BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising... Show moreBACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development. Show less
BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of... Show moreBACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators. Show less
Background Recent longitudinal analyses suggested that low levels of serum 25-hydroxyvitamin D (25-OH-D) predict incident cardiovascular disease in initially healthy populations. Because the... Show moreBackground Recent longitudinal analyses suggested that low levels of serum 25-hydroxyvitamin D (25-OH-D) predict incident cardiovascular disease in initially healthy populations. Because the prognostic value of vitamin D for the occurrence of secondary cardiovascular events remains unclear, we examined the association of baseline 25-OH-D levels with prognosis in patients with stable coronary heart disease (CHD). Methods Serum 25-OH-D levels from 1,125 CHD patients of 2 German clinics undergoing a 3-week rehabilitation program after an acute cardiovascular event were measured, and participants were followed for up to 8 years. We used multivariate Cox regression analysis to model cardiovascular event incidence (fatal and nonfatal, including myocardial infarction, stroke, and death due to cardiovascular diseases) and all-cause mortality according to 25-OH-D quartiles, categories based on cut points of 15 and 30 ng/mL, or continuous vitamin D concentrations. Results During follow-up, 148 cardiovascular events and 121 deaths were recorded. Elevation of risk for the lowest quartile or category in comparison to the highest category was weak and nonsignificant for both incidence (hazard ratio [HR](quartile1) = 1.15 [0.72-1.84], HR<15 ng/mL = 1.17 [0.61-2.23]) and mortality (HRquartile1 = 1.29 [0.77-2.14], HR<15 (ng/mL) = 1.87 [0.91-3.82]) in unadjusted Cox regression analysis and disappeared entirely after adjustment for potential confounders (cardiovascular events: HRquartile1 = 0.84 [0.47-1.50], HR<15 ng/mL = 0.90 [0.41-1.96]; mortality: HRquartile1 = 0.63 [0.33-1.21], HR<15 ng/mL = 0.93 [0.39-2.21]). Models treating vitamin D as a continuous variable likewise suggested no significant associations. Conclusions Unlike previous population-based studies, our analysis in high-risk patients with stable CHD does not support a prognostic value of baseline-25-OH-D levels for secondary cardiovascular event incidence or all-cause mortality. (Am Heart J 2010; 159: 1044-51.) Show less
