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Neurology India
Medknow Publications on behalf of the Neurological Society of India
ISSN: 0028-3886 EISSN: 1998-4022
Vol. 54, Num. 4, 2006, pp. 348-349

Neurology India, Vol. 54, No. 4, October-December, 2006, pp. 348-349

Invited Commentaries

Genetic risk determinants in stroke: A global task

Laboratory of Genetic and Molecular Epidemiology, The Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215
Correspondence Address:Laboratory of Genetic and Molecular Epidemiology, The Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215,

Code Number: ni06121

Thromboembolic disorders including stroke are common, complex diseases, each of which under the influence of a variety of genetic and environmental risk factors. Complex genetic traits do not demonstrate classical Mendelian patterns of inheritance for many reasons. In complex traits, multiple genes may each exert a relatively modest influence and genes influencing complex traits typically show incomplete penetrance. There may be interactions between genes (epistasis), complicating the ability to associate any particular genetic variant with the trait of interest. Gene-environment interactions further complicate the analysis of complex genetic traits.

It has been widely thought that, with the new insights gained from the Human Genome Project and the Hap-Map consortium, scientists will be able to identify the genetic risk markers responsible for complex or polygenic disorders such as stroke. However, the success/progress in identifying these potential risk or causative genetic markers and translating the information obtained into clinical practice for patients' benefits has been relatively slow.

Genetic association studies are widely used for identifying genetic variants in complex diseases.[1] These studies fall into two broad categories: candidate gene approach and whole genome scan. The former requires a priori knowledge of biological relevance of the gene(s) with the trait of interest while the latter makes no such assumptions. An increasing body of evidence suggests that inflammatory responses and low-grade systemic infection play an important role in the pathogenesis of neurodegenerative disorders.[2] It has also been shown that atherosclerotic lesions contain inflammatory cells and cytokines, such as the interleukins, as dominant players.[2]

In this issue of Neurology India, Lai and coauthors[3] conducted a candidate-gene association study evaluating the relationship of an interleukin 1 receptor antagonist VNTR polymorphism and an interleukin 1 beta -511C>T polymorphism with risk of ischaemic stroke in a Chinese population. Their study has shown an association of the IL1RN VNTR polymorphism, but not the IL1B -511C>T polymorphism with ischaemic stroke. Despite the intriguing nature of these findings, positive results from genetic association studies should be interpreted with caution. Epidemiological limitations, including inadequate sample size, failure to ensure that affected and unaffected subjects are from the same background-source population, over-interpretation of data, over-reliance on post-hoc subgroup analyses and ignoring the issue of multiple testing, can lead to spurious findings.[4] As correctly pointed out by Lai and coauthors in their article,[3] replication/confirmation of genetic association studies in other (well-designed, adequately-powered) studies is an important component to further our understanding of the genetic contribution in stroke. The article by Lai and coauthors also serves as a remainder to the scientific community that a concerted, global approach in examining and identifying genetic risk determinants for the pathogenesis of stroke across all ethnicities[5] is much needed.


1.Cordell HJ, Clayton DG. Genetic association studies. Lancet 2005;366:1121-31.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Emsley HC, Tyrrell PJ. Inflammation and infection in clinical stroke. J Cereb Blood Flow Metab 2002;22:1399-419.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Lai J, Zhou D, Xia S, Shang Y, Zhu J, Pan J, et al . Association of interleukin-1 gene cluster polymorphisms with ischemic stroke in a Chinese population. Neurol India 2006;54:367-9  Back to cited text no. 3    
4.Hattersley AT, McCarthy MI. What makes a good genetic association study? Lancet 2005;366:1315-23.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Little J, Bradley L, Bray MS, Clyne M, Dorman J, Ellsworth DL, et al . Reporting, appraising and integrating data on genotype prevalence and gene-disease associations. Am J Epidemiol 2002;156:300-10.  Back to cited text no. 5    

Copyright 2006 - Neurology India

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