MMP-9 gene variants increase the risk for non-atopic asthma in children

Leonardo A Pinto,Christian Vogelberg,Erika Von Mutius,Michael Kabesch,Thomas Illig,Norman Klopp,Martin Depner

doi:10.1186/1465-9921-11-23

Abstract

BackgroundAtopic and non-atopic wheezing may be caused by different etiologies: while eosinophils are more important in atopic asthmatic wheezers, neutrophils are predominantly found in BAL samples of young children with wheezing. Both neutrophils as well as eosinophils may secrete matrix metalloproteinase 9 (MMP-9). Considering that MMP-9 plays an important role in airway wall thickening and airway inflammation, it may influence the development of obstructive airway phenotypes in children. In the present study we investigated whether genetic variations in MMP-9 influence the development of different forms of childhood asthma.MethodsGenotyping of four HapMap derived tagging SNPs in the MMP-9 gene was performed using MALDI-TOF MS in three cross sectional study populations of German children (age 9-11; N = 4,264) phenotyped for asthma and atopic diseases according to ISAAC standard procedures. Effects of single SNPs and haplotypes were studied using SAS 9.1.3 and Haploview.ResultsSNP rs2664538 significantly increased the risk for non-atopic wheezing (OR 2.12, 95%CI 1.40-3.21, p < 0.001) and non-atopic asthma (OR 1.66, 95%CI 1.12-2.46, p = 0.011). Furthermore, the minor allele of rs3918241 may be associated with decreased expiratory flow measurements in non-atopic children. No significant effects on the development of atopy or total serum IgE levels were observed.ConclusionsOur results have shown that homozygocity for MMP-9 variants increase the risk to develop non-atopic forms of asthma and wheezing, which may be explained by a functional role of MMP-9 in airway remodeling. These results suggest that different wheezing disorders in childhood are affected differently by genetic alterations.

Highlights

Atopic and non-atopic wheezing may be caused by different etiologies: while eosinophils are more important in atopic asthmatic wheezers, neutrophils are predominantly found in bronchoalveolar lavage (BAL) samples of young children with wheezing
Atopic and non-atopic asthma show contrasting natural histories and may be caused by different etiologies: while eosinophils are most prevalent in bronchoalveolar lavage (BAL) of older atopic asthmatic wheezers [4], neutrophils are
Using HapMap data, all 11 SNPs in the matrix metalloproteinase 9 (MMP-9) gene could be allocated to four blocks of correlated SNPs showing high levels of linkage disequilibrium (r2 > 0.8) with each other as described in the methods section

Summary

Introduction

Atopic and non-atopic wheezing may be caused by different etiologies: while eosinophils are more important in atopic asthmatic wheezers, neutrophils are predominantly found in BAL samples of young children with wheezing. Both neutrophils as well as eosinophils may secrete matrix metalloproteinase 9 (MMP-9). Diverse wheezing phenotypes can be identified in hindsight based on differences in natural histories, trigger and risk factors [2,3]. Atopic and non-atopic asthma show contrasting natural histories and may be caused by different etiologies: while eosinophils are most prevalent in bronchoalveolar lavage (BAL) of older atopic asthmatic wheezers [4], neutrophils are. In patients with respiratory diseases, macrophages [8], eosinophils [9] mast cells [10], and dendritic cells [11] all may produce MMP-9 under specific stimulation [8,9]

Methods

Results

Discussion

Conclusion