
Vol. 19, No. 1, 2005
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Review Paper
Potential Confounding by Intermediate Phenotypes in Studies of the Genetics of Ischaemic Stroke
Enrico Flossmann, Ursula G.R. Schulz, Peter M. Rothwell
Stroke Prevention Research Unit, University Department of Clinical Neurology, Radcliffe Infirmary, Oxford, UK
Address of Corresponding Author
Cerebrovasc Dis 2005;19:1-10 (DOI: 10.1159/000081905)
Key Words
- Ischaemic stroke
- Hypertension
- Diabetes mellitus
- Ischaemic heart disease
Abstract
Background: Family history (FHx) of stroke is perceived to be an important risk factor for ischaemic stroke. However, there are several intermediate phenotypes that are often involved in the aetiology of ischaemic stroke and that have a substantial genetic component themselves. We studied FHx of ischaemic heart disease (IHD), hypertension (HTN) and diabetes mellitus (DM) as risk factors for ischaemic stroke. Methods: We performed a systematic review of case-control and cohort studies reporting on FHxIHD, FHxHTN or FHxDM as risk factors for stroke using bibliographic databases, and by hand searching reference lists and journals. Odds ratios of FHx as a risk factor for stroke were calculated within individual studies. We included unpublished data from two Oxfordshire population-based studies to assess effects on subtypes of ischaemic stroke. Results: We identified 54 studies that investigated the odds of stroke conferred by a positive FHx, 24 of which reported data on FHx of one or more intermediate phenotypes in addition to FHx of stroke. Most studies reported an increased frequency of FHxIHD and FHxHTN in stroke patients versus controls. The association was significant in 6 out of 14 studies for FHxIHD and 4 out of 11 studies for FHxHTN. In contrast, FHxDM was not associated with stroke. FHxIHD was particularly associated with large vessel strokes (OR 1.72, CI 1.3-2.2, p = 0.00004). Conclusions: FHxIHD and FHxHTN are both risk factors for stroke. It is likely that the apparent heritability of stroke is partly accounted for by heritability of HTN and large vessel atherosclerosis. Analyses of heritability of stroke and candidate gene studies should be adjusted accordingly. Copyright © 2005 S. Karger AG, Basel
Author Contacts
Prof. P.M. Rothwell Stroke Prevention Research Unit, Department of Clinical Neurology, Radcliffe Infirmary Woodstock Road Oxford 0X2 6HE (UK) Tel. +44 1865 224237, Fax +44 1865 228572, E-Mail peter.rothwell@clneuro.ox.ac.uk
Article Information
Received: February 27, 2004
Accepted: June 1, 2004
Published online: November 3, 2004
Number of Print Pages : 10
Number of Figures : 2, Number of Tables : 2, Number of References : 80 |
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