Clinical Commentary APOE and AGT in the Finnish p.Arg133Cys CADASIL population Siitonen M, Mykk€anen K, Pescini F, Rovio S, K€a€ari€ainen H, Baumann M, P€ oyh€ onen M, Viitanen M. APOE and AGT in the Finnish p.Arg133Cys CADASIL population. Acta Neurol Scand 2015: 132: 430–434. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – CADASIL is an inherited systemic small vessel disease, the affected status of brain vessels leading to subcortical vascular dementia. The defective gene is NOTCH3 in which over 230 different pathogenic mutations have been identified. The clinical course of CADASIL is highly variable even within families. Previous studies have shown that additional genetic factors modify the phenotype. Aims and methods – Altogether, 134 Finnish CADASIL patients with p.Arg133Cys mutation were analysed for possible associations between the apolipoprotein E (APOE) genotype, angiotensinogen (AGT) p.Met268Thr polymorphism or neutral p.Ala202Ala NOTCH3 polymorphism and earlier first-ever stroke or migraine. Results – We found no association between the APOE genotypes, AGT polymorphism, NOTCH3 polymorphism and earlier first-ever stroke or migraine. Conclusions – The APOE, AGT and NOTCH3 polymorphism did not modify the onset of strokes or migraine in our CADASIL sample, which is one of the largest mutationally homogenous CADASIL populations published to date. International collaboration, pooled analyses and genomewide approaches are warranted to identify the genetic factors that modify the highly variable CADASIL phenotype. M. Siitonen 1,2 , K. Mykk€anen 1 , F. Pescini 3 , S. Rovio 4 , H. K€a€ari€ainen 5 , M. Baumann 6 , M. P€oyh€onen 7, *, M. Viitanen 8,9, * 1 Department of Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku, Turku, Finland; 2 Department of Medical Genetics, University of Helsinki, Helsinki, Finland; 3 Stroke Unit and Neurology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy; 4 Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku,Turku, Finland; 5 National Institute for Health and Welfare, Helsinki, Finland; 6 Protein Chemistry Unit, Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland; 7 Department of Clinical Genetics, HUSLAB Helsinki University Central Hospital and Department of Medical Genetics, University of Helsinki, Helsinki, Finland; 8 Department of Geriatrics, Turku City Hospital and University of Turku, Turku, Finland; 9 Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden Key words: genotype–phenotype correlation; founder effect; association study; CADASIL; NOTCH3; APOE; AGT M. Siitonen, Institute of Biomedicine, Department of Medical Biochemistry and Genetics, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland Tel.: +358 2333 7456 Fax: +358 2230 1280 e-mail: maija.siitonen@utu.fi *Shared senior authorship. Accepted for publication March 4, 2015 Introduction Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited systemic small vessel disease with characteristic, although variable, clinical features [e.g. transient ischaemic attacks (TIA), strokes, migrainous headache, progressive cognitive decline leading finally to dementia of subcortical vascular type and psychiatric symp- toms]. In magnetic resonance imaging (MRI), typical white matter alterations are common (1). The vascular pathology in the central nervous system is characterized by – CADASIL-specific – electron-dense deposits of granular osmiophilic material (GOM) in close vicinity of vascular smooth muscle cells (VSMCs) with subsequent degeneration of the VSMCs and marked fibrosis and stenosis most prominent in the cerebral white matter (WM) arterioles, which together give rise to extensive leukoaraiosis and multiple lacunar infarcts (1). CADASIL is diagnosed by demon- stration of GOM in a skin biopsy (2) or by genetic verification of a pathogenic mutation in the NOTCH3 gene, located on 19p13.1 (1). A vast majority of over 230 mutations responsible 430 Acta Neurol Scand 2015: 132: 430–434 DOI: 10.1111/ane.12400 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA