Cette étude a mené à l’identification de plusieurs variants rares chez des individus de la population canadienne-française souffrant de MOP. Jusqu’à maintenant, aucune autre étude portant sur les variants rares dans la MOP n’a été rapportée dans la littérature. Par ailleurs, la contribution des variants rares dans l’ostéoporose a été investiguée. (Mendes et al., 2011) Li et coll. (2011) ont observés que quatre variants rares du gène LRP5, délétères selon SIFT, sont plus fréquents dans un groupe d’enfants enclins aux fractures, alors que deux variants rares bénins du même gène sont aussi fréquents chez les cas et chez les témoins. De plus, un variant rare du gène WNK4 est potentiellement associé à une faible densité minérale osseuse dans la population portugaise. La MAF de ce variant est deux fois plus élevée chez les individus ayant une faible densité minérale osseuse (2,2 %) que chez les témoins (0,9 %). (Mendes et al., 2011) Dans la population canadienne-française, des variants rares potentiellement impliqués dans d’autres maladies que la MOP ont aussi déjà été identifiés. Plusieurs de ces variants rares ont été identifiés dans des gènes investigués en raison de leur rôle potentiel dans la physiopathologie du cancer de sein ou du cancer de l’ovaire. (Desjardins et al., 2009, 2008; Durocher et al., 2006, 1996; Guénard et al., 2009; Plourde et al., 2009) Peu de ces variants rares étaient effectivement associés au cancer du sein ou de l’ovaire. D’autres variants rares ont été identifiés chez des individus souffrant de la maladie affective bipolaire originaires de la région du Saguenay-Lac-Saint- Jean. Deux associations génotypiques ont d’ailleurs été observées entre cette maladie et des variants rares des gènes KIAA1595 et CCDC92 (FLJ22471). (Shink et al., 2005)
Jusqu’à maintenant, peu d’études ont tenté d’établir une méthode visant à étudier de façon optimale l’effet des variants rares. Contrairement à la présente étude, où les gènes candidats ont été sélectionnés en fonction de leur position au sein d’un locus associé à la MOP et de leur rôle potentiel dans la physiopathologie de la maladie, la plupart des études réalisées jusqu’à maintenant ont recherché des variants rares ou des mutations
ou sur certaines malformations cardiaques. (Cohen et al., 2004; Hershberger et al., 2010, 2008; Iascone et al., 2011) Dans une étude sur le diabète de type 1, le rôle de certains gènes renfermant un variant commun associé à cette maladie a été investigué, mais les autres gènes à proximité ont été laissés de côté. (Nejentsev et al., 2009) Une autre étude portant sur la dyslipidémie a aussi permis d’identifier des variants rares ayant de grandes effets de taille dans 11 gènes pour lesquels des variants communs responsables d’une faible augmentation du risque de développer cette maladie avaient été identifiés. (Lusis et Pajukanta, 2008) Puisque les variants génétiques causaux responsables de l’observation d’une association génétique via une étude pangénomique d’association peuvent être situés à des millions de paires de bases du variant commun associé, il est probable qu’une telle approche échoue à identifier les variants causaux responsables, en partie, du développement d’une maladie. Des façons de prioriser les variants génétiques identifiés au sein d’un gène selon la fréquence du variant et les prédictions d’outils in silico ont déjà été suggérées. Toutefois, la plupart du temps les critères incluent l’absence de la variation identifiée chez tous les individus sains. (Hershberger et al., 2010, 2008; Iascone et al., 2011) Ce critère est approprié pour identifier des mutations, mais il ne l’est pas pour identifier des variants rares. Des stratégies visant à prioriser les variants génétiques identifiés dans le but de découvrir les variants génétiques rares causaux doivent donc être mises au point.
6. CONCLUSION
Ce projet a mené à l’identification de 74 variants génétiques rares, soit 57 situés au locus 1p13 et 17 situés au locus 8q22. Des associations génétiques ont été identifiées entre la MOP et deux variants génétiques rares du locus 8q22 dans la population canadienne-française. Une association allélique a été identifiée entre la MOP et un variant (c.1189C>T, p.Leu397Phe) du gène TM7SF4 qui encode la protéine DC-STAMP impliquée dans la multinucléation des ostéoclastes et une association génotypique a été identifiée entre la MOP et un variant intronique (c.372+259A>G) du gène CTHRC1 impliqué dans la régulation du remodelage osseux via son action sur l’ostéoblastogénèse. Le rôle des gènes TM7SF4 et CTHRC1 dans la physiopathologie de la MOP mérite d’être investigué davantage.
Ces découvertes pourraient améliorer les connaissances actuelles sur le remodelage osseux, ainsi que sur la pathogenèse de la MOP ou d’autres maladies osseuses métaboliques telles que l’ostéoporose. Ces connaissances pourraient permettre de développer de nouvelles stratégies de prévention ou d’élaborer de nouveaux tests diagnostiques. Elles pourraient aussi permettre d’identifier de nouvelles cibles thérapeutiques afin de contrôler le remodelage osseux. Aussi, les stratégies utilisées pour prioriser les variants rares à investiguer afin d’optimiser l’utilisation des ressources disponibles pourraient être employées dans d’autres études de reséquençage portant sur des maladies génétiques complexes basée sur une approche gènes candidats dans une population à effet fondateur. Évidemment, les améliorations suggérées plus haut devraient être considérées lors de la planification d’un tel projet.
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