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European Journal of Heart Failure 2007 9(10):1010-1017; doi:10.1016/j.ejheart.2007.07.005
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© 2007 European Society of Cardiology

Promoter polymorphism of the matrix metalloproteinase 3 gene is associated with regurgitation and left ventricular remodelling in mitral valve prolapse patients

Delvac Oceandya,*,1, Rahal Yusoffb,1, Florence M. Baudoina, Ludwig Neysesa and Simon G. Rayb

a Division of Cardiovascular Sciences, University of Manchester Oxford Road, Manchester M13 9PT, United Kingdom
b Department of Cardiology, Wythenshawe Hospital Manchester M23 9LT, United Kingdom

* Corresponding author. 1.302 Stopford Building University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom. Tel.: +44 161 2755672; fax: +44 161 2755669. E-mail address: delvac.oceandy{at}manchester.ac.uk (D. Oceandy).


  Abstract

Background and aims: Mitral valve prolapse (MVP) is common and highly variable in its severity, but the factors underlying this variability are unclear. In this study, we tested the hypothesis that polymorphic variations in Matrix Metalloproteinase (MMP) genes might be predictors of left ventricular (LV) remodelling and severity of regurgitation in MVP.

Methods and results: 70 MVP patients and 75 normal subjects were studied. We performed comprehensive echocardiography and analyzed promoter polymorphisms in the MMP-1 and MMP-3 genes. The MMP-3 -1612 5A/6A polymorphism showed strong associations with indices of mitral regurgitation and LV remodelling: Patients with 5A/5A allele had more pronounced remodelling and more severe mitral regurgitation than patients with the 6A/6A or 5A/6A alleles. We then cloned and sequenced 2 kb fragments of MMP-3 promoter from patients with 5A/5A and 6A/6A genotypes and found 4 different sets of promoter haplotypes. Promoter analysis showed that higher promoter activity was related to a more severe phenotype and that the haplotype variants had a more dominant role in determining the activity.

Conclusions: Our data identifies the MMP-3 promoter haplotype as a novel marker of an adverse disease course in MVP, suggesting the presence of genetic determinants for the severity of MVP.

Key Words: Mitral valve • Genetics • Remodelling • Regurgitation • Echocardiography

Received February 27, 2007; Revised June 14, 2007; Accepted July 11, 2007

1 These authors contributed equally to this work.


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