囊性纤维化肺病的基因修饰因子

Genetic modifiers of lung disease in cystic fibrosis.

作者信息

Drumm Mitchell L, Konstan Michael W, Schluchter Mark D, Handler Allison, Pace Rhonda, Zou Fei, Zariwala Maimoona, Fargo David, Xu Airong, Dunn John M, Darrah Rebecca J, Dorfman Ruslan, Sandford Andrew J, Corey Mary, Zielenski Julian, Durie Peter, Goddard Katrina, Yankaskas James R, Wright Fred A, Knowles Michael R

机构信息

Department of Pediatrics, Case Western Reserve University, Cleveland, USA.

出版信息

N Engl J Med. 2005 Oct 6;353(14):1443-53. doi: 10.1056/NEJMoa051469.

DOI:10.1056/NEJMoa051469

PMID:16207846

Abstract

BACKGROUND

Polymorphisms in genes other than the cystic fibrosis transmembrane conductance regulator (CFTR) gene may modify the severity of pulmonary disease in patients with cystic fibrosis.

METHODS

We performed two studies with different patient samples. We first tested 808 patients who were homozygous for the DeltaF508 mutation and were classified as having either severe or mild lung disease, as defined by the lowest or highest quartile of forced expiratory volume in one second (FEV1), respectively, for age. We genotyped 16 polymorphisms in 10 genes reported by others as modifiers of disease severity in cystic fibrosis and tested for an association in patients with severe disease (263 patients) or mild disease (545). In the replication (second) study, we tested 498 patients, with various CFTR genotypes and a range of FEV1 values, for an association of the TGFbeta1 codon 10 CC genotype with low FEV1.

RESULTS

In the initial study, significant allelic and genotypic associations with phenotype were seen only for TGFbeta1 (the gene encoding transforming growth factor beta1), particularly the -509 and codon 10 polymorphisms (with P values obtained with the use of Fisher's exact test and logistic regression ranging from 0.006 to 0.0002). The odds ratio was about 2.2 for the highest-risk TGFbeta1 genotype (codon 10 CC) in association with the phenotype for severe lung disease. The replication study confirmed the association of the TGFbeta1 codon 10 CC genotype with more severe lung disease in comparisons with the use of dichotomized FEV1 for severity status (P=0.0002) and FEV1 values directly (P=0.02).

CONCLUSIONS

Genetic variation in the 5' end of TGFbeta1 or a nearby upstream region modifies disease severity in cystic fibrosis.

摘要

背景

除囊性纤维化跨膜传导调节因子（CFTR）基因外，其他基因的多态性可能会改变囊性纤维化患者肺部疾病的严重程度。

方法

我们对不同的患者样本进行了两项研究。我们首先检测了808名携带DeltaF508突变的纯合子患者，这些患者根据年龄的一秒用力呼气量（FEV1）的最低或最高四分位数分别被分类为患有严重或轻度肺部疾病。我们对其他研究报道的10个基因中的16个多态性进行基因分型，这些基因被认为是囊性纤维化疾病严重程度的调节因子，并在患有严重疾病（263例患者）或轻度疾病（545例）的患者中检测其关联性。在重复（第二项）研究中，我们检测了498名具有各种CFTR基因型和一系列FEV1值的患者，以研究转化生长因子β1（TGFbeta1）密码子10 CC基因型与低FEV1之间的关联性。

结果

在初始研究中，仅在TGFbeta1（编码转化生长因子β1的基因）中观察到与表型有显著的等位基因和基因型关联，特别是-509和密码子10多态性（使用Fisher精确检验和逻辑回归获得的P值范围为0.006至0.0002）。与严重肺部疾病表型相关的最高风险TGFbeta1基因型（密码子10 CC）的优势比约为2.2。重复研究证实，与使用二分法FEV1评估严重程度状态（P = 0.0002）和直接使用FEV1值（P = 0.02）相比，TGFbeta1密码子10 CC基因型与更严重的肺部疾病相关。