Published Online
on July 8, 2009

A more recent version of this article appeared on October 1, 2009

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Original Article

Refining molecular pathways leading to calcific aortic valve stenosis by studying gene expression profile of normal and calcified stenotic human aortic valves

Yohan Bossé^1,3; Ahmed Miqdad²; Dominique Fournier²; Andrée Pépin²; Philippe Pibarot² and Patrick Mathieu²

¹ Laval University & Laval University Hospital Research Center, Québec, Canada;
² Laval University, Québec, Canada

³ E-mail: yohan.bosse{at}crhl.ulaval.ca

Background—Calcific aortic valve stenosis (AS) is a major societal and economic burden that is rising following the current shift toward an older population. Understanding the pathobiology of AS is crucial to implement better preventive and therapeutic options. Research conducted during the past decade clearly point to active molecular and cellular processes involved in disease pathogenesis. However, no genomic approaches were used to identify genes and pathways that are differentially regulated in aortic valves of patients with and without AS.

Methods and Results—A large-scale quantitative measurements of gene expression was performed on five normal and five AS valves using Affymetrix GeneChips. A total of 409 and 306 genes were significantly up- and down-regulated in AS valves, respectively. The two most highly up-regulated genes were matrix metalloproteinase 12 (MMP12) and chitinase 3-like 1 (CHI3L1). The up-regulation of these two biological relevant genes in AS was validated by real-time PCR in 38 aortic valves (12 normal and 26 AS). To provide a global biological validation of the whole-genome gene expression analysis, the microarray experiment was repeated in a second set of aortic valves with (n = 5) or without (n = 5) AS. There was an overrepresentation of small p values among genes claim significant in the first microarray experiment. A total of 223 genes were replicated (p value < 0.05 and fold change > 1.2), including MMP12 and CHI3L1.

Conclusions—This study reveals many unrecognized genes potentially implicated in the pathogenesis of AS. These new genes were overlaid on known pathological pathways leading to AS in order to refine our molecular understanding of this disease.

Key Words: genetics • stenosis • valves • aortic valve • candidate genes • microarray • pathways analyses • real-time PCR