Supplementary Material for: Cerebral Palsy and Polymorphism of the Chemokine <b><i>CCL18</i></b> in Very Preterm Children

Background: Prematurity and hereditary factors predispose to cerebral palsy (CP). Previously, low cord blood levels of the anti-inflammatory chemokine CCL18 have been found to be associated with risk of CP in preterm children. Objectives: To investigate the association between single nucleotide polymorphisms (SNPs) in CCL18 and susceptibility to CP, as well as the association between the SNPs and cord blood levels of CCL18. Methods: The original population comprised very-low-gestational-age (VLGA; <32 weeks) children from northern and central Finland (25 cases, 195 controls). Five CCL18 SNPs were genotyped and examined for associations with CP and cord blood CCL18. The replication population comprised Caucasian VLGA children from southern Finland and Canada (23 cases, 248 controls). Results: In the original population, SNP rs2735835 was associated with CP; the minor allele A was underrepresented in cases compared to controls (OR = 0.42, 95% CI: 0.21-0.83, p = 0.01). This association remained significant after adjustment for multiple testing and risk factors of CP, and after combining the original and replication populations (OR = 0.52, 95% CI: 0.33-0.83, p = 0.005). Intraventricular hemorrhage (IVH) additively predicted CP. The Rs2015086 genotype was modestly associated with CCL18 concentration. Conclusions: A common CCL18 polymorphism together with IVH had an additive influence on CP susceptibility. Developmentally regulated CCL18, confined to primates, may be involved in the complex sequence of events leading to brain injury and predisposition to CP phenotype.背景：早产与遗传因素可使个体易患脑瘫（cerebral palsy, CP）。既往研究显示，早产儿童脐带血中抗炎趋化因子CCL18水平偏低，与脑瘫发病风险存在显著关联。 研究目标：探究CCL18基因的单核苷酸多态性（single nucleotide polymorphisms, SNPs）与脑瘫易感性的关联，以及这些SNPs与脐带血CCL18水平的关联。 研究方法：初始队列纳入芬兰北部与中部的极早早产儿（very-low-gestational-age, VLGA；胎龄<32周），共25例脑瘫病例与195例对照。对5个CCL18基因的SNPs进行基因分型，检测其与脑瘫及脐带血CCL18水平的关联。验证队列纳入芬兰南部及加拿大的高加索裔极早早产儿，共23例病例与248例对照。 研究结果：在初始队列中，SNP rs2735835与脑瘫存在关联：与对照相比，病例组中次要等位基因A的占比偏低（比值比odds ratio, OR=0.42，95%置信区间confidence interval, CI：0.21~0.83，p=0.01）。在校正多重检验及脑瘫相关危险因素后，该关联仍具有统计学意义；合并初始队列与验证队列后，该关联依然显著（OR=0.52，95%CI：0.33~0.83，p=0.005）。脑室内出血（intraventricular hemorrhage, IVH）可对脑瘫发生风险产生相加性预测作用。基因型rs2015086与CCL18浓度呈轻度关联。 研究结论：常见的CCL18基因多态性与脑室内出血共同对脑瘫易感性产生相加性影响。仅在灵长类动物中表达的发育调控型CCL18，可能参与了导致脑损伤及脑瘫表型易感性的一系列复杂病理生理过程。