Modelling Feasibility of Genetic Approaches to Human Stroke
Background Twin, population and animal studies suggest that genetic factors are important in stroke. To date all research in humans has used case control (CC) methods to determine association between candidate genes and stroke. Alternative approaches include linkage analysis with the advantage of allowing detection of novel genes and transmission disequilibrium testing, which uses internal family controls e.g.parents(TDT) or unaffected sibs (S-TDT)to reduce the risk of population stratification which is a problem in case control studies. Despite theoretical benefits, the feasiblity of these methods remains unknown. Methods Family history was prospectively determined in 727 consecutive cerebrovascular patients and 623 age matched controls. Patients with suspected Mendelian syndromes were excluded. Parent and sibling status (alive or dead and the presence of stroke)was documented. The data was used to model the number of stroke patients required for the different study designs. Results Family history of young stroke (≤65)was an independent risk factor for ischaemic stroke OR 1.45 (95% CI 1.01–2.09) p=0.05, early onset proband stroke (≤65) OR 2.22(1.42–3.50)p=0.0005 and stroke due to large vessel disease OR 1.75 (1.09–2.83) p=0.02. In the age group <65 (n=305), 14 affected sibs, 19 parent offspring trios and 626 discordant sibling pairs were identified. The adjusted sibling relative risk ratio was estimated to be 1.78. If 3 genetic loci play an important role in stroke, this translates into 1000 affected sibling pairs being required for an affected sib pair linkage study. Over 100 000 patients would require screening based on a 50% recruitment rate in relatives. For candidate gene studies, assuming an odds ratio of 2 and allele frequency of 0.1, 986 (CC),31681 (TDT) and 3635 (S-TDT) patients would need to be screened to achieve the necessary sample sizes. Conclusion This study supports the role of independent genetic risk factors in stroke which have greater influence in young individuals. Novel approaches are potentially feasible, although linkage studies and TDT would require large scale multicentre collaborations.