Genetic risk factors for cerebral small-vessel disease in hypertensive patients from a genetically isolated population
- M Schuur1,2,
- J C van Swieten2,
- S Schol-Gelok1,
- M A Ikram1,
- M W Vernooij1,3,
- F Liu1,
- A Isaacs1,
- R de Boer1,4,
- I de Koning2,
- W J Niessen3,4,5,
- H Vrooman4,
- B A Oostra6,
- A van der Lugt3,
- M M B Breteler1,
- C M van Duijn1
- 1Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- 2Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- 3Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands
- 4Biomedical Imaging Group Rotterdam, Departments of Radiology and Medical Informatics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- 5Faculty of Applied Sciences, Delft University of Technology, Delft, The Netherlands
- 6Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- Correspondence to Professor Cornelia M van Duijn, Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands; c.vanduijn{at}erasmusmc.nl
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Contributors MS conceived and designed the research, analysed and interpreted the data, performed statistical analysis, and drafted the manuscript. JCS conceived and designed the research, handled funding and supervision, and made critical revision of the important intellectual content. SS-G conceived and designed the research, and made critical revision of the important intellectual content. MAI conceived the research, analysed and interpreted the data, and made critical revision of the important intellectual content. MWV conceived the research, analysed and interpreted the data, and made critical revision of the important intellectual content. AI analysed and interpreted the data and made critical revision of the important intellectual content. FL analysed and interpreted the data, and made critical revision of the important intellectual content. RB analysed and interpreted the data, and made critical revision of the important intellectual content. IK conceived and designed the research, handled funding and supervision, and made critical revision of the important intellectual content. WJN handled supervision and made critical revision of the important intellectual content. HAV handled supervision and made critical revision of the important intellectual content. BAO conceived and designed the research, handled funding and supervision, and made critical revision of the important intellectual content. AL conceived and designed the research, analysed and interpreted the data, handled funding and supervision, and made critical revision of the important intellectual content. MMBB conceived and designed the research, analysed and interpreted the data, handled funding and supervision, and made critical revision of the important intellectual content .CMD conceived and designed the research, analysed and interpreted the data, handled funding and supervision, drafted the manuscript, and made critical revision of the important intellectual content.
- Received 27 February 2009
- Revised 22 July 2009
- Accepted 23 July 2009
- Published Online First 28 July 2010
Abstract
Background Asymptomatic cerebral lesions on MRI such as white matter lesions (WML), lacunes and microbleeds are commonly seen in older people. We examined the role of a series of candidate genes involved in blood pressure regulation and amyloid metabolism.
Materials and Methods The study was embedded in a family-based cohort sampled from a Dutch genetically isolated population. We selected individuals between 55 and 75 years of age with hypertension (N=129). Volumes of WML and presence of lacunes and microbleeds were assessed with MRI. We studied three genes involved in blood pressure regulation (angiotensin, angiotensin II type 1 receptor, α-adducin) and two genes involved in the amyloid pathway (apolipoprotein E (APOE) and sortilin-related receptor gene (SORL1)).
Results All participants had WML (median volume, 3.1 ml; interquartile range, 1.5–6.5 ml); lacunar infarcts were present in 15.5% and microbleeds in 23.3%. Homozygosity for the APOE ε4 allele was associated with lacunes (OR, 4.8; 95% CI, 1.2 to 19.3). Individuals carrying two copies of the variant allele of four single nucleotide polymorphism (SNPs) located at the 3′-end of SORL1 (rs1699102, rs3824968, rs2282649, rs1010159) had significantly more often microbleeds (highest OR, 6.87; 95% CI, 1.78 to 26.44).
Conclusion The association of SORL1 with microbleeds suggests that the amyloid cascade is involved in the aetiology of microbleeds in populations with hypertension.
Footnotes
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Funding This study is financially supported by the Netherlands Organization for Scientific Research (NWO), the Internationale Stichting Alzheimer Onderzoek (ISAO), the Hersenstichting Nederland (HSN) and the Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI).
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Competing interests None.
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Ethics approval The study was approved by the Medical Ethics Committee at Erasmus MC University Medical Center Rotterdam.
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Provenance and peer review Not commissioned; externally peer reviewed.
