Centers for Diabetes Research and Human Genomics

Wake Forest, NC, United States

Centers for Diabetes Research and Human Genomics

Wake Forest, NC, United States
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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.


Hruska K.A.,University of Washington | Divers J.,Public Health science | Bowden D.W.,Centers for Diabetes Research and Human Genomics | Palmer N.D.,Centers for Diabetes Research and Human Genomics | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Background: Bone mineral density (BMD) and atherosclerotic arterial calcified plaque (CP) demonstrate inverse relationships throughunknownmechanisms. Dickkopf-1 (DKK1) is an endogenous inhibitor of bone formation, and serum DKK1 has been associated with impaired osteoblast activation and susceptibility toboneloss. Plasma DKK1, BMD in the spine, and CP in three arterial beds were assessed in African-Americans (AAs) to determine relationships of serum DKK1 with atherosclerotic vascular calcification. Methods: Plasma DKK1, computed tomography-derived trabecular volumetric BMD (vBMD) in thoracic and lumbar vertebrae, and coronary artery, carotid artery, and aortoiliac CP were measured in 450 unrelated AAs with type 2 diabetes. Generalized linear models were fitted to test for associations between DKK1, vBMD, and CP. Results: Participants were 56% female with mean/SD/median age of 55.4/9.5/55.0 yr, diabetes duration of 10.3/8.2/8.0 yr, plasma DKK1 of 481.6/271.8/417 pg/ml, coronary artery CP mass score of 284/648/13, carotid artery CP mass score of 46/132/0, and aortoiliac CP mass score of 1613/2910/282. Adjusting for age, sex, body mass index, mean arterial blood pressure, smoking, hemoglobin A1c, and low-density lipoprotein-cholesterol, DKK1 was inversely associated with coronary artery and aortoiliac CP [parameter estimates -0.0011 (P = 0.0137) and -0.0010 (P = 0.0214), respectively], with a trend for carotid artery CP (P = 0.1404). No associations were observed between DKK1 and vBMD in the thoracic or lumbar vertebrae. Conclusions: Plasma DKK1 levels were inversely associated with coronary artery and aortoiliac CP, but not vBMD, in this cross-sectional study of AAs with type 2 diabetes. DKK1 may play a role in vascular mineral metabolism in this clinical setting. Copyright © 2013 by The Endocrine Society.


Palmer N.D.,Centers for Diabetes Research and Human Genomics | Hicks P.J.,Centers for Diabetes Research and Human Genomics | Smith S.C.,Centers for Diabetes Research and Human Genomics | Xu J.,Centers for Diabetes Research and Human Genomics | And 13 more authors.
Circulation: Cardiovascular Genetics | Year: 2013

Background-The presence and severity of coronary artery calcified plaque (CAC) differs markedly between individuals of African and European descent, suggesting that admixture mapping may be informative for identifying genetic variants associated with subclinical cardiovascular disease. Methods and Results-Admixture mapping of CAC was performed in 1040 unrelated African Americans with type 2 diabetes mellitus from the African American-Diabetes Heart Study, Multi-Ethnic Study of Atherosclerosis and Family Heart Study using the Illumina custom ancestry informative marker panel. All cohorts obtained computed tomography scanning of the coronary arteries using identical protocols. For each ancestry informative marker, the probability of inheriting 0, 1, and 2 copies of a European-derived allele was determined. Linkage analysis was performed by testing for association between each ancestry informative marker using these probabilities and CAC, accounting for global ancestry, age, sex, and study. Markers on 1p32.3 in the GLIS1 gene (rs6663966, logarithm of odds [LOD]=3.7), 1q32.1 near CHIT1 (rs7530895, LOD=3.1), 4q21.2 near PRKG2 (rs1212373, LOD=3.0), and 11q25 in the OPCML gene (rs6590705, LOD=3.4) had statistically significant LOD scores, whereas markers on 8q22.2 (rs6994682, LOD=2.7), 9p21.2 (rs439314, LOD=2.7), and 13p32.1 (rs7492028, LOD=2.8) manifested suggestive evidence of linkage. These regions were uniformly characterized by higher levels of European ancestry associating with higher levels or odds of CAC. Findings were replicated in 1350 African Americans without diabetes mellitus and 2497 diabetic European Americans from Multi-Ethnic Study of Atherosclerosis and the Diabetes Heart Study. Conclusions-Fine mapping these regions will likely identify novel genetic variants that contribute to CAC and clarify racial differences in susceptibility to subclinical cardiovascular disease. © 2012 American Heart Association, Inc.


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.


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 32 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.


Sellers M.B.,Section on Cardiology | Xu J.,Centers for Diabetes Research and Human Genomics | Smith S.C.,Centers for Diabetes Research and Human Genomics | Bowden D.W.,Centers for Diabetes Research and Human Genomics | And 4 more authors.
Journal of Epidemiology and Global Health | Year: 2014

Background: Electrocardiographic (ECG) abnormalities are independently associated with poor outcomes in the general population. Their prevalence and determinants were assessed in the understudied African American population with type 2 diabetes. Methods: Standard 12-lead ECGs were digitally recorded in 635 unrelated African American-Diabetes Heart Study (AA-DHS) participants, automatically processed at a central lab, read, and coded using standard Minnesota ECG Classification. Age- and sex-specific prevalence rates of ECG abnormalities were calculated and logistic regression models were fitted to examine cross-sectional associations between participant characteristics and ECG abnormalities. Results: Participants were 56% women with a mean age of 56. years; 60% had at least one minor or major ECG abnormality [23% ≥1 major (or major plus minor), and 37% ≥1 minor (with no major)]. Men had a higher prevalence of ≥1 minor or major ECG abnormality (66.1% men vs. 55.6% women, p=. 0.0089). In univariate analysis, age, past history of cardiovascular disease, diabetes duration, systolic blood pressure, sex and statin use were associated with the presence of any (major or minor) ECG abnormalities. In a multivariate model including variables, female sex (OR [95% CI] 0.79 [0.67, 0.93]), statin use (0.79 [0.67, 0.93]) and diabetes duration (1.03 [1.0, 1.05]) remained statistically significant. Conclusions: Nearly three out of five African Americans with diabetes had at least one ECG abnormality. Female sex and statin use were significantly associated with lower odds of any ECG abnormality and diabetes duration was significantly associated with higher odds of any ECG abnormality in the multivariable model. © 2014 Ministry of Health, Saudi Arabia.


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.


PubMed | Section on Cardiology, Section on Nephrology, Epidemiological Cardiology Research Center and Centers for Diabetes Research and Human Genomics
Type: Journal Article | Journal: Journal of epidemiology and global health | Year: 2014

Electrocardiographic (ECG) abnormalities are independently associated with poor outcomes in the general population. Their prevalence and determinants were assessed in the understudied African American population with type 2 diabetes.Standard 12-lead ECGs were digitally recorded in 635 unrelated African American-Diabetes Heart Study (AA-DHS) participants, automatically processed at a central lab, read, and coded using standard Minnesota ECG Classification. Age- and sex-specific prevalence rates of ECG abnormalities were calculated and logistic regression models were fitted to examine cross-sectional associations between participant characteristics and ECG abnormalities.Participants were 56% women with a mean age of 56 years; 60% had at least one minor or major ECG abnormality [23% 1 major (or major plus minor), and 37% 1 minor (with no major)]. Men had a higher prevalence of 1 minor or major ECG abnormality (66.1% men vs. 55.6% women, p=0.0089). In univariate analysis, age, past history of cardiovascular disease, diabetes duration, systolic blood pressure, sex and statin use were associated with the presence of any (major or minor) ECG abnormalities. In a multivariate model including variables, female sex (OR [95% CI] 0.79 [0.67, 0.93]), statin use (0.79 [0.67, 0.93]) and diabetes duration (1.03 [1.0, 1.05]) remained statistically significant.Nearly three out of five African Americans with diabetes had at least one ECG abnormality. Female sex and statin use were significantly associated with lower odds of any ECG abnormality and diabetes duration was significantly associated with higher odds of any ECG abnormality in the multivariable model.


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.

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