Faculty Bibliography

Background:African Americans typically perform worse than European Americans on cognitive testing. Contributions of cardiovascular disease (CVD) risk factors and educational quality to cognitive performance and brain volumes were compared in European Americans and African Americans with type 2 diabetes. Methods:Association between magnetic resonance imaging-determined cerebral volumes of white matter (WMV), gray matter (GMV), white matter lesions (WMLV), hippocampal GMV, and modified mini-mental state exam (3MSE), digit symbol coding (DSC), Rey Auditory Verbal Learning Test (RAVLT), Stroop, and verbal fluency performance were assessed in Diabetes Heart Study Memory in Diabetes (MIND) participants. Marginal models incorporating generalized estimating equations were employed with serial adjustment for risk factors. Results:The sample included 520 African Americans and 684 European Americans; 56 per cent female with mean ± SD age 62.8 ± 10.3 years and diabetes duration 14.3 ± 7.8 years. Adjusting for age, sex, diabetes duration, BMI, HbA1c, total intracranial volume, scanner, statins, CVD, smoking, and hypertension, WMV (p = .001) was lower and WMLV higher in African Americans than European Americans (p = .001), with similar GMV (p = .30). Adjusting for age, sex, education, HbA1c, diabetes duration, hypertension, BMI, statins, CVD, smoking, and depression, poorer performance on 3MSE, RAVLT, and DSC were seen in African Americans (p = 6 × 10-23-7 × 10-62). Racial differences in cognitive performance were attenuated after additional adjustment for WMLV and nearly fully resolved after adjustment for wide-range achievement test (WRAT) performance (p = .0009-.65). Conclusions:African Americans with type 2 diabetes had higher WMLV and poorer cognitive performance than European Americans. Differences in cognitive performance were attenuated after considering WMLV and apparent poorer educational quality based on WRAT.

Background:Inheritance of apolipoprotein L1 gene (APOL1) renal-risk variants in a recessive pattern strongly associates with non-diabetic end-stage kidney disease (ESKD). Further evidence supports risk modifiers in APOL1-associated nephropathy; some studies demonstrate that heterozygotes possess excess risk for ESKD or show earlier age at ESKD, relative to those with zero risk alleles. Nearby loci are also associated with ESKD in non-African Americans. Methods:We assessed the role of the APOL3 null allele rs11089781 on risk of non-diabetic ESKD. Four cohorts containing 2781 ESKD cases and 2474 controls were analyzed. Results:Stratifying by APOL1 risk genotype (recessive) and adjusting for African ancestry identified a significant additive association between rs11089781 and ESKD in each stratum and in a meta-analysis [meta-analysis P  =  0.0070; odds ratio (OR) = 1.29]; ORs were consistent across APOL1 risk strata. The biological significance of this association is supported by the finding that the APOL3 gene is co-regulated with APOL1, and that APOL3 protein was able to bind to APOL1 protein. Conclusions:Taken together, the genetic and biological data support the concept that other APOL proteins besides APOL1 may also influence the risk of non-diabetic ESKD.

AIMS:To determine among adolescents and young adults with youth-onset type 1 diabetes and type 2 diabetes the rates and risk factors for albuminuria regression and progression. METHODS:Data from SEARCH, a longitudinal observational study of youth-onset type 1 diabetes (N = 1316) and type 2 diabetes (N = 143) were analyzed. Urine albumin:creatinine ratio (UACR) was measured from random urine specimens at baseline and follow-up visits (mean 7 years later). Albuminuria regression was defined as halving of baseline UACR when baseline UACR was ≥30 μg/mg; progression was defined as doubling of baseline UACR when follow-up UACR was ≥30 μg/mg, respectively. Multivariable regression assessed risk factors associated with low-risk albuminuria category (combined persistently-low albuminuria and regression) versus moderate-risk albuminuria category (combined persistently-high albuminuria and progression). RESULTS:Albuminuria progression was more common in type 2 diabetes versus type 1 diabetes (15.4% versus 6.0%, p<0.001). Moderate-risk albuminuria was associated with increasing HbA1c (adjusted OR (aOR) = 1.3, 95% CI 1.1-1.6) and lack of private health insurance (aOR = 2.7, 95%CI 1.1-6.5) in type 1 diabetes; and African American race (OR = 4.6, 95% CI 1.2-14.2), lower estimated insulin sensitivity score (aOR = 2.1, 95% CI 1.4-3.3), baseline UACR (aOR = 3.2, 95% CI 1.7-5.8), and follow-up estimated glomerular filtration rate (eGFR) (10-unit increase aOR = 1.3, 95% CI 1.0, 1.5) in type 2 diabetes. CONCLUSIONS:In the first decade of diabetes duration, kidney complications in type 2 diabetes are significantly more aggressive than in type 1 diabetes and may be associated with less modifiable risk factors including race, insulin sensitivity, and eGFR. Early interventions may help reduce long-term kidney complications.

Background:Viral infections can trigger chronic kidney disease (CKD) and the urine virome may inform risk. The Natural History of APOL1-Associated Nephropathy Study (NHAANS) reported that urine JC polyomavirus (JCPyV) associated with a lower risk of APOL1-associated nephropathy in African Americans. Herein, association was assessed between urine JCPyV with CKD in African Americans independent from the APOL1 genotype. Methods:Quantitative polymerase chain reaction was performed for urinary detection of JCPyV and BK polyoma virus (BKPyV) in 200 newly recruited nondiabetic African Americans. A combined analysis was performed in these individuals plus 300 NHAANS participants. Results:In the 200 new participants, urine JCPyV was present in 8.8% of CKD cases and 45.8% of nonnephropathy controls (P = 3.0 × 10-8). In those with APOL1 renal-risk genotypes, JCPyV was detected in 5.1% of cases and 40.0% of controls (P = 0.0002). In those lacking APOL1 renal-risk genotypes, JCPyV was detected in 12.2% of cases and 48.8% of controls (P = 8.5 × 10-5). BKPyV was detected in 1.3% of cases and 0.8% of controls (P  =  0.77). In a combined analysis with 300 NHAANS participants (n = 500), individuals with urine JCPyV had a 63% lower risk of CKD compared with those without urine JCPyV (odds ratio 0.37; P = 4.6 × 10-6). RNA fluorescence in situ hybridization confirmed the presence of JCPyV genomic DNA and JCPyV messenger RNA (mRNA) in nondiseased kidney. Conclusions:Inverse relationships exist between JCPyV viruria and non-diabetic CKD. Future studies should determine whether renal inflammation associated with CKD is less permissive for JCPyV reactivation/replication or whether JCPyV is a marker of reduced host immune responsiveness that diminishes immune pathologic contributions to CKD.

BACKGROUND:Type 2 diabetes mellitus is a major risk factor for cardiovascular disease; however, outcomes in individual patients vary. Soluble urokinase plasminogen activator receptor (suPAR) is a bone marrow-derived signaling molecule associated with adverse cardiovascular and renal outcomes in many populations. We characterized the determinants of suPAR in African Americans with type 2 diabetes mellitus and assessed whether levels were useful for predicting mortality beyond clinical characteristics, coronary artery calcium (CAC), and high-sensitivity C-reactive protein (hs-CRP). METHODS AND RESULTS:We measured plasma suPAR levels in 500 African Americans with type 2 diabetes mellitus enrolled in the African American-Diabetes Heart Study. We used Kaplan-Meier curves and Cox proportional hazards models adjusting for clinical characteristics, CAC, and hs-CRP to examine the association between suPAR and all-cause mortality. Last, we report the change in C-statistics comparing the additive values of suPAR, hs-CRP, and CAC to clinical models for prediction of mortality. The suPAR levels were independently associated with female sex, smoking, insulin use, decreased kidney function, albuminuria, and CAC. After a median 6.8-year follow-up, a total of 68 deaths (13.6%) were recorded. In a model incorporating suPAR, CAC, and hs-CRP, only suPAR was significantly associated with mortality (hazard ratio 2.66, 95% confidence interval 1.63-4.34). Addition of suPAR to a baseline clinical model significantly improved the C-statistic for all-cause death (Δ0.05, 95% confidence interval 0.01-0.10), whereas addition of CAC or hs-CRP did not. CONCLUSIONS:In African Americans with type 2 diabetes mellitus, suPAR was strongly associated with mortality and improved risk discrimination metrics beyond traditional risk factors, CAC and hs-CRP. Studies addressing the clinical usefulness of measuring suPAR concentrations are warranted.

African Americans carrying two apolipoprotein L1 gene (APOL1) renal risk variants have a high risk for nephropathy. However, only a minority develops end-stage renal disease (ESRD). Hence, modifying factors likely contribute to initiation of kidney disease such as endogenous (HIV infection) or exogenous (interferon treatment) environmental modifiers. In this report, genome-wide association studies and a meta-analysis were performed to identify novel loci for nondiabetic ESRD in African Americans and to detect genetic modifiers in APOL1-associated nephropathy. Two African American cohorts were analyzed, 1749 nondiabetic ESRD cases and 1136 controls from Wake Forest and 901 lupus nephritis (LN)-ESRD cases and 520 controls with systemic lupus erythematosus but lacking nephropathy from the LN-ESRD Consortium. Association analyses adjusting for APOL1 G1/G2 renal-risk variants were completed and stratified by APOL1 risk genotype status. Individual genome-wide association studies and meta-analysis results of all 2650 ESRD cases and 1656 controls did not detect significant genome-wide associations with ESRD beyond APOL1. Similarly, no single nucleotide polymorphism showed significant genome-wide evidence of an interaction with APOL1 risk variants. Thus, although variants with small individual effects cannot be ruled out and are likely to exist, our results suggest that APOL1-environment interactions may be of greater clinical importance in triggering nephropathy in African Americans than APOL1 interactions with other single nucleotide polymorphisms.

AIMS:To estimate short-term mortality rates for individuals with type 1 or type 2 diabetes diagnosed before age 20 years from the SEARCH for Diabetes in Youth study. METHODS:We included 8358 individuals newly-diagnosed with type 1 (n = 6840) or type 2 (n = 1518) diabetes from 1/1/2002-12/31/2008. We searched the National Death Index through 12/31/2010. We calculated standardized mortality ratios (SMRs) based on age, sex, and race for the comparable US population in the geographic areas of the SEARCH study. RESULTS:During 44,893 person-years (PY) of observation (median follow-up = 5.3 years), 41 individuals died (91.3 deaths/100,000 PY); 26 with type 1 (70.6 deaths/100,000 PY) and 15 with type 2 (185.6 deaths/100,000 PY) diabetes. The expected mortality rate was 70.9 deaths/100,000 PY. The overall SMR (95% CI) was 1.3 (1.0, 1.8) and was high among individuals with type 2 diabetes 2.4 (1.3, 3.9), females 2.2 (1.3, 3.3), 15-19 year olds 2.7 (1.7,4.0), and non-Hispanic blacks 2.1 (1.2, 3.4). CONCLUSIONS:Compared to the state populations of similar age, sex, and race, our results show excess mortality in individuals with type 2 diabetes, females, older youth, and non-Hispanic blacks. We did not observe excess short-term mortality in individuals with type 1 diabetes.

OBJECTIVE:Cardiovascular and renal complications contribute to higher mortality in patients with diabetes. We assessed novel and conventional predictors of mortality in African American-Diabetes Heart Study (AA-DHS) participants. RESEARCH DESIGN AND METHODS:) were assessed in 513 African Americans with type 2 diabetes; analyses were performed using Cox proportional hazards models. RESULTS:renal-risk genotypes (HR 0.07 [95% CI 0.01-0.69]) as the strongest predictors of mortality. CONCLUSIONS:non-renal-risk genotypes associated with higher mortality in African Americans with diabetes. These data add to growing evidence supporting FGF23 association with mortality; mechanisms whereby these novel predictors impact survival remain to be determined.

BACKGROUND:Relationships between cognitive function and brain structure remain poorly defined in African Americans with type 2 diabetes. METHODS:Cognitive testing and cerebral magnetic resonance imaging in African Americans from the Diabetes Heart Study Memory IN Diabetes (n = 480) and Action to Control Cardiovascular Risk in Diabetes MIND (n = 104) studies were examined for associations. Cerebral gray matter volume (GMV), white matter volume (WMV) and white matter lesion volume (WMLV) and cognitive performance (Mini-mental State Exam [MMSE and 3MSE], Digit Symbol Coding (DSC), Stroop test, and Rey Auditory Verbal Learning Test) were recorded. Multivariable models adjusted for age, sex, BMI, scanner, intracranial volume, education, diabetes duration, HbA1c, LDL-cholesterol, smoking, hypertension and cardiovascular disease assessed associations between cognitive tests and brain volumes by study and meta-analysis. RESULTS:). CONCLUSIONS:In African Americans with diabetes, smaller GMV and increased WMLV associated with poorer performance on tests of global cognitive and executive function. These data suggest that WML burden and gray matter atrophy associate with cognitive performance independent of diabetes-related factors in this population.