Faculty Bibliography

Background/UNASSIGNED:Worry is a common problem among older adults. Cognitive-behavioral therapy is the most studied nonpharmacological intervention and it has demonstrated efficacy in reducing late-life worry and anxiety. Although the evidence-base is smaller, yoga has been shown to reduce anxiety and stress. However, little is known about the relative effectiveness of these two nonpharmacological interventions. Further, the impact of patient preference on outcomes is unknown.Purpose: The purpose to this study is to compare the effectiveness of cognitive-behavioral therapy (CBT) with yoga for improving late-life worry, anxiety, and sleep. We will also examine the effects of preference and selection on outcomes, adherence, and attrition. Methods/UNASSIGNED:We are conducting a two-stage randomized preference trial comparing CBT and yoga for the reduction of worry in a sample of anxious older adults. Five hundred participants will be randomized to either the preference trial (participants choose the intervention; N = 250) or to the randomized trial (participants are randomized to one of the two interventions; N = 250) with equal probability. CBT consists of 10 telephone-based sessions with an accompanying workbook. Yoga consists of 10 weeks of group yoga classes (twice a week) that is modified for use with older adults. Conclusions/UNASSIGNED:The study design is based on feedback from anxious older adults who wanted more nonpharmacological options for intervention as well as more input into the intervention they receive. It is the first head-to-head comparison of CBT and yoga for reducing late-life worry and anxiety. It will also provide information about how intervention preference affects outcomes. Trial registration/UNASSIGNED:ClinicalTrials.gov NCT02968238.

Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6×10^-7). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; P_EA=4.5×10^-8) partially independent of known common signal ( P_{EA(conditional)}=1.4×10^-3). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; P_all=1.9×10^-10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( P_rs34136221=2.8×10^-8). Conclusions- Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

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.

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.

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: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.

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.

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.

AIM:Recent studies revealed a correlation between skeletal muscle mass index and density with longevity; these studies largely evaluated appendicular skeletal muscles in older Caucasians. This retrospective cohort study assessed the association between axial skeletal muscles size and density with survival in African Americans with type 2 diabetes mellitus. METHODS:) and radiographic density (in Hounsfield Units) were measured using computed tomography in African American-Diabetes Heart Study participants, 314 women and 256 men, with median (25th, 75th quartile) age 55.0(48.0, 62.0) and 57.0(50.0, 64.0) years, respectively. Covariates in fully-adjusted model included age, sex, BMI, smoking, hormone replacement therapy (women), cardiovascular disease, hypertension, coronary artery calcified plaque mass, carotid artery calcified plaque mass, and African ancestry proportion. RESULTS:After median of 7.1(5.9, 8.2) years follow-up, 30(9.6%) of women and 49(19.1%) of men were deceased. In fully-adjusted models, psoas muscle mass index and paraspinous muscle mass index were inversely associated with mortality in men (psoas muscle mass index, hazard ratio [HR] = 0.61, P = 0.004; paraspinous muscle mass index, HR = 0.64, P = 0.004), but not in women. Psoas and paraspinous muscle densities did not associate with all-cause mortality. A penalized Cox regression that involved all covariates and predictors associated with mortality showed that only paraspinous muscle mass index remained a significant predictor of mortality (HR = 0.65, P = 0.02). CONCLUSION:Independent from established risk factors for mortality, higher psoas and paraspinous muscle index associate with reduced all-cause mortality in middle-aged African American men with type 2 diabetes mellitus.