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Reeves-Daniel A.M.,Section on Nephrology | Depalma J.A.,Section on Nephrology | Bleyer A.J.,Section on Nephrology | Rocco M.V.,Section on Nephrology | And 5 more authors.
American Journal of Transplantation | Year: 2011

Coding variants in the apolipoprotein L1 gene (APOL1) are strongly associated with nephropathy in African Americans (AAs). The effect of transplanting kidneys from AA donors with two APOL1 nephropathy risk variants is unknown. APOL1 risk variants were genotyped in 106 AA deceased organ donors and graft survival assessed in 136 resultant kidney transplants. Cox-proportional hazard models tested for association between time to graft failure and donor APOL1 genotypes. The mean follow-up was 26.4 ± 21.8 months. Twenty-two of 136 transplanted kidneys (16%) were from donors with two APOL1 nephropathy risk variants. Twenty-five grafts failed; eight (32%) had two APOL1 risk variants. A multivariate model accounting for donor APOL1 genotype, overall African ancestry, expanded criteria donation, recipient age and gender, HLA mismatch, CIT and PRA revealed that graft survival was significantly shorter in donor kidneys with two APOL1 risk variants (hazard ratio [HR] 3.84; p = 0.008) and higher HLA mismatch (HR 1.52; p = 0.03), but not for overall African ancestry excluding APOL1. Kidneys from AA deceased donors harboring two APOL1 risk variants failed more rapidly after renal transplantation than those with zero or one risk variants. If replicated, APOL1 genotyping could improve the donor selection process and maximize long-term renal allograft survival. © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons. Source


Agarwal S.,Oakwood | Cox A.J.,Centers for Diabetes Research and Human Genomics | Herrington D.M.,Section of Cardiology | Jorgensen N.W.,University of Washington | And 4 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-In type 2 diabetesmellitus (T2DM), it remains unclear whether coronary artery calcium (CAC) provides additional information about cardiovascular disease (CVD) mortality beyond the Framingham Risk Score (FRS) factors. RESEARCH DESIGN AND METHODS-A total of 1,123 T2DM participants, ages 34- 86 years, in the Diabetes Heart Study followed up for an average of 7.4 years were separated using baseline computed tomography scans of CAC (0-9, 10-99, 100-299, 300-999, and ≥1,000). Logistic regression was performed to examine the association between CAC and CVD mortality adjusting for FRS. Areas under the curve (AUC) with and without CAC were compared. Net reclassification improvement (NRI) compared FRS (model 1) versus FRS+CAC (model 2) using 7.4-year CVD mortality risk categories 0% to <7%, 7% to <20%, and ≥20%. RESULTS-Overall, 8% of participants died of cardiovascular causes during follow-up. In multivariate analysis, the odds ratios (95%CI) for CVDmortality using CAC 0-9 as the reference group were, CAC 10-99: 2.93 (0.74-19.55); CAC 100-299: 3.17 (0.70-22.22); CAC 300-999: 4.41(1.15-29.00); and CAC≥1,000: 11.23 (3.24-71.00). AUC (95%CI)without CACwas 0.70 (0.67-0.73), AUC with CAC was 0.75 (0.72-0.78), and NRI was 0.13 (0.07-0.19). CONCLUSIONS-In T2DM, CAC predicts CVD mortality and meaningfully reclassifies participants, suggesting clinical utility as a risk stratification tool in a population already at increased CVD risk. © 2013 by the American Diabetes Association. Source


Dauriz M.,Massachusetts General Hospital | Dauriz M.,University of Verona | Porneala B.C.,Massachusetts General Hospital | Guo X.,University of California at Los Angeles | And 31 more authors.
Circulation: Cardiovascular Genetics | Year: 2015

Background - Type 2 diabetes mellitus (T2D) and cardiovascular disease share risk factors and subclinical atherosclerosis (SCA) predicts events in those with and without diabetes mellitus. T2D genetic risk may predict both T2D and SCA. We hypothesized that greater T2D genetic risk is associated with higher extent of SCA. Methods and Results - In a cross-sectional analysis, including ≤9210 European Americans, 3773 African Americans, 1446 Hispanic Americans, and 773 Chinese Americans without known cardiovascular disease and enrolled in the Framingham Heart Study, Coronary Artery Risk Development in Young Adults, Multi-Ethnic Study of Atherosclerosis, and Genetic Epidemiology Network of Arteriopathy studies, we tested a 62 T2D-loci genetic risk score for association with measures of SCA, including coronary artery or abdominal aortic calcium score, common and internal carotid artery intima-media thickness, and ankle-brachial index. We used ancestry-stratified linear regression models, with random effects accounting for family relatedness when appropriate, applying a genetic-only (adjusted for sex) and a full SCA risk factors-adjusted model (significance, P<0.01=0.05/5, number of traits analyzed). An inverse association with coronary artery calcium score in Multi-Ethnic Study of Atherosclerosis Europeans (fully-adjusted P=0.004) and with common carotid artery intima-media thickness in the Framingham Heart Study (P=0.009) was not confirmed in other study cohorts, either separately or in meta-analysis. Secondary analyses showed no consistent associations with β-cell and insulin resistance genetic risk sub-scores in the Framingham Heart Study and in the Coronary Artery Risk Development in Young Adults. Conclusions - SCA does not have a major genetic component linked to a burden of 62 T2D loci identified by large genome-wide association studies. A shared T2D-SCA genetic basis, if any, might become apparent from better functional information about both T2D and cardiovascular disease risk loci. © 2015 American Heart Association, Inc. Source


Hugenschmidt C.,Centers for Diabetes Research and Human Genomics | Sink K.M.,Sticht Center on Aging | Williamson J.D.,Sticht Center on Aging | Smith S.C.,Centers for Diabetes Research and Human Genomics | And 2 more authors.
Journal of Stroke and Cerebrovascular Diseases | Year: 2013

Previous studies involving inner city populations detected higher cerebral white matter hyperintensity (WMH) scores in African Americans (AAs) compared with European Americans (EAs). This finding might be attributable to the higher prevalence of cardiovascular disease (CVD) risk factors and poorer access to healthcare in AAs. Despite racial differences in CVD risk factor profiles, AAs have paradoxically lower levels of subclinical CVD. We hypothesized that AAs with diabetes and good access to healthcare would have comparable or lower levels of WMH as EAs. Racial differences in the distribution of WMH were analyzed in 46 AAs and 156 EAs with type 2 diabetes enrolled in the Diabetes Heart Study (DHS)-Mind, and replicated in a sample of 113 AAs and 61 EAs patients who had clinically indicated cerebral magnetic resonance imaging. Wilcoxon 2-sample tests and linear models were used to compare the distribution of WMH in AAs and EAs and to test for association between WMH and race. The unadjusted mean WMH score from the Diabetes Heart Study-Mind was 1.9 in AAs and 2.3 in EAs (P =.3244). Among those with clinically indicated magnetic resonance imaging, the mean WMH score was 2.9 in AAs and 3.9 in EAs (P =.0503). Adjustment for age and sex produced no statistically significant differences in WMH score between AAs and EAs. These independent datasets reveal comparable WMH scores in AAs and EAs, suggesting that disparities in access to healthcare and environmental exposures likely underlie the previously reported excess burden of WMH in AAs. © 2013 by National Stroke Association. Source


Murea M.,Medical Center Boulevard | Bowden D.W.,Centers for Diabetes Research and Human Genomics | Xu J.,Centers for Diabetes Research and Human Genomics | Smith S.C.,Centers for Diabetes Research and Human Genomics | And 2 more authors.
BMC Nephrology | Year: 2012

Background: Monocyte chemoattractant protein-1 (MCP-1) plays important roles in kidney disease susceptibility and atherogenesis in experimental models. Relationships between serum MCP-1 concentration and early nephropathy and subclinical cardiovascular disease (CVD) were assessed in African Americans (AAs) with type 2 diabetes (T2D). Methods. Serum MCP-1 concentration, urine albumin:creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and atherosclerotic calcified plaque (CP) in the coronary and carotid arteries and infrarenal aorta were measured in 479 unrelated AAs with T2D. Generalized linear models were fitted to test for associations between MCP-1 and urine ACR, eGFR, and CP. Results: Participants were 57% female, with mean ± SD (median) age 55.6±9.5 (55.0) years, diabetes duration 10.3±8.2 (8.0) years, urine ACR 149.7±566.7 (14.0) mg/g, CKD-EPI eGFR 92.4±23.3 (92.0) ml/min/1.73m2, MCP-1 262.9±239.1 (224.4) pg/ml, coronary artery CP 280.1±633.8 (13.5), carotid artery CP 47.1±132.9 (0), and aorta CP 1616.0±2864.0 (319.0). Adjusting for age, sex, smoking, HbA1c, BMI, and LDL, serum MCP-1 was positively associated with albuminuria (parameter estimate 0.0021, P=0.04) and negatively associated with eGFR (parameter estimate -0.0003, P=0.001). MCP-1 remained associated with eGFR after adjustment for urine ACR. MCP-1 levels did not correlate with the extent of CP in any vascular bed, HbA1c or diabetes duration, but were positively associated with BMI. No interaction between BMI and MCP-1 was detected on nephropathy outcomes. Conclusions: Serum MCP-1 levels are associated with eGFR and albuminuria in AAs with T2D. MCP-1 was not associated with subclinical CVD in this population. Inflammation appears to play important roles in development and/or progression of kidney disease in AAs. © 2012 Murea et al.; licensee BioMed Central Ltd. Source

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