CP, is classified by the number and distribution of the impaired limbs [29, 30]. Quadriplegia was diagnosed when both the upper and lower limbs of the patients were paralyzed. Global developmental delay (GDD) diagnosis was limited to individuals under five years old when they were significant delay in at least two developmental domains: including motor skills, speech and language, cognitive skills, and social and emotional skills [31].

Genotyping and statistical analysis

Peripheral blood samples were obtained from the participants for genomic DNA extraction. Altogether, 6 SNPs (rs12244380, rs2025345, rs12722561, rs4749926, rs2104286 and rs706778) in IL2RA gene with minor allele frequency (MAF) in the Chinese Han population greater than 0.1 were selected from the dbSNP database (https://www.ncbi.nlm.nih.gov/snp/) and the phase II genotyping data of the HapMap project (http://www.1000genomes.org/). All 6 SNPs were reported in published literature online, which were associated with immune dysfunction, such as type 1 diabetes, autoimmune disease. Rs12244380 (exon 8, chr10:6,053,374) is located in 3’UTR, while the other 5 SNPs are located in introns: rs2025345 (intron 2, chr10:6,067,688), rs12722561 (intron 1, chr10:6,069,893), rs4749926 (intron 1, chr10:6,085,312), rs2104286 (intron 1, chr10:6,099,045) and rs706778 (intron 1, chr10:6,098,949) (Fig. 1). According to the single nucleotide polymorphism (SNP) location in IL2RA, a MAF > 0.1 and potential function, six SNPs were selected as candidates and genotyped by the MassARRAY system (Shanghai Perchant Biotechnology Co., Ltd. synthesized primers and probes).

Fig. 1
figure 1

The location of studied SNPs in IL2RA (NM_000417.3, chr10:6,052,652-6,104,330). Yellow boxes represent exons of IL2RA

Statistical analysis was performed with SHEsis, an online program (http://analysis.bio-x.cn/) that can test Hardy–Weinberg equilibrium (HWE) and linkage disequilibrium (LD) and calculate allele frequencies, genotype frequencies and haplotype frequencies in the case and control groups. The P values were two-tailed, and P < 0.05 was considered significant. The odds ratio (OR) and its 95% confidence interval (CI) were also calculated. The Bonferroni correction was applied to account for multiple testing on each individual SNP and haplotype. G*power 3.1 software was used to evaluate statistical efficacy.

Results

Overall analysis

Power calculations analysis showed that the sample size in this study had > 85% power to detect a significant association with an effect size index of 0.1 (α < 0.05). Except for rs706778 (P = 0.042), the genotype distribution of the selected SNPs did not deviate from HWE in the control population (P > 0.05). Therefore, rs706778 was excluded from further testing. For the other 5 SNPs, rs12244380, rs2025345, rs12722561, rs4749926 and rs2104286, the allele frequency of rs12722561 (P = 0.025) was different between all CP patients and the control group, but the difference disappeared after Bonferroni correction. There were no significant differences in the allele or genotype frequencies of rs12244380, rs2025345, rs4749926 and rs2104286 between CP cases and controls (Table 2).

Table 2 Genotype and allele frequencies of SNPs in IL2RA between CP and controls

Haplotype analysis is a powerful strategy to determine whether SNPs have greater predictive value when analyzed together. These polymorphisms, rs2025345, rs12722561 and rs4749926, exhibit a strong LD (D’ > 0.85) and form four principal haplotypes (ACA, ACG, ATG and GCA). The ATG haplotype was associated with CP (P = 0.026), but the difference disappeared after correction (Table 3).

Table 3 Haplotype analysis of rs2025345-rs12722561-rs4749926

Subgroup analysis

CP is a syndrome with strong phenotypic and etiological heterogeneity. The genetic diagnosis rate of different clinical subtypes of CP is inconsistent, suggesting that different types of CP may have different genetic etiologies. Then, we conducted a subgroup analysis to explore the association of different CP types with IL2RA genetic variants. The results indicated that the association of spastic tetraplegia with rs2025345 (OR = 0.868, 95% CI = 0.706–1.066, P genotype = 0.0097) and the association of CP + GDD with rs12722561 (OR = 1.518, 95% CI = 1.107–2.082, P allele = 0.0091) were both significant, even after Bonferroni correction. Moreover, the analysis of the other three SNPs in CP types and controls revealed a nonsignificant difference in allelic and genotypic distributions (Tables 4 and 5).

Table 4 Allele and genotype frequencies of IL2RA in CP with spastic tetraplegia and controls
Table 5 Allele and genotype frequencies of IL2RA in CP with GDD and controls

The analysis of the association between IL2RA and various risk factors detected a significant influence on CP by the interactions between genotype distribution in rs12244380 and pregnancy-induced hypertension; even after Bonferroni correction, the association between them was still significant (OR = 0.531, 95% CI = 0.266–1.059, P = 0.0005) (Table 6). However, the proportions of pregnancy-induced hypertension exposure in CP cases and controls presented a large difference, which may have weakened the feasibility of the P value. In addition, rs12722561 presented a significant association with CP + asphyxia, CP + neonatal encephalopathy (NE) and CP + intracranial hemorrhage, but the significance disappeared after Bonferroni correction.

Table 6 Allele and genotype frequencies of IL2RA in CP with pregnancy-induced hypertension and controls

Discussion

CP is the most common physical disability of childhood and is a heterogeneous condition resulting from damage to the developing brain [32]. CP has no curative therapy and few disease-modifying interventions [33]. Earlier and accurate diagnosis of CP has become highly desirable because it allows earlier initiation of treatments that may improve long-term outcomes during periods of rapid brain growth and neuroplasticity, which suggests the importance of uncovering the etiology of CP [34]. However, these known CP causes, such as periventricular leukomalacia (PVL), NE, infarct, and premature delivery, account for only a minority of the total cases [18]. The pathogenesis of CP is largely unknown and needs further study.

Cytokines coordinate the host response to infection and mediate normal, ongoing signaling between cells of nonimmune tissues, including the CNS [16]. Cytokines can profoundly impact fetal neurodevelopment in response to maternal infection or prenatal hypoxia [35]. CP has been linked to early life immune activation and inflammation [36, 37], and several cytokines, including IL-6, IL-8, IL-10, IL-17 and IL-23R, have been proven to be related to CP [18, 34, 38, 39]. IL-2 is a pleiotropic cytokine produced after antigen activation. IL-2 can promote CD8+ T cell and natural killer cells cytolytic activity, modulate T-cell differentiation programs in response to antigens and control the development and maintenance of Treg cells to mediate immune responses and maintain self-tolerance by the IL-2/IL2R complex signaling pathway [40]. IL2RA provides a higher affinity to the IL2R complex and a more stable state through which to transmit signals. Studies have shown that the expression of the anti-inflammatory cytokine IL-2 is decreased in infants with CP [41, 42], which implies that the IL2/IL2R complex pathway is related to CP. Here, we first investigated the relationship between CP and IL2RA by a case–control study in Han Chinese individuals and found that IL2RA was associated with an increased risk of CP.

Several kinds of immune-activated cells have been shown to secrete IL-2, including T cells, natural killer cells, dendritic cells (DCs) and mast cells [43]. During immune activation, IL-2 expression increases rapidly. Activated DCs secrete low levels of IL-2 as an early source, thereby stimulating T cell activation [44]. Activated T cells (including CD4+ and CD8+ T cells) begin to secrete large amounts of IL-2 for their own use and stimulate adjacent IL2R+ cells by paracrine signaling [40, 45, 46]. After IL-2 binds to the IL2R complex, signal transduction occurs through three main pathways: (i) Janus kinase (JAK)-signal transducer and activator of transcription (STAT), (ii) the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR)-p70 S6 kinase pathway and (iii) mitogen-activated protein kinase (MAPK). Phosphorylated STAT5A and STAT5B then oligomerize to form STAT5 dimers and tetramers before undergoing nuclear translocation, where they bind to key target genes (including IL2RA) responsible for cell activation, differentiation, and proliferation, while mTOR and MAPK promote cell growth and survival [22, 40, 45]. It is reasonable to hypothesize that IL2/IL2R complex signaling pathways are disturbed by functional genetic variants, immune cells are unable to proliferate and differentiate normally and the immune system cannot respond optimally to antigen stimulation, causing damage to the developing brain (CP).

Previous studies have shown that disruption of IL2/IL2R complex signaling pathways can lead to adverse cerebral events. In IL-2 knockout (IL-2 KO) mice, brain IL2R complexes are enriched in hippocampal formation, and loss of IL-2 results in cytoarchitectural alterations in the hippocampus and septum. These alterations include decreased cholinergic somata in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB) and decreased distance across the infrapyramidal (IP) granule cell layer (GCL) of the dentate gyrus (DG) [47]. The deletion of IL-2 alters the neuroimmunological status of the mouse hippocampus through dysregulation of cytokines produced by CNS cells [48]. A study in 2015 suggested that complex interactions between IL2 deficiency in the brain and the immune system may modify brain processes involved in different modalities of learning and memory [49]. In this study, we analyzed the correlation between five SNPs of IL2RA and CP and finally ascertained the association of IL2RA with CP. The results of our study showed that there might be an association between IL2RA and susceptibility to CP, implying that SNPs in the IL2RA gene might be involved in the occurrence and development of CP.

Our study has several limitations. First, our study was based on a single gene for susceptibility to CP. Given the genetic heterogeneity and gene–gene interactions related to CP etiology, other candidate genes that are part of the IL2/IL2R complex signaling pathway should also be analyzed. Second, we were unable to examine IL2RA protein expression in the brains of the subjects in the current study. Future studies are encouraged to measure inflammatory cytokine alterations in the brain. Third, although our study demonstrated an association between IL2RA and CP, further functional studies are necessary to verify the results.

Conclusion

We examined the influence of 6 SNPs (rs12244380, rs2025345, rs12722561, rs4749926, rs2104286 and rs706778) in IL2RA on susceptibility to CP and identified IL2RA as a risk gene for CP. To our knowledge, the role of genetic variation in IL2RA in susceptibility to CP has not been investigated before. The full effect of the IL2RA gene on CP cannot be revealed by the analysis of a limited number of SNPs. Future studies on a larger number of samples and on different ethnic groups will be required to better understand the contribution of IL2RA variants to the risk of CP.

Availability of data and materials

The authors are unable to share detailed clinical data due to full anonymization of the data is very difficult. But the datasets analyzed and generated during the study are available from the corresponding author on reasonable request.

Abbreviations

CP:

Cerebral palsy

SNP:

Single nucleotide polymorphism

CNS:

Central nervous system

OR:

Odds ratio

CI:

Confidence interval

HWE:

Hardy-weinberg equilibrium

MAF:

Minor allele frequency

GDD:

Global developmental delay

NE:

Neonatal encephalopathy

PIH:

Pregnancy-induced hypertension

References

  1. Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Damiano D, Dan B, Jacobsson B. A report: the definition and classification of cerebral palsy April 2006. Dev Med Child Neurol Suppl. 2007;109:8–14.

    PubMed  Google Scholar 

  2. Vitrikas K, Dalton H, Breish D. Cerebral palsy: an overview. Am Fam Phys. 2020;101(4):213–20.

    Google Scholar 

  3. Maisonneuve E, Lorthe E, Torchin H, Delorme P, Devisme L, L’Helias LF, Marret S, Subtil D, Bodeau-Livinec F, Pierrat V, et al. Association of chorioamnionitis with cerebral palsy at two years after spontaneous very preterm birth: the EPIPAGE-2 cohort study. J Pediatr. 2020;222(71–78):e76.

    Google Scholar 

  4. Oskoui M, Coutinho F, Dykeman J, Jette N, Pringsheim T. An update on the prevalence of cerebral palsy: a systematic review and meta-analysis. Dev Med Child Neurol. 2013;55(6):509–19.

    Article  PubMed  Google Scholar 

  5. MacLennan AH, Thompson SC, Gecz J. Cerebral palsy: causes, pathways, and the role of genetic variants. Am J Obstet Gynecol. 2015;213(6):779–88.

    Article  PubMed  Google Scholar 

  6. Nelson KB. Causative factors in cerebral palsy. Clin Obstet Gynecol. 2008;51(4):749–62.

    Article  PubMed  Google Scholar 

  7. Novak I, Morgan C, Adde L, Blackman J, Boyd RN, Brunstrom-Hernandez J, Cioni G, Damiano D, Darrah J, Eliasson AC, et al. Early, accurate diagnosis and early intervention in cerebral palsy: advances in diagnosis and treatment. JAMA Pediatr. 2017;171(9):897–907.

    Article  PubMed  Google Scholar 

  8. Moreno-De-Luca A, Ledbetter DH, Martin CL. Genetic insights into the causes and classification of cerebral palsies. Lancet Neurol. 2012;11(3):283–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Xu J, Xia L, Shang Q, Du J, Zhu D, Wang Y, Bi D, Song J, Ma C, Gao C, et al. A variant of the autophagy-related 5 gene is associated with child cerebral palsy. Front Cell Neurosci. 2017;11:407.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Yu T, Xia L, Bi D, Wang Y, Shang Q, Zhu D, Song J, Wang Y, Wang X, Zhu C, et al. Association of NOS1 gene polymorphisms with cerebral palsy in a Han Chinese population: a case-control study. BMC Med Genom. 2018;11(1):56.

    Article  Google Scholar 

  11. Sun L, Xia L, Wang M, Zhu D, Wang Y, Bi D, Song J, Ma C, Gao C, Zhang X, et al. Variants of the OLIG2 gene are associated with cerebral palsy in Chinese Han infants with hypoxic-ischemic encephalopathy. Neuromol Med. 2019;21(1):75–84.

    Article  CAS  Google Scholar 

  12. Xia L, Xu J, Song J, Xu Y, Zhang B, Gao C, Zhu D, Zhou C, Bi D, Wang Y, et al. Autophagy-related gene 7 polymorphisms and cerebral palsy in Chinese infants. Front Cell Neurosci. 2019;13:494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zareen Z, Strickland T, Fallah L, McEneaney V, Kelly L, McDonald D, Molloy EJ. Cytokine dysregulation in children with cerebral palsy. Dev Med Child Neurol. 2021;63(4):407–12.

    Article  PubMed  Google Scholar 

  14. Stolp HB, Ek CJ, Johansson PA, Dziegielewska KM, Bethge N, Wheaton BJ, Potter AM, Saunders NR. Factors involved in inflammation-induced developmental white matter damage. Neurosci Lett. 2009;451(3):232–6.

    Article  CAS  PubMed  Google Scholar 

  15. Kannan S, Saadani-Makki F, Muzik O, Chakraborty P, Mangner TJ, Janisse J, Romero R, Chugani DC. Microglial activation in perinatal rabbit brain induced by intrauterine inflammation: detection with 11C-(R)-PK11195 and small-animal PET. J Nucl Med. 2007;48(6):946–54.

    Article  CAS  PubMed  Google Scholar 

  16. Deverman BE, Patterson PH. Cytokines and CNS development. Neuron. 2009;64(1):61–78.

    Article  CAS  PubMed  Google Scholar 

  17. Magalhaes RC, Moreira JM, Lauar AO, da Silva AAS, Teixeira AL. ACS ES: inflammatory biomarkers in children with cerebral palsy: a systematic review. Res Dev Disabil. 2019;95:103508.

    Article  PubMed  Google Scholar 

  18. Wang Y, Xu Y, Fan Y, Bi D, Song J, Xia L, Shang Q, Gao C, Zhang X, Zhu D, et al. The association study of IL-23R polymorphisms with cerebral palsy in Chinese population. Front Neurosci. 2020;14:590098.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Chen M, Li T, Lin S, Bi D, Zhu D, Shang Q, Ma C, Wang H, Wang L, Zhang Y, et al. Association of Interleukin 6 gene polymorphisms with genetic susceptibilities to spastic tetraplegia in males: a case-control study. Cytokine. 2013;61(3):826–30.

    Article  CAS  PubMed  Google Scholar 

  20. Bi D, Chen M, Zhang X, Wang H, Xia L, Shang Q, Li T, Zhu D, Blomgren K, He L, et al. The association between sex-related interleukin-6 gene polymorphisms and the risk for cerebral palsy. J Neuroinflammation. 2014;11:100.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Nelson BH, Willerford DM. Biology of the interleukin-2 receptor. Adv Immunol. 1998;70:1–81.

    Article  CAS  PubMed  Google Scholar 

  22. Damoiseaux J. The IL-2 - IL-2 receptor pathway in health and disease: the role of the soluble IL-2 receptor. Clin Immunol. 2020;218:108515.

    Article  CAS  PubMed  Google Scholar 

  23. Abbas AK, Trotta E, Das RS, Marson A, Bluestone JA. Revisiting IL-2: biology and therapeutic prospects. Sci Immunol. 2018;3(25):889.

    Article  Google Scholar 

  24. Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA. Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A. 2006;103(8):2788–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang HM, Smith KA. The interleukin 2 receptor. Functional consequences of its bimolecular structure. J Exp Med. 1987;166(4):1055–69.

    Article  CAS  PubMed  Google Scholar 

  26. Caudy AA, Reddy ST, Chatila T, Atkinson JP, Verbsky JW. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol. 2007;119(2):482–7.

    Article  CAS  PubMed  Google Scholar 

  27. Goudy K, Aydin D, Barzaghi F, Gambineri E, Vignoli M, Ciullini Mannurita S, Doglioni C, Ponzoni M, Cicalese MP, Assanelli A, et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol. 2013;146(3):248–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sharfe N, Dadi HK, Shahar M, Roifman CM. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci U S A. 1997;94(7):3168–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shavelle RM, Straus DJ, Day SM. Comparison of survival in cerebral palsy between countries. Dev Med Child Neurol. 2001;43(8):574–574.

    Article  CAS  PubMed  Google Scholar 

  30. Gorter JW, Rosenbaum PL, Hanna SE, Palisano RJ, Bartlett DJ, Russell DJ, Walter SD, Raina P, Galuppi BE, Wood E. Limb distribution, motor impairment, and functional classification of cerebral palsy. Dev Med Child Neurol. 2004;46(7):461–7.

    Article  PubMed  Google Scholar 

  31. Belanger SA, Caron J. Evaluation of the child with global developmental delay and intellectual disability. Paediatr Child Health. 2018;23(6):403–19.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Morgan C, Fahey M, Roy B, Novak I. Diagnosing cerebral palsy in full-term infants. J Paediatr Child Health. 2018;54(10):1159–64.

    Article  PubMed  Google Scholar 

  33. Wimalasundera N, Stevenson VL. Cerebral palsy. Pract Neurol. 2016;16(3):184–94.

    Article  PubMed  Google Scholar 

  34. Michael-Asalu A, Taylor G, Campbell H, Lelea LL, Kirby RS. Cerebral palsy: diagnosis, epidemiology, genetics, and clinical update. Adv Pediatr. 2019;66:189–208.

    Article  PubMed  Google Scholar 

  35. Brandenburg JE, Fogarty MJ, Sieck GC. A critical evaluation of current concepts in cerebral palsy. Physiology (Bethesda). 2019;34(3):216–29.

    Google Scholar 

  36. Knuesel I, Chicha L, Britschgi M, Schobel SA, Bodmer M, Hellings JA, Toovey S, Prinssen EP. Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol. 2014;10(11):643–60.

    Article  CAS  PubMed  Google Scholar 

  37. Jiang NM, Cowan M, Moonah SN, Petri WA Jr. The impact of systemic inflammation on neurodevelopment. Trends Mol Med. 2018;24(9):794–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Strle K, Zhou JH, Shen WH, Broussard SR, Johnson RW, Freund GG, Dantzer R, Kelley KW. Interleukin-10 in the brain. Crit Rev Immunol. 2001;21(5):427–49.

    Article  CAS  PubMed  Google Scholar 

  39. Chiricozzi A, Guttman-Yassky E, Suarez-Farinas M, Nograles KE, Tian S, Cardinale I, Chimenti S, Krueger JG. Integrative responses to IL-17 and TNF-alpha in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. J Invest Dermatol. 2011;131(3):677–87.

    Article  CAS  PubMed  Google Scholar 

  40. Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013;38(1):13–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Carlo WA, McDonald SA, Tyson JE, Stoll BJ, Ehrenkranz RA, Shankaran S, Goldberg RN, Das A, Schendel D, Thorsen P, et al. Cytokines and neurodevelopmental outcomes in extremely low birth weight infants. J Pediatr. 2011;159(6):919-925 e913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kaukola T, Satyaraj E, Patel DD, Tchernev VT, Grimwade BG, Kingsmore SF, Koskela P, Tammela O, Vainionpaa L, Pihko H, et al. Cerebral palsy is characterized by protein mediators in cord serum. Ann Neurol. 2004;55(2):186–94.

    Article  CAS  PubMed  Google Scholar 

  43. Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12(3):180–90.

    Article  CAS  PubMed  Google Scholar 

  44. Zelante T, Fric J, Wong AY, Ricciardi-Castagnoli P. Interleukin-2 production by dendritic cells and its immuno-regulatory functions. Front Immunol. 2012;3:161.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Arenas-Ramirez N, Woytschak J, Boyman O. Interleukin-2: biology, design and application. Trends Immunol. 2015;36(12):763–77.

    Article  CAS  PubMed  Google Scholar 

  46. Malek TR, Castro I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity. 2010;33(2):153–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Beck RD Jr, King MA, Ha GK, Cushman JD, Huang Z, Petitto JM. IL-2 deficiency results in altered septal and hippocampal cytoarchitecture: relation to development and neurotrophins. J Neuroimmunol. 2005;160(1–2):146–53.

    Article  CAS  PubMed  Google Scholar 

  48. Beck RD Jr, Wasserfall C, Ha GK, Cushman JD, Huang Z, Atkinson MA, Petitto JM. Changes in hippocampal IL-15, related cytokines, and neurogenesis in IL-2 deficient mice. Brain Res. 2005;1041(2):223–30.

    Article  CAS  PubMed  Google Scholar 

  49. Petitto JM, Cushman JD, Huang Z. Effects of brain-derived IL-2 deficiency and the development of autoimmunity on spatial learning and fear conditioning. J Neurol Disord. 2015;3(1):196.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all participants involved in this study and all authors.

Funding

This work was supported by the Shanghai Municipal Commission of Science and Technology Research Project (19JC1411001), the National Natural Science Foundation of China (31972880, 32170615, 31611130035, 31371274), the National Key Research and Development Program from the Ministry of Science and Technology of the People's Republic of China (2021YFC2700801), the National Key Research and Development Plan for Stem Cell and Transformation Research (2017YFA0104202), the collaborative innovation center project construction for Shanghai women and children's health (No. 15GWZK0401).

Author information

Authors and Affiliations

Authors

Contributions

QX and CZ conceived and designed the study. YX, DB, JS, LX, ML, XZ, DZ and XW recruited subjects and sorted out clinical information. YQ, YW, JZ, YS, YC, TW and JD performed the laboratory work. YQ, YW and YX performed all data and statistical analysis. YQ and YW drafted the manuscript. QX and CZ revised the manuscript critically for important intellectual content. All authors contributed and critically reviewed the final version of the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Changlian Zhu or Qinghe Xing.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Zhengzhou University (No: 2017-09) in accordance with the principles of the Declaration of Helsinki. Statements of informed consent were obtained from the guardians of all children after full explanation of the procedure.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Qiao, Y., Wang, Y., Xu, Y. et al. An association study of IL2RA polymorphisms with cerebral palsy in a Chinese population. BMC Med Genomics 15, 208 (2022). https://doi.org/10.1186/s12920-022-01350-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12920-022-01350-5

Keywords

  • Association study
  • IL2RA
  • Cerebral palsy
  • Chinese population
  • Gene polymorphism