(Stroke. 2005;36:1852.)
© 2005 American Heart Association, Inc.
Original Contributions |
Editorial Comment—Are We in Another Unavoidable ‘Diagnose and Adios’ Era?
Associate Professor of Neurology, Chief, Stroke Section, Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan Medical College, Chang Gun University, Taiwan
Assistant Professor of Neurology, Department of Neurology, Chang Gung Memorial Hospital Kaohsiung,, Taiwan Medical College, Chang Gung University, Taiwan
Key Words: genetics • stroke management • treatment outcome
None of us in stroke management regret the passage of the "diagnose and adios" era, humorously criticized earlier. We know well that opportunities for stroke management are arising for more definitive studies. A revolution in imaging, the rush to apply results from clinical trials, and attempts to shorten the time frame for action are daily practice because neurologists are interventionists similar to their colleagues in cardiology and emergency medicine.1 However, with the pace of accumulated data from leisurely approached genetic association studies, we confront the issue of hereditary risk factors.
In this issue of Stroke, Howard et al2 report on a well-organized, population-based study in 15- to 44-year-old women. Among the 5 nitric oxide synthase (NOS)3 polymorphisms in 110 cases (46% black) with ischemic stroke and 206 controls (38% black) who were recruited over 4 years, these investigators found that the –922 G/A and –786 T/C polymorphisms may be associated with ischemic stroke susceptibility among young black women. Although the small sample size precluded extensive analysis, this study highlights the importance of genetic studies of stroke at a young age in different ethnic groups.
Genetic factors may play a role in cerebral vascular disease and may act via endothelial dysfunction, predominantly in the young. NO synthesized by endothelial NOS is a key mediator of endothelial function, and it could be a candidate gene for stroke. The NOS3 intron 4ab insertion/deletion genotype, but not the –786 T/C or the G894T genotype, was reported to be associated with isolated lacunar infarction in an English study3 but not a Japanese study.4 The NOS3 exon 7 polymorphism (G894T) was reported to not be associated with stroke and transient ischemic attack or the degree of carotid stenosis in patients with cerebrovascular disease.5–7 The aforementioned results show that the association between the NOS gene and ischemic stroke is controversial and that there is a possible positive association between the NOS3 intron 4ab insertion/deletion genotype and small-vessel disease in white populations or a possible negative association in other ethnicities.
It is known that the etiology of ischemic stroke in the young is heterogeneous and diverse and that there might be racial differences.8 Previous reports regarding ischemic stroke in the young showed that blacks, unlike whites, more commonly had the stroke subtype of small-vessel occlusion than large-artery atherosclerosis and that strokes due to other determined and undetermined causes occurred in more than half of young stroke patients in most studies.8–11 The finding that the –922 G/A and –786 T/C polymorphisms may be associated with ischemic stroke susceptibility among young black women should be confirmed in a large, international, cooperative study. The population-based study design of Howard et al2 yielded important information, but the phenotype approach to the study of stroke, as designed by Hassan et al,3 might provide other useful data. Before international cooperative studies are organized, several methodologic problems need to be solved.
We earnestly agree that those studies, which described lacunar infarcts beyond Fisher’s early observations, had methodological limitations: sample sizes were generally small; risk factors were inconsistently defined; and studies used a variety of classification methods to define ischemic stroke subtypes.12 Attempts to refine the stroke subtype classification are worth anticipating.13 However, efforts to define reproducible subtype classifications of lacunar infarcts or small-vessel occlusion are mandatory for future gene association studies.
Next, the study sample size must be carefully calculated. A small sample size may preclude assessment of any genetic association by stroke subtype, race, or sex and may limit the power of detecting interactions among common risk factors for stroke. Even more, partial digestion might be common in restriction fragment length polymorphism studies; although results of 0% for rare alleles might indicate a very low frequency, they might still exist in the population. Furthermore, conclusions drawn from such "nonexistent" alleles may be misleading. At present, a large, multiethnic, population-based study to explore differences in genetics by association studies might not be feasible because the parameters to generate hypotheses are lacking. We need more high-quality genetic descriptions from stroke-prone areas of persons with early-onset stroke, such as Asia, Russia, and Africa, with different environmental exposures and different non-NOS3 genetic backgrounds.
We agree that genetics has revolutionized neurologic research. Ironically, however, it is not known how many single-nucleotide polymorphisms would be sufficient for such a project. Genetic studies are time consuming and costly, not to mention the pricey proteomics methods afterward. Genomics might be more appealing for winning grants at universities, an approach that may be useful to the faculty to popularize study proposals but that may not have sufficient power to determine whether a true functional polymorphism exists, let alone a correlation between the polymorphism and patient outcomes.
The results of Howard et al, although inconclusive, point out the many challenges of genetic studies in ethnically different populations. With more understanding of these genetic differences that are not yet modifiable, we may be caught in another unavoidable "diagnose and adios" era.
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Related Article:
- Promoter Polymorphisms in the Nitric Oxide Synthase 3 Gene Are Associated With Ischemic Stroke Susceptibility in Young Black Women
- Timothy D. Howard, Wayne H. Giles, Jianfeng Xu, Marcella A. Wozniak, Ann M. Malarcher, Leslie A. Lange, Richard F. Macko, Monica J. Basehore, Deborah A. Meyers, John W. Cole, and Steven J. Kittner
Stroke 2005 36: 1848-1851.[Abstract] [Full Text] [PDF]
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