Genetic polymorphisms in MMP7 and reduced serum levels associate with the development of bronchiolitis obliterans syndrome after lung transplantation

Kastelijn, Elisabeth A.; van Moorsel, Coline H.; Ruven, Henk J.; Karthaus, Vincent; Kwakkel-van Erp, Johanna M.; van de Graaf, Ed A.; Zanen, Pieter; van Kessel, Diana A.; Grutters, Jan C.; van den Bosch, Jules M.

doi:10.1016/j.healun.2010.01.008

« Previous Next »The Journal of Heart and Lung Transplantation
Volume 29, Issue 6 , Pages 680-686, June 2010

Genetic polymorphisms in MMP7 and reduced serum levels associate with the development of bronchiolitis obliterans syndrome after lung transplantation

Elisabeth A. Kastelijn, MD
- Centre of Interstitial Lung Diseases, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands
Coline H. van Moorsel, PhD
- Centre of Interstitial Lung Diseases, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands
Henk J. Ruven, PhD
- Department of Clinical Chemistry, St Antonius Hospital, Nieuwegein, The Netherlands
Vincent Karthaus, MSc
- Centre of Interstitial Lung Diseases, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands
Johanna M. Kwakkel-van Erp, MD
- Division of Heart and Lungs, University Medical Centre Utrecht, Utrecht, The Netherlands
Ed A. van de Graaf, MD, PhD
- Division of Heart and Lungs, University Medical Centre Utrecht, Utrecht, The Netherlands
Pieter Zanen, MD
- Division of Heart and Lungs, University Medical Centre Utrecht, Utrecht, The Netherlands
Diana A. van Kessel, MD
- Centre of Interstitial Lung Diseases, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands
Jan C. Grutters, MD, PhD
- Centre of Interstitial Lung Diseases, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands
- Division of Heart and Lungs, University Medical Centre Utrecht, Utrecht, The Netherlands
- Reprint requests: J.C. Grutters, MD, PhD, St. Antonius Hospital, Postbox 2500, 3420 EM Nieuwegein, The Netherlands. Telephone: +31-0-30-609-2428. Fax: +31-0-30-605-2001
Jules M. van den Bosch, MD, PhD
- Centre of Interstitial Lung Diseases, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands
- Division of Heart and Lungs, University Medical Centre Utrecht, Utrecht, The Netherlands

published online 29 March 2010.

Background

Pulmonary epithelium is the primary target of injury in the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. Matrix metalloproteinases (MMP)-8 and -9 already have been implicated in the pathogenesis of BOS. MMP-7, which is involved in the repair of the lung epithelium, has not been studied in this respect. We hypothesized that genetic polymorphisms in MMP7 influence its expression and correlate with serum MMP-7 levels and the development of BOS.

Methods

DNA was collected from 110 lung transplant recipients, including 21 patients with BOS. We genotyped 7 single nucleotide polymorphisms in MMP7 and measured serum MMP-7 levels. The control group comprised 422 healthy individuals.

Results

BOS^pos patients had lower levels of MMP-7 than BOS^neg patients (7.87 vs 10.18 ng/ml). Significant differences in genotype and haplotype distribution between the BOS^pos and BOS^neg patients and controls were found. An increased risk for BOS development was found in patients homozygous for the major alleles of rs17098318, rs11568818, and rs12285347, and for the minor allele rs10502001 (odds ratio, 3.88–5.30). Haplotypes constructed with 3 or 4 risk alleles correlated with lower MMP-7 levels.

Conclusions

Genetic polymorphisms of MMP7 predispose to the development of BOS. Patients carrying these risk alleles express lower levels of MMP-7, which may contribute to aberrant tissue repair and culminate in the development of BOS.

Keywords: bronchiolitis obliterans syndrome, matrix metalloproteinase-7 (MMP-7), serum, genetic polymorphism, lung transplantation