Published online before print July 3, 2003, doi: 10.1161/01.STR.0000079816.60008.73
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(Stroke. 2003;34:1869.)
© 2003 American Heart Association, Inc.
Original Contributions |
Editorial Comment—How to Search for the Role of Genetic Polymorphisms in Stroke: Theory Versus Practice
Neurological Section, SMDN-Center for Cardiovascular Medicine and Cerebrovascular Disease Prevention, Sulmona, L’Aquila, Italy
In this issue of the Stroke, Acalovschi and colleagues1 furnish new evidence on the hot topic of inflammatory response after stroke and its regulatory mechanisms, pointing our attention to the interleukin-6 (IL-6) genetic polymorphisms. In the last years, part of this picture has been discovered, but many issues remain to be explored. It is very clear that ischemic stroke is a multifactorial and dynamic process.2 However, not all questions are answered. We should search for the origin of the acute-phase response after stroke; so far, no hypothesis on the source of inflammation has been proved. We should search for the reasons for a strong association between inflammatory markers and prognosis.3 We should search for anti-inflammatory therapies; these therapies, if effective, could prove definitely the pathogenic role of inflammation in acute ischemic stroke.4 These points represent a rich task for future exploration, but will answering these questions shed light on all problems? For example, why do some patients have a marked inflammatory response after stroke and others do not? The degree of inflammatory response to ischemic stroke is variable: 
25% of patients with ischemic stroke have normal levels of inflammatory markers after stroke, implying that ischemic stroke itself does not induce a full-blown acute-phase response.3,5
To respond to these questions, Acalovschi et al1 analyze the IL-6 system and the acute-phase response after stroke, showing that there is a genetically determined difference in the degree of IL-6 response to stroke between individuals. The immune haplotype A-G-8/12-C was associated with lower levels of IL-6 after stroke and with a reduced induction of stimulated IL-6 transcription in human astrocytoma cells. However, they did not find any differences, as we could have been expected, in the acute-phase response when comparing different haplotypes, as suggested by levels of C-reactive protein, an IL-6 hepatic induced acute-phase reactant. What can we learn from such a study?
The answer lies at many levels and ultimately may point to the futility of our present approach to the genetics of complex disorders. We have much work to do before we will know how to apply these data in practice. It is clear that genes do not commonly operate in isolation from the environment in the development of complex multifactorial disorders. This being so, it is possible that all genetic markers are either neutral or relatively protective in the absence of an environmental influence, and studies clearly need to take this in account. Furthermore, the response to environmental factors is variable among individuals, and we need to identify the genes and alleles that show variations in response to pattern.
The phenotype of ischemic stroke is incredibly complex, with variable environmental interactions. In the candidate gene philosophy approach, some genes are more important than others. This view is difficult to sustain, and we may need to study dozens of genes and hundreds of polymorphisms. For IL-6, in which there is wide interindividual variation in levels, and despite convincing evidence of a significant heritable component, the currently identified polymorphisms account for a very limited proportion of this variation.6 It is therefore highly unlikely that a polymorphic variant accounting for such a relatively small variation in levels would be related to disease.7 Additionally, any polymorphisms identified within the genes encoding these proteins may interact to either augment or attenuate the influence of another, thereby confounding the difficulty in interpretation of the results of gene-disease associations.8 One clear solution to this is to account for the total genetic variance in the gene of interest by evaluation of all polymorphic variants and to analyze the association of common haplotypes with plasma levels and presence of disease. An additional important factor to consider is that we tend to focus on proteins that contribute to inflammation and forget that there are many that module inflammatory response. An enhanced inflammatory response might also depend on the failure to turn off inflammation when it is no longer useful to the organism. Therefore, genetic variation in all of the genes encoding these proteins and the proteins involved in their regulation may influence an individual’s inflammatory response. In this context, the inability to identify significant and consistent genetic contribution of 1 genotype in particular reflects the underlying genetic complex.
Stroke prognosis is a clearly modifiable, and although a single polymorphism or cluster of polymorphisms within a single candidate gene will not be particularly informative in determining the overall risk, analysis of the functional effects of polymorphisms will provide invaluable information regarding protein function and regulation. This information is likely to be fundamental in identification of novel targets for the development of new agents. In addition, knowledge of an individual’s genetic profile may help in defining individual drug regimens to elicit maximum therapeutic benefits. Finally, we should begin to turn our attention toward the transcriptional regulation for factors that regulate the whole system rather than just individual proteins. Careful clinical identification of very homogeneous subgroups of patients according to their history, risk factors, and inflammation markers will be the first step of this search. The amount of inflammatory response produced after stroke may represent a further marker of individual susceptibility. Once the profile of the patients is drawn, the causes, genetic or acquired, of the hyperresponsiveness can be sought. We should continue our work in this area with optimism but use genetic markers as tools for investigation rather than as the answer in itself. We must develop better skills in postgenomic functional analysis of polymorphisms to inform us as to how we can better understand the systems we study and to develop novel therapeutics and markers for therapeutic responses. Finally, we should approach molecular epidemiology in this area with caution, understanding the many pitfalls that lie in the path of attempting to nail a single polymorphism to this complex disorders. Only international, multicenter, prospective, well-designed studies will provide the currently lacking information and will gradually improve our knowledge in the field before implementing the use of genetic polymorphisms in the stroke medicine daily practice.
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- Acalovschi D, Wiest T, Hartmann M, Farahmi M, Mansmann U, Auffarth GU, Grau AJ, Green FR, Grond-Ginsbach C, Schwaninger M. Multiple levels of regulation of the interleukin-6 system in stroke. Stroke. 2003; 34: 1864–1870.
[Abstract/Free Full Text] - Boysen G, Christensen H. Early stroke: a dynamic process. Stroke. 2001; 32: 2423–2425.
[Free Full Text] - Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke. 2001; 32: 917–924.
[Abstract/Free Full Text] - Di Napoli M, Papa F. Inflammation, hemostatic markers and antithrombotic agents in relations to long-term risk of new cardiovascular events in first-ever ischemic stroke patients. Stroke. 2002; 33: 1763–1771.
[Abstract/Free Full Text] - Di Napoli M, Papa F, Bocola V. Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke. 2001; 32: 133–138.
[Abstract/Free Full Text] - Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem. 2000; 275: 18138–18144.
[Abstract/Free Full Text] - Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P. The effect of novel polymorphisms in the interleukin (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998; 102: 1369–1376.[Medline] [Order article via Infotrieve]
- Pola R, Flex A, Gaetani E, Flore R, Serricchio M, Pola P. Synergistic effect of -174 G/C polymorphism of the interleukin-6 gene promoter and 469 E/K polymorphism of the intercellular adhesion molecule-1 gene in Italian patients with history of ischemic stroke. Stroke. 2003; 34: 881–885.
[Abstract/Free Full Text]
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