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Objective: Mixed results have been reported of matrix metalloproteinases (MMP) and their association with restenosis after percutaneous coronary intervention (PCI). The current study examines whether multiple single nucleotide polymorphisms (SNPs), covering the full genomic region of MMP2 and MMP3, were associated with restenosis in the GENDER study population. Methods and results: The GENetic DEterminants of Restenosis (GENDER) study enrolled 3104 consecutive patients after successful PCI. The primary endpoint was clinical restenosis, defined as target vessel revascularization (TVR), occurring in 9.8% of the patients. From the Hapmap database, 19 polymorphisms of MMP2 and 11 of MMP3 were selected. Furthermore, in a subpopulation, a genome-wide association analysis (GWA) was performed. No significant association was found with any of the investigated SNPs, including the previously reported 5A/6A polymorphism (rs3025058), with regard to TVR using single SNP analysis or haplotype analysis. Conclusion: We found no significant association of MMP2 or MMP3 with TVR with this SNP-broad gene approach. Although we did not test all the known polymorphisms of these genes, using tagging analyses we examined those SNPs covering all known haplotypes of MMP2 and MMP3 to conclude that these genes do not correlate with a genetic risk of coronary restenosis after successful PCI. [ABSTRACT FROM AUTHOR]

Proinflammatory cytokines, like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), are implicated in the development of atherosclerosis. The role of anti-inflammatory cytokines, like IL-10, is largely unknown. We investigated the association of four single nucleotide polymorphisms (SNPs) in the promoter region of the IL-10 gene (4259AG, −1082GA, −592CA, and −2849GA), with coronary and cerebrovascular disease in participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. All associations were assessed with Cox proportional hazards models adjusted for sex, age, pravastatin use, and country. Haplotype analysis of the four SNPs showed a significant association between haplotype 4 (containing the −592A variant allele) and risk of coronary events ( P= 0.019). Moreover, analysis of separate SNPs found a significant association between −2849AA carriers with incident stroke (HR (95%CI) 1.50 (1.04–2.17), P value = 0.02). Our study suggests that not only proinflammatory processes contribute to atherosclerosis, but that also anti-inflammatory cytokines may play an important role. [ABSTRACT FROM AUTHOR]

Genetic factors appear to be important in the process of restenosis after percutaneous coronary intervention (PCI), as well as in inflammation, a pivotal factor in restenosis. An important mediator in the inflammatory response is interleukin (IL)-10. Our aim was to study whether genetic variants in IL-10 predispose to the risk of restenosis. The GENetic DEterminants of Restenosis (GENDER) study included 3104 patients treated with successful PCI. Target vessel revascularization (TVR) was chosen as primary end point. Genotyping of the −2849G/A, −1082G/A, −592C/A and +4259A/G polymorphisms of the IL-10 gene was performed by MassArray platform. After adjusting for clinical variables, three polymorphisms significantly increased the risk of restenosis (−2849AA: relative risk (RR), 1.7, 95% confidence interval (CI), 1.2–2.5; −1082AA: RR, 1.4, 95% CI, 1.1–1.8 and +4259GG: RR, 2.0, 95% CI, 1.4–2.8). To further exclude possible involvement of neighboring genes due to LD in the IL-10 locus, additional polymorphisms were genotyped. The results reveal that association of the IL-10 gene with restenosis is independent of flanking genes. Our findings demonstrate that IL-10 is associated with restenosis and therefore support the hypothesis that anti-inflammatory genes also may be involved in developing restenosis. Furthermore, they may provide a new targeting gene for drug-eluting stents.Genes and Immunity (2007) 8, 44–50. doi:10.1038/sj.gene.6364343; published online 23 November 2006 [ABSTRACT FROM AUTHOR]

Abstract: Research into the pathologic mechanisms of neurodegenerative diseases has revealed that CREB binding protein (CBP) plays an important role in cognitive dysfunction. Loss of one copy of this gene leads to a syndrome with severe cognitive dysfunction. We investigated the association between four common variants in the CBP gene and cognitive function in 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Baseline associations between genetic variation and cognitive function were assessed with linear regression. Longitudinal associations were assessed with linear mixed models. All analyses were adjusted for sex, age, education, country, version of test, and pravastatin use. The intron 4CT and intron 3AC polymorphisms in the CBP gene were associated with better cognitive performance at baseline and during follow-up. Furthermore, the haplotype with the variant alleles of these two polymorphisms also showed a protective effect on cognitive function in all cognitive domains (all p <0.03). Genetic variation in the CBP gene is associated with better cognitive performance in an elderly population. Future research is necessary to investigate the effect of these polymorphisms on the expression of CBP levels and how these polymorphisms affect the gene expression mediated by CBP. [Copyright &y& Elsevier]