A genetic polymorphism in the CAV1gene associates with the development of bronchiolitis obliterans syndrome after lung transplantation

Van, Kastelijn, Kazemier, Roothaan, Ruven, Kwakkel-Van, Zanen Pieter, Grutters

Description

Caveolin 1 (Cav-1) is the primary structural component of cell membrane invaginations called 'caveolae'. Expression of Cav-1 is implicated in the pathogenesis of pulmonary fibrosis. Genetic polymorphisms in the CAV1 gene influence the function of Cav-1 in malignancies and associate with renal allograft fibrosis. Chronic allograft rejection after lung transplantation, called 'bronchiolitis obliterans syndrome' (BOS), is also characterised by the development of fibrosis. In this study, we investigated whether CAV1 genotypes associate with BOS and whether Cav-1 serum levels are influenced by the CAV1 genotype and can be used as a biomarker to predict the development of BOS. Methods Twenty lung transplant recipients with BOS (BOS pos ), ninety without BOS (BOS neg ) and four hundred twenty-two healthy individuals donated DNA samples. Four SNPs in CAV1 were genotyped. Serial Cav-1 serum levels were measured in a matched cohort of 10 BOS pos patients and 10 BOS neg patients. Furthermore, single-time point Cav-1 serum levels were measured in 33 unmatched BOS neg patients and 60 healthy controls. Results Homozygosity of the minor allele of rs3807989 was associated with an increased risk for BOS (odds ratio: 6.13; P = 0.0013). The median Cav-1 serum level was significantly higher in the BOS pos patients than in the matched BOS neg patients ( P = 0.026). Longitudinal analysis did not show changes in Cav-1 serum levels over time in both groups. The median Cav-1 serum level in the group of 43 BOS neg patients was lower than that in the healthy control group ( P = 0.046). In lung transplant recipients, homozygosity of the minor allele of rs3807989 and rs3807994 was associated with increased Cav-1 serum levels. Conclusion In lung transplant recipients, the CAV1 SNP rs3807989 was associated with the development of BOS and Cav-1 serum levels were influenced by the CAV1 genotype.

Sujets

• Caveolin 1
• Polymorphism (biology)
• Sérum
• Lung transplantation

Informations

• Publié par: biomed
• Publié le: 01 janvier 2011
• Nombre de lectures: 12
• Langue: English

Extrait

Kastelijnet al.Fibrogenesis & Tissue Repair2011,4:24 http://www.fibrogenesis.com/content/4/1/24

R E S E A R C H

Open Access

A genetic polymorphism in theCAV1gene associates with the development of bronchiolitis obliterans syndrome after lung transplantation 1* 1,2 2 3 4 Elisabeth A Kastelijn , Coline HM van Moorsel , Karin M Kazemier , Suzan M Roothaan , Henk JT Ruven , 2 2 2 1 1,2 Johanna M Kwakkelvan Erp , Ed A van de Graaf , Pieter Zanen , Diana A van Kessel and Jan C Grutters

Abstract Background:Caveolin 1 (Cav1) is the primary structural component of cell membrane invaginations called ‘caveolae’. Expression of Cav1 is implicated in the pathogenesis of pulmonary fibrosis. Genetic polymorphisms in theCAV1gene influence the function of Cav1 in malignancies and associate with renal allograft fibrosis. Chronic allograft rejection after lung transplantation, called‘bronchiolitis obliterans syndrome’(BOS), is also characterised by the development of fibrosis. In this study, we investigated whetherCAV1genotypes associate with BOS and whether Cav1 serum levels are influenced by theCAV1genotype and can be used as a biomarker to predict the development of BOS. pos neg Methods:Twenty lung transplant recipients with BOS (BOS ) and four hundred), ninety without BOS (BOS twentytwo healthy individuals donated DNA samples. Four SNPs inCAV1were genotyped. Serial Cav1 serum pos neg levels were measured in a matched cohort of 10 BOS patients and 10 BOS patients. Furthermore, singletime neg point Cav1 serum levels were measured in 33 unmatched BOS patients and 60 healthy controls. Results:Homozygosity of the minor allele ofrs3807989was associated with an increased risk for BOS (odds ratio: pos 6.13;Ppatients than in the= 0.0013). The median Cav1 serum level was significantly higher in the BOS neg matched BOS patients (P= 0.026). Longitudinal analysis did not show changes in Cav1 serum levels over time neg in both groups. The median Cav1 serum level in the group of 43 BOS patients was lower than that in the healthy control group (P= 0.046). In lung transplant recipients, homozygosity of the minor allele ofrs3807989andrs3807994was associated with increased Cav1 serum levels. Conclusion:In lung transplant recipients, theCAV1SNPrs3807989was associated with the development of BOS and Cav1 serum levels were influenced by theCAV1genotype. Keywords:caveolin 1, genetic polymorphism, serum, lung transplantation, bronchiolitis obliterans syndrome

Background Caveolae are 50 to 100nm flaskshaped cell membrane invaginations in which the primary structural compo nent is caveolin 1 (Cav1) [1]. Cav1 has been found in many cell types, but is abundantly expressed in endothe lial cells, type 1 pneumocytes, epithelial cells, smooth muscle cells and fibroblasts [25]. It has many cellular

* Correspondence: [e-mail] 1 Centre of Interstitial Lung Diseases, Department of Pulmonology, St Antonius Hospital, Postbox 2500, NL3420 EM, Nieuwegein, The Netherlands Full list of author information is available at the end of the article

functions, including vesicular transport, signal transduc tion and cholesterol homeostasis [1,4,6]. Kasperet al.[5] were the first investigators to link Cav1 to a fibrotic phenotype in the lungs of rats. Sub sequently, studies of the role of Cav1 in pulmonary fibrosis in humans were conducted. In patients with idiopathic pulmonary fibrosis (IPF), Cav1 mRNA expression was found to be reduced in epithelial cells and fibroblasts [7]. In patients with systemic sclerosis, Cav1 expression was markedly decreased in tissue of affected lungs and skin [8]. Knockdown of Cav1

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