Advances in Stroke 2008

2008 has brought us the first fruits from genomewide association studies (GWASs), an unbiased and comprehensive approach to identify common risk alleles for complex diseases of adulthood. By genotyping 310 000 single nucleotide polymorphisms (SNPs) in over 1700 intracranial aneurysm (IA) cases and 7400 controls from Finland and the Netherlands, a multinational team of investigators recently identified several common SNPs that showed significant association with IA.1 SNPs on chromosomes 2q, 8q and 9p were found to replicate in an independent sample from Japan with similar odds ratios (OR) in all 3 samples. Pooled OR were between 1.24 and 1.36, and analyses of the combined effects suggested a significant linear relationship with risk score in each cohort, with a more than 3-fold increase from the lowest to highest strata. Collectively, the 3 loci were calculated to account for 38% to 46% of the population– attributable fraction of IA, which is substantial. Although additional work in other ethnic groups is required, the consistency emphasizes the robustness of the findings. The critical genetic intervals on chromosomes 8q and 9p both harbor genes that are implicated in the regulation of stem (progenitor) cell populations and expressed in the adult vasculature. SOX17, the main candidate gene on 8q, is required for both endothelial formation and maintenance—an interesting aspect when considering the predominant location of IA at arterial branch points and sites of endothelial shear stress. The association between common variants at 9p and IA had already been reported in another study earlier last year.2 The 9p21.3 region was originally identified as a major risk locus for coronary artery disease and myocardial infarction.3 Subsequent analyses revealed that the same chromosomal region is also implicated in the risk of IA and abdominal aortic aneurysms. The estimated risk for IA conferred by the main risk allele (rs10757278-G) was very similar across sample sets from Iceland, Finland, and the Netherlands and comparable to that for abdominal aortic aneurysms and coronary artery disease. Moreover, the risk for abdominal aortic aneurysms and IA was found to be independent of the risk for coronary artery disease, thus indicating a broader role of the 9p21.3 region in arterial disease.2 Extending these findings, investigators of the international stroke genetics consortium recently demonstrated associations between several SNPs in the 9p21.3 region and large artery stroke.4 The study included 4376 ischemic stroke patients, 970 of whom were classified as having large artery stroke. ORs for the lead SNP (rs1537378-C) were remarkably consistent across populations from different geographical regions and ethnic backgrounds (pooled OR 1.21). In contrast, no associations were found with other etiologic stroke subtypes, thus stressing the specific impact of the 9p21.3 region on large artery disease. The estimate for the population–attributable fraction was 20%, which renders the 9p21.3 region a major locus for large artery stroke. The influence of the 9p21.3 region on risk of vascular disease seems to be independent of conventional vascular risk factors. This would suggest that we are dealing with an entirely new risk factor for various arterial phenotypes.2,4 There is some indication that the effects of 9p21.3 are mediated through vascular remodeling. However, additional studies are needed to disentangle the mechanisms leading to such diverse arterial phenotypes. The next challenge now is to identify the responsible genes and associated mechanisms. Positional candidates include CDKN2B (encoding p15), CDKN2A (encoding p16, and ARF) and ANRIL (a nonprotein-coding transcript), all of which are expressed in the vasculature. Of interest, p16 like SOX17 has been shown to be implicated in the regulation of stem (progenitor) cells.5 Another important finding has been the identification of risk variants for ischemic stroke on chromosome 4q25. Investigators from Iceland, Germany, Sweden and the United Kingdom recently reported a multistage GWAS including 6222 ischemic stroke patients and 29 474 controls. A single SNP (rs2200733-T) on chromosome 4q25 was significantly associated with cardioembolic stroke in various European populations. Again, ORs were remarkably similar between samples, the combined OR being 1.52 (P 5.8 10 ).6 The same variant has previously been associated with atrial fibrillation,7 which suggests that the risk of stroke is mediated through atrial fibrillation, although this was not specifically addressed in the study by Gretarsdottir et al. Of interest, rs2200733-T was also associated with ischemic stroke not classified as cardioembolic stroke (combined