Download PDF
Thromb Haemost 2016; 116(06): 1165-1771
DOI: 10.1160/TH16-02-0113
Stroke, Systemic or Venous Thromboembolism
Schattauer Publishers Schattauer

Whole exome sequencing analysis reveals TRPV3 as a risk factor for cardioembolic stroke/subtitle

Caty Carrera
1   Neurovascular Research Laboratory, Valld’Hebron Institute of Research, Universitat Autonoma de Barcelona, Barcelona, Spain
,
Jordi Jiménez-Conde
2   Department of Neurology, Neurovascular Research Group, IMIM-Hospital del Mar (Institut Hospital del Mar d’Investigacions Mediques), Universitat Autonoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
,
Sophia Derdak
3   National Center for Genome Analysis, CNAG, Barcelona, Spain
,
Kelly Rabionet
4   Center for Genomic Regulation, IMIM, Barcelona, Spain
,
Cristofol Vives-Bauzá
5   Research Unit, Son Espases University Hospital, IdISPa, Palma de Mallorca, Spain
,
Carolina Soriano-Tárrega
2   Department of Neurology, Neurovascular Research Group, IMIM-Hospital del Mar (Institut Hospital del Mar d’Investigacions Mediques), Universitat Autonoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
,
Eva Giralt-Steinhauer
2   Department of Neurology, Neurovascular Research Group, IMIM-Hospital del Mar (Institut Hospital del Mar d’Investigacions Mediques), Universitat Autonoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
,
Marina Mola-Caminal
2   Department of Neurology, Neurovascular Research Group, IMIM-Hospital del Mar (Institut Hospital del Mar d’Investigacions Mediques), Universitat Autonoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
,
Rosa M. Diaz-Navarro
6   Neurology Department, Son Espases University Hospital, IdISPa, Palma de Mallorca, Spain
,
Silvia Tur
6   Neurology Department, Son Espases University Hospital, IdISPa, Palma de Mallorca, Spain
,
Elena Muiño
7   Stroke Pharmacogenomics and Genetics, Fundacio Docencia i Recerca Mutua Terrassa, Mutua de Terrassa Hospital, Terrassa (Barcelona), Spain
,
Cristina Gallego-Fabrega
7   Stroke Pharmacogenomics and Genetics, Fundacio Docencia i Recerca Mutua Terrassa, Mutua de Terrassa Hospital, Terrassa (Barcelona), Spain
,
Sergi Beltran
3   National Center for Genome Analysis, CNAG, Barcelona, Spain
,
Jaume Roquer
2   Department of Neurology, Neurovascular Research Group, IMIM-Hospital del Mar (Institut Hospital del Mar d’Investigacions Mediques), Universitat Autonoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
,
Agustin Ruiz
8   ACE Foundation, Institut Català de Neurociències Aplicades, Research Center, Barcelona, Spain
,
Oscar Sotolongo-Grau
8   ACE Foundation, Institut Català de Neurociències Aplicades, Research Center, Barcelona, Spain
,
Jurek Krupinski
9   Neurology Unit, Neuroscience Department, Mutua de Terrassa Hospital, Terrassa (Barcelona), Spain
,
Jin-Moo Lee
10   Washington University School of Medicine, St. Louis, Missouri, USA
,
Carlos Cruchaga
10   Washington University School of Medicine, St. Louis, Missouri, USA
,
Pilar Delgado
1   Neurovascular Research Laboratory, Valld’Hebron Institute of Research, Universitat Autonoma de Barcelona, Barcelona, Spain
,
Rainer Malik
11   Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany
,
Brad B. Worrall
12   Departments of Neurology and Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA
,
Sudha Seshadri
13   Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA
,
Joan Montaner
1   Neurovascular Research Laboratory, Valld’Hebron Institute of Research, Universitat Autonoma de Barcelona, Barcelona, Spain
,
Israel Fernández-Cadenas
7   Stroke Pharmacogenomics and Genetics, Fundacio Docencia i Recerca Mutua Terrassa, Mutua de Terrassa Hospital, Terrassa (Barcelona), Spain
,
the Metastroke Consortium, ISGC Consortium and Genestroke Consortium › Author Affiliations Financial support: I. F-C. is supported by the Miguel Servet program(CP12/03298), Instituto de Salud Carlos III. The Neurovascular Research Laboratory is supported by the Spanish stroke research network (INVICTUS) and the European Stroke Network (EUSTROKE 7FP Health F2–08–202213). The IMIM-Hospital del Mar group is supported by RIC, RD12/0042/0020 FEDER.
Further Information

Publication History

Received 11 February 2016

Accepted after major revision: 15 August 2016

Publication Date:
09 March 2018 (online)

Also available at
    Permissions and Reprints

Summary

Genetic studies suggest that hundreds of genes associated with stroke remain unidentified. Exome sequencing proves useful for finding new genes associated with stroke. We aimed to find new genetic risk factors for cardioembolic stroke by analysing exome sequence data using new strategies. For discovery, we analysed 42 cardioembolic stroke cases and controls with extreme phenotypes (cohort 1), and for replication, 32 cardioembolic stroke cases and controls (cohort 2) using the SeqCapExome capture kit. We then analysed the replicated genes in two new cohorts that comprised 834 cardioembolic strokes and controls (cohort 3) and 64,373 cardioembolic strokes and controls (cohort 4). Transcriptomic in-silico functional analyses were also performed. We found 26 coding regions with a higher frequency of mutations in cardioembolic strokes after correcting for the number of mutations found in the whole exome of every patient. The TRPV3 gene was associated with cardioembolic stroke after replication of exome sequencing analysis (p-value-discovery: 0.018, p-value-replication: 0.014). The analysis of the TRPV3 gene using polymorphisms in cohort 3 and 4 revealed two polymorphisms associated with cardioembolic stroke in both cohorts, the most significant polymorphism being rs151091899 (p-value: 3.1 × 10−05; odds ratio: 5.4) in cohort 3. The genotype of one polymorphism of TRPV3 was associated with a differential expression of genes linked to cardiac malformations. In conclusion, new strategies using exome sequence data have revealed TRPV3 as a new gene associated with cardioembolic stroke. This strategy among others might be useful in finding new genes associated with complex genetic diseases.

Keywords

Genetics - cerebrovascular disease/stroke - ischaemic stroke

 

  • References

  • 1 Traylor M, Farrall M, Holliday EG. et al. International Stroke Genetics Consortium. Genetic risk factors for ischaemic stroke and its subtypes (the META-STROKE collaboration): a meta-analysis of genome-wide association studies. Lancet Neurol 2012; 11: 951-962
    CrossrefPubMedSearch in Google Scholar
  • 2 Woo D, Falcone GJ, Devan WJ. et al. International Stroke Genetics Consortium. Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebralhemorrhage. Am J Hum Genet 2014; 94: 511-521.
    CrossrefPubMedSearch in Google Scholar
  • 3 Traylor M, Mäkelä KM, Kilarski LL. et al. A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach. PLoS Genet 2014; 10: e1004469.
    CrossrefPubMedSearch in Google Scholar
  • 4 Holliday EG, Maguire JM, Evans TJ. et al. Australian Stroke Genetics Collaborative; International Stroke Genetics Consortium; Wellcome Trust Case Control Consortium 2. Common variants at 6p21.1 are associated with large artery atherosclerotic stroke. Nat Genet 2012; 44: 1147-1151.
    CrossrefPubMedSearch in Google Scholar
  • 5 Kilarski LL, Achterberg S, Devan WJ. et al. GARNET Collaborative Research Group, Wellcome Trust Case Control Consortium 2, Australian Stroke Genetic Collaborative, the METASTROKEConsortium, and the International Stroke Genetics Consortium. Meta-analysis in more than 17,900 cases of ischaemic stroke reveals a novel association at 12q24.12. Neurology 2014; 83: 678-685.
    CrossrefPubMedSearch in Google Scholar
  • 6 Bevan S, Traylor M, Adib-Samii P. et al. Genetic heritability of ischaemic stroke and the contribution of previously reported candidate gene and genome wide associations. Stroke 2012; 43: 3161-3167.
    CrossrefPubMedSearch in Google Scholar
  • 7 Kim DS, Crosslin DR, Auer PL. et al. on behalf of the NHLBI Exome Sequencing Project. Rare coding variation in paraoxonase-1 is associated with ischaemic stroke in the NHLBI Exome Sequencing Project. J Lipid Res 2014; 55: 1173-1178.
    CrossrefPubMedSearch in Google Scholar
  • 8 Auer PL, Nalls M, Meschia JF. et al. National Heart, Lung, and Blood Institute Exome Sequencing Project. Rare and Coding Region Genetic Variants Associated With Risk of Ischaemic Stroke: The NHLBI Exome Sequence Project. JAMA Neurol 2015; 72: 781-788.
    CrossrefPubMedSearch in Google Scholar
  • 9 Adams HP, Bendixen BH, Kappelle 3rd LJ. et al. Classification of subtype of acute ischaemic stroke: definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24: 35-41.
    CrossrefPubMedSearch in Google Scholar
  • 10 Anderson CA, Pettersson FH, Clarke GM. et al. Data quality control in genetic case-control association studies. Nat Protoc 2010; 05: 1564-1573.
    CrossrefPubMedSearch in Google Scholar
  • 11 Adams DR, Sincan M, Fuentes Fajardo K. et al. Analysis of DNA sequence variants detected by high-throughput sequencing. HumMutat 2012; 33: 599-608.
    PubMedSearch in Google Scholar
  • 12 Mercader JM, Saus E, Agüera Z. et al. Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophinsignaling pathway in eating disorders. Hum Mol Genet 2008; 17: 1234-1244.
    CrossrefPubMedSearch in Google Scholar
  • 13 Adzhubei IA, Schmidt S, Peshkin L. et al. A method and server for predicting damaging missense mutations. Nat Methods 2010; 07: 248-249.
    CrossrefPubMedSearch in Google Scholar
  • 14 Ichida F. Left ventricular noncompaction. Circ J 2009; 73: 19-26.
    CrossrefPubMedSearch in Google Scholar
  • 15 Moric-Janiszewska E. Markiewicz-Łoskot G. Genetic heterogeneity of left-ventricular noncompaction cardiomyopathy. Clin Cardiol 2008; 31: 201-204.
    CrossrefPubMedSearch in Google Scholar
  • 16 Fernandez-Cadenas I, Andreu AL, Gamez J. et al. Splicing mosaic of the myop-hosphorylase gene due to a silent mutation in McArdle disease. Neurology 2003; 61: 1432-1434.
    CrossrefPubMedSearch in Google Scholar
  • 17 Cole JW, Stine OC, Liu X. et al. Rare variants in ischaemic stroke: an exome pilot study. PLoS One 2012; 07: e35591.
    CrossrefPubMedSearch in Google Scholar
  • 18 Lin H, Sinner MF, Brody JA. et al. CHARGE Atrial Fibrillation Working Group. Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study. Heart Rhythm 2014; 11: 452-457.
    CrossrefPubMedSearch in Google Scholar
  • 19 Thodeti CK, Paruchuri S, Meszaros JG. A TRP to cardiac fibroblast differentiation. Channels 2013; 07: 211-214.
    CrossrefPubMedSearch in Google Scholar
  • 20 Nakayama H, Wilkin BJ, Bodi I. et al. Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart. FASEB J 2006; 20: 1660-1670.
    CrossrefPubMedSearch in Google Scholar
  • 21 Onohara N, Nishida M, Inoue R. et al. TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. EMBO J 2006; 25: 5305-5316.
    CrossrefPubMedSearch in Google Scholar
  • 22 Greiser M, Lederer WJ. Schotten U. Alterations of atrial Ca(2+) handling as cause and consequence of atrial fibrillation. Cardiovasc Res 2011; 89: 722-733.
    CrossrefPubMedSearch in Google Scholar
  • 23 Earley S, Heppner TJ, Nelson MT. et al. TRPV4 forms a novel Ca2+ signaling complex with ryanodine receptors and BKCa channels. Circ Res 2005; 97: 1270-1279.
    CrossrefPubMedSearch in Google Scholar