Cholesteryl ester transfer protein genetic polymorphisms, HDL cholesterol, and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis

The cholesteryl ester transfer protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, −629C/A, Taq1B, and −2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, carotid intimal-medial thickness (IMT), and carotid artery plaque measured by ultrasonography. Carriers of the 451Q and 373P alleles have a significantly higher CETP concentration (22.4% and 19.5%, respectively; p < 0.001) and activity (13.1% and 9.4%, respectively; p < 0.01) and lower HDL-C (5.6% and 6.0%, respectively; p < 0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p = 0.006 and p = 0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p = 0.036). Polymorphism is associated with neither common nor internal carotid IMT. We confirmed that the −629A, Taq1B B2, and −2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p < 0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p < 0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p < 0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.     

Retinal vascular caliber, cardiovascular risk factors, and inflammation: the multi-ethnic study of atherosclerosis (MESA)

PURPOSE: To describe the relationship of retinal arteriolar and venular caliber with cardiovascular risk factors, including inflammatory biomarkers, in a multiethnic population of whites, blacks, Hispanics, and Chinese. METHODS: A cross-sectional study comprising 5979 persons aged 45 to 84 years residing in six U.S. communities. Retinal vascular caliber was measured and summarized from digital retinal photographs. Standard cardiovascular risk factors, including biomarkers of inflammation (e.g., high-sensitivity C-reactive protein [hsCRP], interleukin [IL]-6, and plasma fibrinogen) and endothelial dysfunction (e.g., soluble intercellular adhesion molecule [sICAM]-1 [, plasminogen activator inhibitor [PAI]-1) were assessed. RESULTS: Mean retinal arteriolar caliber was 144.1+/-14.4 (SD) microm, and venular caliber 214.0+/-22.2 microm. In models controlling for age, gender, race-ethnicity, and center, smaller retinal arteriolar caliber was related to higher systolic and diastolic blood pressure, hypertension status, current alcohol consumption, greater body mass index, and higher levels of total homocysteine; larger retinal arteriolar caliber was related to diabetes, current cigarette smoking, and higher levels of plasma fibrinogen; and larger retinal venular caliber was related to diabetes, current cigarette smoking, greater body mass index and waist-hip ratio, higher levels of serum glucose, plasma triglyceride, plasma LDL-cholesterol, hsCRP, plasma fibrinogen, IL6, sICAM-1, and PAI-1 and lower levels of HDL-cholesterol. In multivariate analyses, blacks and Hispanics had larger retinal arteriolar and venular calibers than did whites and Chinese. CONCLUSIONS: Retinal arteriolar and venular caliber is associated with a range of cardiovascular risk factors, including hypertension, diabetes, measures of obesity, and dyslipidemia. Venular caliber is also associated with systemic inflammation.     

Plasma MCP-1 level and risk for peripheral arterial disease and incident coronary heart disease: Atherosclerosis Risk in Communities study

Monocyte chemoattractant protein-1 (MCP-1), which mediates the recruitment of monocytes, has been suggested to play a role in atherosclerosis. Because the correlation between circulating MCP-1 and cardiovascular risk has not been thoroughly investigated, we determined the relationship between MCP-1 level and peripheral arterial disease (PAD) or coronary heart disease (CHD). In the Atherosclerosis Risk in Communities (ARIC) study, 209 cases with lower extremity PAD and 412 cases with incident CHD were compared with 733 and 709 subjects without PAD and CHD, respectively. Mean plasma MCP-1 levels were significantly higher in PAD cases (468.7 versus 416.5 pg/mL in non-cases). MCP-1 levels correlated significantly with other inflammatory markers in comparison subjects. Logistic regression analyses showed a significant association of MCP-1 with PAD, independent of traditional CHD risk factors, with an odds ratio of 2.14 (95% CI, 1.28-3.60) for the highest MCP-1 tertile compared with the lowest. Incident CHD risk increased significantly per 1 standard deviation (S.D.) difference in MCP-1 level independent of other cardiovascular risk factors, including inflammatory markers. These data show that MCP-1 is associated with atherosclerotic disease in two vascular beds and suggest that MCP-1 may be a novel target for atherosclerosis therapy.     

Inflammatory Markers and Risk of Cerebrovascular Events in Patients Initiating Dialysis

Summary

Background and objectives

Stroke remains a leading cause of morbidity and mortality for patients on dialysis; however, its risk factors in this population and measures to prevent it are not well understood.

Design, setting, participants, & measurements

We investigated whether inflammation was associated with cerebrovascular events in a national US cohort of 1041 incident dialysis patients enrolled from October 1995 to June 1998 and followed until January 31, 2004. Incident cerebrovascular events were defined as nonfatal (hospitalized stroke, carotid endarterectomy) and fatal (stroke death) events after dialysis initiation. With Cox proportional hazards regression analysis accounting for the competing risk of nonstroke death, we assessed the independent event risk associated with baseline levels of multiple inflammatory markers (high-sensitivity C-reactive protein [hsCRP], interleukin-6 (IL-6), matrix metalloproteinase-3 [MMP-3], and P-selectin) and hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) use, which may have pleiotropic inflammatory effects.

Results

165 patients experienced a cerebrovascular event during 3548 person-years of follow-up; overall incidence rate was 4.9/100 person-years. None of the inflammatory markers were associated with cerebrovascular event risk (adjusted hazard ratios [HRs] per log unit [95% confidence interval]: hsCRP, 0.97 [0.85 to 1.11]; IL-6, 1.04 [0.85 to 1.26]; MMP-3, 1.02 [0.70 to 1.48]; P-selectin, 0.98 [0.57 to 1.68]). Statin use was also not associated with significant risk of events in unadjusted (HR 1.07 [0.69 to 1.68]) or propensity-score adjusted analyses (HR 0.98 [0.61 to 1.56]).

Conclusions

In conclusion, neither inflammatory markers nor statin use was associated with risk of cerebrovascular events. Further studies are needed to understand the pathophysiology and prevention of stroke in patients on dialysis.     

Glycated hemoglobin and the risk of kidney disease and retinopathy in adults with and without diabetes

OBJECTIVE

Glycated hemoglobin was recently recommended for use as a diagnostic test for diabetes. We examined the association between 2010 American Diabetes Association diagnostic cut points for glycated hemoglobin and microvascular outcomes (chronic kidney disease, end-stage renal disease [ESRD], and retinopathy) and formally tested for the presence of risk thresholds in the relationships of glycated hemoglobin with these outcomes.

RESEARCH DESIGN AND METHODS

Prospective cohort and cross-sectional analyses of 11,357 participants (773 with a history of diagnosed diabetes) from the Atherosclerosis Risk in Communities (ARIC) Study.

RESULTS

During a median of 14 years of follow-up of individuals without diagnosed diabetes at baseline, clinical categories of glycated hemoglobin were associated with risk of chronic kidney disease, with adjusted hazard ratios (HRs) of 1.12 (0.94–1.34) and 1.39 (1.04–1.85) for glycated hemoglobin 5.7–6.4% and ≥6.5%, respectively, as compared with <5.7% (P trend = 0.002). The corresponding HRs for ESRD were 1.51 (0.82–2.76) and 1.98 (0.83–4.73), respectively (P trend = 0.047). In the absence of diagnosed diabetes, glycated hemoglobin was cross sectionally associated with the presence of moderate/severe retinopathy, with adjusted odds ratios of 1.42 (0.69–2.92) and 2.91 (1.19–7.11) for glycated hemoglobin 5.7–<6.5% and ≥6.5%, respectively, compared with <5.7% (P trend = 0.011). Risk associations were stronger among individuals with a history of diabetes. We did not observe significant thresholds in the associations of glycated hemoglobin with kidney disease risk or retinopathy.

CONCLUSIONS

These data from a community-based, biracial population support the use of new 2010 American Diabetes Association glycated hemoglobin cut points for the diagnosis of diabetes.Measurement of glycated hemoglobin has long been central to the management and treatment of diabetes. The evidence for the use of glycated hemoglobin in clinical practice is largely based on its associations with retinopathy in observational studies (1–5) and clinical trial data demonstrating that lowering glycated hemoglobin can prevent microvascular outcomes in individuals with diabetes (6–10). Diagnostic criteria for diabetes have been traditionally based exclusively on fasting or 2-h glucose testing. In a major change to clinical practice, the 2010 guidelines from the American Diabetes Association recommend the use of glycated hemoglobin as a diagnostic test for diabetes (11), with 6.5% designated as the diagnostic threshold. However, few studies have investigated the relationship of new glycated hemoglobin cut points with microvascular disease.The objective of this study was to characterize the associations of glycated hemoglobin with risk of kidney disease and retinopathy in a community-based population. We compared these associations to those for fasting glucose. We hypothesized that among individuals without a history of diabetes, new American Diabetes Association cut points for glycated hemoglobin would identify risk for future kidney disease and would be cross-sectionally associated with prevalent retinopathy. We undertook analyses to characterize the shapes of the associations and to formally test for the presence of possible threshold effects in these data.