Stéphanie Debette1, Hugh S Markus. 1. Clinical Neuroscience, St George's University of London, UK. stephdebette@wanadoo.fr
Abstract
BACKGROUND AND PURPOSE: The pathophysiology of cervical artery dissections (CAD), a major cause of ischemic stroke in young adults, is poorly understood. Several arguments suggest a genetic predisposition. METHODS: We systematically reviewed all published data on genetic risk factors for CAD and performed a meta-analysis of association studies with the MTHFR C677T polymorphism. RESULTS: Rarely, CAD is associated with a known monogenic connective tissue disease, mainly vascular Ehlers-Danlos syndrome. However, in the large majority of CAD cases, there is no evidence for a known monogenic disease. Several arguments, including the association of CAD with dermal connective tissue abnormalities that are inherited, suggest that genetic factors also play a role in "sporadic" CAD as part of a multifactorial predisposition. We identified 15 genetic association studies: 10 were negative and 5 reported associations of 3 genetic variants in 3 different candidate genes. Two studies reported associations with polymorphisms in ICAM-1 and COL3A1, but neither has been replicated. Three studies reported an association with the MTHFR 677TT genotype, but 3 other studies did not replicate this. A meta-analysis of these data identified an overall significant association of the MTHFR 677TT genotype with CAD (OR, 1.67; 95% CI, 1.21 to 2.31). We also identified 9 studies screening candidate genes for mutations and 4 linkage studies, yielding mostly negative results. CONCLUSIONS: Although several interesting hypotheses were generated, the majority of genetic studies in CAD have been negative until now, but they were markedly underpowered. Progress in unraveling the genetics of CAD will require the collection of DNA samples from large multicenter series.
BACKGROUND AND PURPOSE: The pathophysiology of cervical artery dissections (CAD), a major cause of ischemic stroke in young adults, is poorly understood. Several arguments suggest a genetic predisposition. METHODS: We systematically reviewed all published data on genetic risk factors for CAD and performed a meta-analysis of association studies with the MTHFRC677T polymorphism. RESULTS: Rarely, CAD is associated with a known monogenic connective tissue disease, mainly vascular Ehlers-Danlos syndrome. However, in the large majority of CAD cases, there is no evidence for a known monogenic disease. Several arguments, including the association of CAD with dermal connective tissue abnormalities that are inherited, suggest that genetic factors also play a role in "sporadic" CAD as part of a multifactorial predisposition. We identified 15 genetic association studies: 10 were negative and 5 reported associations of 3 genetic variants in 3 different candidate genes. Two studies reported associations with polymorphisms in ICAM-1 and COL3A1, but neither has been replicated. Three studies reported an association with the MTHFR 677TT genotype, but 3 other studies did not replicate this. A meta-analysis of these data identified an overall significant association of the MTHFR 677TT genotype with CAD (OR, 1.67; 95% CI, 1.21 to 2.31). We also identified 9 studies screening candidate genes for mutations and 4 linkage studies, yielding mostly negative results. CONCLUSIONS: Although several interesting hypotheses were generated, the majority of genetic studies in CAD have been negative until now, but they were markedly underpowered. Progress in unraveling the genetics of CAD will require the collection of DNA samples from large multicenter series.
Authors: Caspar Grond-Ginsbach; Bowang Chen; Rastislav Pjontek; Tina Wiest; Yanxiang Jiang; Barbara Burwinkel; Sandrine Tchatchou; Michael Krawczak; Stefan Schreiber; Tobias Brandt; Manja Kloss; Marie-Luise Arnold; Kari Hemminki; Christoph Lichy; Philippe A Lyrer; Ingrid Hausser; Stefan T Engelter Journal: Eur J Hum Genet Date: 2012-05-23 Impact factor: 4.246
Authors: Louis R Caplan; Juan Arenillas; Steven C Cramer; Anne Joutel; Eng H Lo; James Meschia; Sean Savitz; Elizabeth Tournier-Lasserve Journal: Arch Neurol Date: 2011-05-09
Authors: Stéphanie Debette; Yoichiro Kamatani; Tiina M Metso; Manja Kloss; Ganesh Chauhan; Stefan T Engelter; Alessandro Pezzini; Vincent Thijs; Hugh S Markus; Martin Dichgans; Christiane Wolf; Ralf Dittrich; Emmanuel Touzé; Andrew M Southerland; Yves Samson; Shérine Abboud; Yannick Béjot; Valeria Caso; Anna Bersano; Andreas Gschwendtner; Maria Sessa; John Cole; Chantal Lamy; Elisabeth Medeiros; Simone Beretta; Leo H Bonati; Armin J Grau; Patrik Michel; Jennifer J Majersik; Pankaj Sharma; Ludmila Kalashnikova; Maria Nazarova; Larisa Dobrynina; Eva Bartels; Benoit Guillon; Evita G van den Herik; Israel Fernandez-Cadenas; Katarina Jood; Michael A Nalls; Frank-Erik De Leeuw; Christina Jern; Yu-Ching Cheng; Inge Werner; Antti J Metso; Christoph Lichy; Philippe A Lyrer; Tobias Brandt; Giorgio B Boncoraglio; Heinz-Erich Wichmann; Christian Gieger; Andrew D Johnson; Thomas Böttcher; Maurizio Castellano; Dominique Arveiler; M Arfan Ikram; Monique M B Breteler; Alessandro Padovani; James F Meschia; Gregor Kuhlenbäumer; Arndt Rolfs; Bradford B Worrall; Erich-Bernd Ringelstein; Diana Zelenika; Turgut Tatlisumak; Mark Lathrop; Didier Leys; Philippe Amouyel; Jean Dallongeville Journal: Nat Genet Date: 2014-11-24 Impact factor: 38.330