Department of Respiratory Medicine, The Royal Children's Hospital, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia.
Department of Paediatric Respiratory Medicine, Monash Medical Centre, Melbourne, Australia.
J Cyst Fibros. 2014 Dec;13(6):699-705. doi: 10.1016/j.jcf.2014.04.007. Epub 2014 May 19.
The search for modifier genes to explain inconsistencies in cystic fibrosis (CF) genotype-phenotype relationships has yielded mixed results. In a previous cross-sectional study from our centre the clinical effect (as described by FEV1, BMI z-score, admitted days and NIH score) of single nucleotide polymorphisms (SNPs) of four cytokine genes (IL-8, TNF-α, IL-1β and IL-10) was examined in 158 children with CF. No association between cytokine genotype and any biological outcome measure was found. In this present study a cross-sectional and longitudinal examination of this relationship was undertaken to test the hypothesis that pro-inflammatory SNPs would affect longitudinal changes in CF lung disease.
Using the cohort examined in our earlier study we performed both longitudinal and cross-sectional data analyses examining the relationship between SNPs (TNF-α, IL-8, IL-10 and IL-1β) and clinical outcome measurements. In the first part of this current study, lung function data (annual decline of FEV1 percent predicted) was compared with the cytokine genotype over a 13 year period. In the second part of this current study multiple regression was used to assess associations between clinical outcomes (best FEV1 percent predicted and BMI at the age of 10 years) and alleles of cytokine genes, adjusting for gender, CF genotype and lung infection status.
A total of 152 patients with CF were analysed in the longitudinal study and data from 130 patients at the age of 10 years were analysed in the cross-sectional study. There was evidence for an association between pro-inflammatory SNPs of the IL-8, IL-10 and IL-1β genes and more severe lung disease. Multiple regression of the longitudinal data with a total of 10,956 lung function measurements showed an additional annual decline of the percentage predicted FEV1 of -1.15 (IL-8, p<0.001), -0.24 (IL-10, p=0.049) and -0.41 (IL-1β, p<0.001) for patients with any of the pro-inflammatory alleles. None of the cross-sectional data showed a significant association between the cytokine genotypes and the clinical outcomes.
Pro-inflammatory alleles of three cytokine genotypes, IL-8, IL-10 and IL-1β, appear to be associated with slightly more severe lung disease in patients with CF over a 13 year period. Further studies are required to exclude influence of confounders on the severity of lung disease.
寻找修饰基因来解释囊性纤维化（CF）基因型-表型关系中的不一致性，结果喜忧参半。在我们中心进行的一项先前的横断面研究中，我们检查了四个细胞因子基因（IL-8、TNF-α、IL-1β和 IL-10）的单核苷酸多态性（SNP）在 158 名 CF 儿童中的临床效果（FEV1、BMI z 评分、住院天数和 NIH 评分描述）。未发现细胞因子基因型与任何生物学结果测量之间存在关联。在本研究中，对这种关系进行了横断面和纵向检查，以检验假设，即促炎 SNP 会影响 CF 肺疾病的纵向变化。
使用我们早期研究中检查的队列，我们进行了纵向和横断面数据分析，检查了 SNP（TNF-α、IL-8、IL-10 和 IL-1β）与临床结果测量之间的关系。在本研究的第一部分中，比较了 13 年内的肺功能数据（FEV1 预计百分比的年下降）与细胞因子基因型。在本研究的第二部分中，使用多元回归评估细胞因子基因等位基因与临床结果（最佳 FEV1 预计百分比和 10 岁时的 BMI）之间的关联，同时调整性别、CF 基因型和肺部感染状态。
对 152 名 CF 患者进行了纵向研究分析，对 130 名 10 岁患者进行了横断面研究分析。IL-8、IL-10 和 IL-1β 基因的促炎 SNP 与更严重的肺部疾病有关。对总共 10956 次肺功能测量的纵向数据进行多元回归显示，任何促炎等位基因的患者的 FEV1 预计百分比的额外年下降为 -1.15（IL-8，p<0.001）、-0.24（IL-10，p=0.049）和 -0.41（IL-1β，p<0.001）。横断面数据均未显示细胞因子基因型与临床结果之间存在显著关联。
在 13 年的时间里，IL-8、IL-10 和 IL-1β 三种细胞因子基因型的促炎等位基因似乎与 CF 患者的肺部疾病稍严重有关。需要进一步的研究来排除混杂因素对肺部疾病严重程度的影响。
