Mean telomere length and risk of incident venous thromboembolism: a prospective, nested case-control approach.

BACKGROUND: Recent studies have shown telomere-length shortening as a risk predictor for cardiovascular disease. However, to date, no prospective data are available on its potential involvement in venous thromboembolism (VTE). METHODS: Using leukocyte DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the relationship of mean telomere repeat copy number to single gene copy number (T/S ratio), using a modified quantitative polymerase chain reaction protocol, amongst 108 White males who subsequently developed a first ever VTE event and amongst an equal number of age- and smoking-matched White males who remained free of vascular events during follow-up (controls). RESULTS: An inverse correlation between T/S ratios and age was observed in our controls (p=0.04). However, the T/S ratios were similar between cases and controls (p=0.31). Furthermore, in a multi-variable adjusted analysis, we found no evidence for an association of the observed T/S ratios with VTE risk (odds ratio=1.20; 95%CI=0.58-2.52; p=0.62). CONCLUSIONS: The present investigation found no evidence for an association of relative telomere length with risk of incident VTE.

Association of shorter mean telomere length with risk of incident myocardial infarction: a prospective, nested case-control approach.

BACKGROUND: Recent data have implicated telomere length shortening as a potential risk predictor for cardiovascular disease. However, to date, prospective epidemiological data are scarce. METHODS: Using leukocyte DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the relationship of mean telomere repeat copy number to single gene copy number (T/S ratio), using a re-modified quantitative polymerase chain reaction protocol, among 337 white males who subsequently developed an incident myocardial infarction (MI), and among an equal number of age- and smoking-matched white males who remained free of reported vascular disease during follow-up (controls). RESULTS: The mean follow-up time since randomization was 3.85 y. The T/S ratio was inversely correlated with age in the controls (R=-0.114; p=0.036). The log(e)-transformed T/S ratios were significantly smaller in the MI cases (3.41+/-0.63) than the MI controls (3.52+/-0.78) (p=0.01). In a multi-variable adjusted analysis, decreased T/S ratio was significantly associated with risk of MI (odds ratio=1.621; 95%CI=1.140-2.304; p=0.007). CONCLUSIONS: The present investigation has shown an association of telomere length shortening with increased risk of incident myocardial infarction, further suggesting the importance of telomere biology in atherogenesis.

Genetic variants within the interleukin-1 gene cluster, and risk of incident myocardial infarction, and ischemic stroke: a nested case-control approach.

BACKGROUND AND PURPOSE: Recent findings implicating specific gene polymorphisms of the interleukin-1 superfamily gene cluster in the risk of developing athero-thrombotic disorders have generated great interest. However, to date, no prospective, genetic-epidemiological data are available. METHODS: Using DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we evaluated seven gene polymorphisms within the interleukin-1 gene cluster among 599 individuals who subsequently developed athero-thrombotic event and among 599 age- and smoking-matched individuals who remained free of reported cardiovascular disease during follow-up (341 incident myocardial infarction matched case-control pairs and 258 incident ischemic stroke matched case-control pairs). RESULTS: Overall, we observed little evidence of association between the polymorphisms tested and risk of incident athero-thrombotic events. Further adjustment for traditional cardiovascular risk factors yielded similar null findings. Of note, a modest association of rs1143623 with reduced risk of incident MI was found (recessive model: OR=0.455, 95% CI=0.215-0.960, uncorrected p=0.039). However, this finding was not corrected for multiple testing, and thus requires cautious interpretation. CONCLUSION: In contrast to prior retrospective studies, our prospective data suggest that the IL-1 cluster gene variation is not associated with risk of athero-thrombotic disorders.

Purinergic receptor P2Y, G-protein coupled, 12 gene variants and risk of incident ischemic stroke, myocardial infarction, and venous thromboembolism.

Recent data have implicated a haplotype of the purinergic receptor P2Y, G-protein coupled, 12 gene (P2RY12), as potential risk determinant for atherothrombosis. However, to date, no prospective, genetic-epidemiological data are available. Using DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the possible association of P2RY12 genetic variants, in particular a haplotype H2 (constituted by dbSNP rs10935838, rs2046934, rs5853517, and rs6809699) amongst 708 white males who subsequently developed a thromboembolic event (incident myocardial infarction (MI), ischemic stroke, or deep venous thromboembolism/pulmonary embolism (DVT/PE)) and amongst an equal number of age- and smoking-matched white males who remained free of reported vascular disease during follow-up (controls). The P2RY12 gene variants tested were in linkage disequilibrium. The haplotype H2 distribution was significantly different between the DVT/PE cases (12%) and their matched controls (21%), p-permuted=0.02. In an adjusted conditional logistic regression analysis, the haplotype H2 was significantly associated with a lower risk of incident DVT/PE as compared to the reference haplotype H1 (odds ratio=0.50, 95% CI=0.27-0.93, p=0.028). However, we found no evidence for an association of the P2RY12 variants or the haplotype H2 with incident MI or ischemic stroke. The present investigation provides evidence for an association of the P2RY12 haplotype H2 with lower risk of DVT/PE; however these findings require replication in other well-designed studies.