Faculty Bibliography
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238
Mortality in youth-onset type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth study
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.
PMCID:6089078
PMID: 29685480
ISSN: 1873-460x
CID: 4318732
Cardiovascular autonomic neuropathy in adolescents and young adults with type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth Cohort Study
OBJECTIVE:To estimate the prevalence of and risk factors for cardiovascular autonomic neuropathy (CAN) in adolescents and young adults with type 1 and type 2 diabetes enrolled in the SEARCH for Diabetes in Youth Study. METHODS:The study included 1646 subjects with type 1 diabetes (age 18 ± 4 years, diabetes duration 8 ± 2 years, HbA1c 9.1 ± 1.9%, 76% non-Hispanic Whites) and 252 with type 2 diabetes (age 22 ± 4 years, diabetes duration 8 ± 2 years, HbA1c 9.2 ± 3.0%, 45% non-Hispanic Blacks). Cross-sectional and longitudinal risk factors were assessed at baseline and follow-up visits. Area under the curve (AUC) was used to assess the longitudinal glycemic exposure and cardiovascular risk factors. CAN was assessed by time and frequency domain indices of heart rate variability (HRV). CAN was defined as the presence of ≥3 of 5 abnormal HRV indices. RESULTS:The prevalence of CAN was 12% in adolescents and young adults with type 1 diabetes and 17% in those with type 2 diabetes. Poor long-term glycemic control (AUC HbA1c), high blood pressure, and elevated triglyceride levels were correlates of CAN in subjects with type 1 diabetes. In those with type 2 diabetes, CAN was associated with elevated triglycerides and increased urinary albumin excretion. CONCLUSIONS:The prevalence of CAN in this multiethnic cohort of adolescents and young adults with type 1 and type 2 diabetes are comparable to those reported in adults with diabetes. Suboptimal glycemic control and elevated triglycerides were the modifiable risk factors associated with CAN.
PMCID:5938122
PMID: 29292558
ISSN: 1399-5448
CID: 4318662
Predicting Mortality in African Americans With Type 2 Diabetes Mellitus: Soluble Urokinase Plasminogen Activator Receptor, Coronary Artery Calcium, and High-Sensitivity C-Reactive Protein
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.
PMCID:6015289
PMID: 29716888
ISSN: 2047-9980
CID: 4318742
Response to Comment on Chan et al. FGF23 Concentration and APOL1 Genotype Are Novel Predictors of Mortality in African Americans With Type 2 Diabetes. Diabetes Care 2018;41:178-186 [Comment]
PMID: 29678870
ISSN: 1935-5548
CID: 4318722
Transethnic Evaluation Identifies Low-Frequency Loci Associated With 25-Hydroxyvitamin D Concentrations
Context:Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry. Objective:The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries. Design:Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL). Patients or Other Participants:In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study. Main Outcome Measures:Blood concentrations of 25(OH)D were measured for all participants. Results:Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively. Conclusions:Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.
PMCID:6276579
PMID: 29325163
ISSN: 1945-7197
CID: 3985502
Journals of gerontology. Series A. Biological sciences & medical sciences. 2018:73(3):407-414.DOI: 10.1093/gerona/glx255
Cerebral Structure and Cognitive Performance in African Americans and European Americans With Type 2 Diabetes
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.
PMCID:5861881
PMID: 29309525
ISSN: 1758-535x
CID: 4318672
A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure
Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
PMCID:5985266
PMID: 29455858
ISSN: 1537-6605
CID: 3141612
Response to Comment on Jaiswal et al. Prevalence of and Risk Factors for Diabetic Peripheral Neuropathy in Youth With Type 1 and Type 2 Diabetes: SEARCH for Diabetes in Youth Study. Diabetes Care 2017;40:1226-1232 [Comment]
PMID: 29463674
ISSN: 1935-5548
CID: 4318702
A null variant in the apolipoprotein L3 gene is associated with non-diabetic nephropathy
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.
PMCID:5837424
PMID: 28339911
ISSN: 1460-2385
CID: 4318582
FGF23 Concentration and APOL1 Genotype Are Novel Predictors of Mortality in African Americans With Type 2 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.
PMID: 29113983
ISSN: 1935-5548
CID: 4318642
