Evaluation Of A Multigenic Model Of Stroke Risk In A Prospective Study Of Patients With Type 2 Diabetes: Results From The Go-Darts Study

Background Recently, in a case-control study, we showed that history of ischemic stroke is significantly associated with genetic profiles determined by the combination of single polymorphisms of gene encoding inflammatory molecules ( Flex et al., Stroke 2004; 35: 2270–5). Following this observation, we investigated the influence of this multigenic model on stroke susceptibility in a large population-based prospective study. Methods This is a prospective study of 2,147 individuals with type 2 diabetes. Patients were part of the Go-DARTS Study, which is a sub-population of the large prospective diabetes register known as the DARTS (Diabetes Audit Research in Tayside Scotland) study, a continuously expanding region-wide register of subjects with diabetes containing clinical data on over 97% of patients in the Tayside region of Scotland. The following inflammatory single nucleotide polymorphisms (SNPs) were investigated, using the Taqman-based allelic discrimination assay: IL-6 -174 G/C, MCP-1 A2518G, ICAM-1 E469K, E-selectin Ser128Arg, MMP-3 5A/6A. The end-point of the study was the occurrence of non-fatal or fatal stroke. The mean follow-up was 6.2 years. Results During the period of observation, 108 strokes occurred. When considered alone, none of the investigated gene variants increased the risk for stroke, although the ICAM-1 polymorphism demonstrated a significant association with stroke in smokers (HR 2.6, P=0.02). However, when polymorphisms were evaluated in association, the incidence of stroke increased progressively according to the number of SNPs concomitantly carried by a given individual, from 1.0% in subjects bearing no risk variations to 10.8% in subjects with four pro-inflammatory genotypes. Among these individuals, the risk of developing stroke over the follow-up period exhibited a 13-fold increase compare to that observed in subjects with no risk variations. Conclusions This a large prospective cohort study providing evidence that pro-inflammatory genetic profiles, determined by the concomitant presence of inflammation-associated gene polymorphisms, increase the risk of stroke. This model might be used as template to test the synergistic role of multiple gene variations in the development of cardiovascular diseases.