Circulating Soluble CD163, Associations With Cardiovascular Outcomes and Mortality, and Identification of Genetic Variants in Older Individuals: The Cardiovascular Health Study.

Background Monocytes/macrophages participate in cardiovascular disease. CD163 (cluster of differentiation 163) is a monocyte/macrophage receptor, and the shed sCD163 (soluble CD163) reflects monocyte/macrophage activation. We examined the association of sCD163 with incident cardiovascular disease events and performed a genome-wide association study to identify sCD163-associated variants. Methods and Results We measured plasma sCD163 in 5214 adults (aged ≥65 years, 58.7% women, 16.2% Black) of the CHS (Cardiovascular Health Study). We used Cox regression models (associations of sCD163 with incident events and mortality); median follow-up was 26 years. Genome-wide association study analyses were stratified on race. Adjusted for age, sex, and race and ethnicity, sCD163 levels were associated with all-cause mortality (hazard ratio [HR], 1.08 [95% CI, 1.04-1.12] per SD increase), cardiovascular disease mortality (HR, 1.15 [95% CI, 1.09-1.21]), incident coronary heart disease (HR, 1.10 [95% CI, 1.04-1.16]), and incident heart failure (HR, 1.18 [95% CI, 1.12-1.25]). When further adjusted (eg, cardiovascular disease risk factors), only incident coronary heart disease lost significance. In European American individuals, genome-wide association studies identified 38 variants on chromosome 2 near MGAT5 (top result rs62165726, P=3.3×10-18),19 variants near chromosome 17 gene ASGR1 (rs55714927, P=1.5×10-14), and 18 variants near chromosome 11 gene ST3GAL4. These regions replicated in the European ancestry ADDITION-PRO cohort, a longitudinal cohort study nested in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment Intensive Treatment In peOple with screeNdetcted Diabetes in Primary Care. In Black individuals, we identified 9 variants on chromosome 6 (rs3129781 P=7.1×10-9) in the HLA region, and 3 variants (rs115391969 P=4.3×10-8) near the chromosome 16 gene MYLK3. Conclusions Monocyte function, as measured by sCD163, may be predictive of overall and cardiovascular-specific mortality and incident heart failure.

A Randomised Trial Examining Cardiovascular Morbidity and All-Cause Mortality 24 years Following General Health Checks: the Ebeltoft Health Promotion Project (EHPP).

INTRODUCTION: Global prevalence of risk factors for cardiovascular disease (CVD) and all-cause mortality is increasing. Treatments are available but can only be implemented if individuals at risk are identified. General health checks have been suggested to facilitate this process. OBJECTIVES: To examine the long-term effect of population-based general health checks on CVD and all-cause mortality. DESIGN AND SETTING: The Ebeltoft Health Promotion Project (EHPP) is a parallel randomised controlled trial in a Danish primary care setting. PARTICIPANTS: The EHPP enrolled individuals registered in the Civil Registration System as (1) inhabitants of Ebeltoft municipality, (2) registered with a general practitioner (GP) participating in the study and (3) aged 30-49 on 1 January 1991. A total of 3464 individuals were randomised as invitees (n=2000) or non-invitees (n=1464). Of the invitees, 493 declined. As an external control group, we included 1 511 498 Danes living outside the municipality of Ebeltoft. INTERVENTIONS: Invitees were offered a general health check and, if test-results were abnormal, recommended a 15-45 min consultation with their GP. Non-invitees in Ebeltoft received a questionnaire at baseline and were offered a general health check at year 5. The external control group, that is, the remaining Danish population, received routine care only. OUTCOME MEASURES: HRs for CVD and all-cause mortality. RESULTS: Every individual randomised was analysed. When comparing invitees to non-invitees within the municipality of Ebeltoft, we found no significant effect of general health checks on CVD (HR=1.11 (0.88; 1.41)) or all-cause mortality (HR=0.93 (0.75; 1.16)). When comparing invitees to the remaining Danish population, we found similar results for CVD (adjusted HR=0.99 (0.86; 1.13)) and all-cause mortality (adjusted HR=0.96 (0.85; 1.09)). CONCLUSION: We found no effect of general health checks offered to the general population on CVD or all-cause mortality. TRIAL REGISTRATION NUMBER: NCT00145782; 2015-57-0002; 62908, 187.

Correction to: Soluble CD163, adiponectin, C-reactive protein and progression of dysglycaemia in individuals at high risk of type 2 diabetes mellitus: the ADDITION-PRO cohort.

The authors have discovered a coding error in the statistical analysis syntax file used for the mixed-effect model analyses in this paper. The error has led to differences (first decimal) in the estimates for the main results.

Soluble CD163, adiponectin, C-reactive protein and progression of dysglycaemia in individuals at high risk of type 2 diabetes mellitus: the ADDITION-PRO cohort.

AIM/HYPOTHESIS: Our aim was to investigate the association between the macrophage-activation marker soluble CD163 (sCD163), adiponectin, C-reactive protein (CRP) and changes in glycaemia, insulin resistance and insulin secretion in individuals at high risk of type 2 diabetes mellitus. METHODS: This prospective study included 1014 individuals at high risk of type 2 diabetes mellitus participating in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment In PeOple with ScreeN-detected Diabetes in Primary Care (ADDITION-Europe trial) baseline examination in 2001-2006 and follow-up examination (ADDITION-Progression [ADDITION-PRO]) in 2009-2011. Baseline serum samples were analysed for sCD163, adiponectin and CRP. The associations between sCD163, adiponectin and CRP per doubling of concentration, and changes per year in HbA1c, fasting plasma glucose, 2 h glucose, fasting insulin, HOMA-IR and HOMA-ß were assessed using a mixed-effects model. RESULTS: A doubling of sCD163 concentration was positively associated with changes in fasting insulin (ß = 1.078 per year, 95% CI 0.454, 1.702) and HOMA-ß (ß = 1.313 per year, 95% CI 0.537, 2.089), and a doubling of CRP concentration was positively associated with HbA 1c (ß = 0.004 per year, 95% CI 0.001, 0.007) and fasting insulin (ß = 0.267 per year, 95% CI 0.029, 0.504) after adjustment for age and sex. A doubling of adiponectin was inversely associated with changes in fasting glucose (ß = −0.017 per year, 95% CI −0.028, −0.005), 2 h glucose (ß = −0.063 per year, 95% CI −0.107, −0.019), fasting insulin (ß = −1.558 per year, 95% CI −2.020, −1.096), HOMA-IR (ß = −0.040 per year, 95% CI −0.062, −0.019) and HOMA-ß (ß = −1.009 per year, 95% CI −1.589, −0.429) after adjustment for age and sex. The associations were robust to adjustment for baseline waist circumference and smoking. Adjustment for CRP did not change the associations for sCD163 or adiponectin. CONCLUSIONS/INTERPRETATION: Our findings indicate that mechanisms related to inflammation, including macrophage activation and adipocyte metabolism, may play a role in changes in glucose homeostasis in individuals at high risk of type 2 diabetes mellitus.