African American-Diabetes Heart Study Research Articles

Serum Bicarbonate Is Associated with Bone Density Among Adults with Type 2 Diabetes: Results from the African American Diabetes Heart Study

Serum Bicarbonate Is Associated with Bone Density Among Adults with Type 2 Diabetes: Results from the African American Diabetes Heart Study

Genome-wide association study of vitamin D concentrations and bone mineral density in the African American-Diabetes Heart Study.

Relative to European Americans, African Americans have lower 25-hydroxyvitamin D (25OHD) and vitamin D binding protein (VDBP) concentrations, higher 1,25-dihydroxyvitamin D (1,25(OH)2D3) concentrations and bone mineral density (BMD), and paradoxically reduced burdens of calcified atherosclerotic plaque (subclinical atherosclerosis). To identify genetic factors contributing to vitamin D and BMD measures, association analysis of >14M variants was conducted in a maximum of 697 African American-Diabetes Heart Study participants with type 2 diabetes (T2D). The most significant association signals were detected for VDBP on chromosome 4; variants rs7041 (β = 0.44, SE = 0.019, P = 9.4x10-86) and rs4588 (β = 0.17, SE = 0.021, P = 3.5x10-08) in the group-specific component (vitamin D binding protein) gene (GC). These variants were found to be independently associated. In addition, rs7041 was also associated with bioavailable vitamin D (BAVD; β = 0.16, SE = 0.02, P = 3.3x10-19). Six rare variants were significantly associated with 25OHD, including a non-synonymous variant in HSPG2 (rs116788687; β = -1.07, SE = 0.17, P = 2.2x10-10) and an intronic variant in TNIK (rs143555701; β = -1.01, SE = 0.18, P = 9.0x10-10), both biologically related to bone development. Variants associated with 25OHD failed to replicate in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of vitamin D metabolism and bone mineral density phenotypes in an African American population enriched for T2D could provide insight into ethnic specific differences in vitamin D metabolism and bone mineral density.

Abstract P189: Metabolomic Signatures Of Serum Creatinine Among Hypertensive African Americans.

Background: The prevalence of chronic kidney disease (CKD) in African Americans (AAs) is high. Although ancestry-specific biomarkers have been identified, few translate to the clinic. Metabolomic studies may identify novel biomarkers useful for prevention, diagnosis and treatment. Methods: Plasma from 300 AA Hypertension Genetic Epidemiology Network (HyperGEN) study participants age ≥40 years with serum creatinine (SCr) <2 mg/dL were assayed for an untargeted metabolomic study of SCr using an ultra-high performance liquid chromatography mass spectrometry platform (Metabolon ® ). SCr was measured using a thin-film adaptation of the amidohydrolase enzymatic method on fasting blood samples. Each metabolite was tested for normality and a rank-based inverse normal transformation was performed as appropriate. Multivariable linear regression was used to test for association between the metabolite (outcome) and SCr (exposure of interest) adjusting for age, gender, waist circumference and center. A Bonferroni correction was used to adjust for multiple testing using. The top 25 most significant metabolites were evaluated for replication in 367 participants from the African American-Diabetes Heart Study (AA-DHS). An exploratory pathway analysis was conducted among significant (p< 6.0*10 -5 6.0e -5 metabolites in HyperGEN. Results: Among 300 participants from HyperGEN the mean age was 54.5 years (SD=9.5) and 58.7% were female. Mean SCr was 0.93 (SD=0.25). Eighty percent were treated for hypertension and 28% had diabetes. A total of 809 metabolites were annotated in HyperGEN samples. Of those, 391 were associated with SCr at p<0.05 and 256 metabolites met the Bonferroni significance criteria (p< 6.0*10 -5 ). The top SCr associated metabolites were tartonate(hydroxymalonate)(β[SE]= 2.99[0.07], p=3.98e -117 ), 1-stearoyl-GPC(18:0)(β[SE]= 2.49[0.14], p=2.28e -44 ), 2S-3R-dihydroxybutyrate)(β[SE]= 2.36[0.14],p=1.53e -40 ) and isovalerate(C5)( β[SE]= 2.30[0.15], p = 2.78e -36 ). The association of these metabolites with SCr replicated in AA-DHS [(tartonate(hydroxymalonate)(β[SE]= 0.66[0.19], p=0.001), 1-stearoyl-GPC(18:0)(β[SE]= 1.30[0.20], p=1.61 -10 ), 2S-3R-dihydroxybutyrate)(β[SE]= 1.20[0.18],p=4.69e -11 ) and isovalerate(C5)( β[SE]= 1.24[0.20], p = 1.91e -09 )]. An exploratory pathway analysis highlighted xenobiotics and the lysophospholipid pathway. Significance: Tartronate is a xenobiotic that is related to BMI, insulin resistance and adiponectin. 1-stearoyl-GPC (18:0) is a lysophospholipid metabolite found to be associated with oxidative stress. Conclusion: The current study discovered and replicated metabolites associated with SCr in a population of AAs with a high prevalence of hypertension. If validated, these could provide new insights in kidney disease pathways or aid in the treatment and prevention of CKD in the AA population.

Plasma apoM and S1P levels are inversely associated with mortality in African Americans with type 2 diabetes mellitus

apoM is a minor HDL apolipoprotein and carrier for sphingosine-1-phosphate (S1P). HDL apoM and S1P concentrations are inversely associated with atherosclerosis progression in rodents. We evaluated associations between plasma concentrations of S1P, plasma concentrations of apoM, and HDL apoM levels with prevalent subclinical atherosclerosis and mortality in the African American-Diabetes Heart Study participants (N = 545). Associations between plasma S1P, plasma apoM, and HDL apoM with subclinical atherosclerosis and mortality were assessed using multivariate parametric, nonparametric, and Cox proportional hazards models. At baseline, participants' median (25th percentile, 75th percentile) age was 55 (49, 62) years old and their coronary artery calcium (CAC) mass score was 26.5 (0.0, 346.5). Plasma S1P, plasma apoM, and HDL apoM were not associated with CAC. After 64 (57.6, 70.3) months of follow-up, 81 deaths were recorded. Higher concentrations of plasma S1P [odds ratio (OR) = 0.14, P = 0.01] and plasma apoM (OR = 0.10, P = 0.02), but not HDL apoM (P = 0.89), were associated with lower mortality after adjusting for age, sex, statin use, CAC, kidney function, and albuminuria. We conclude that plasma S1P and apoM concentrations are inversely and independently associated with mortality, but not CAC, in African Americans with type 2 diabetes after accounting for conventional risk factors.

Fully automatic liver attenuation estimation combing CNN segmentation and morphological operations.

Manually tracing regions of interest (ROIs) within the liver is the de facto standard method for measuring liver attenuation on computed tomography (CT) in diagnosing nonalcoholic fatty liver disease (NAFLD). However, manual tracing is resource intensive. To address these limitations and to expand the availability of a quantitative CT measure of hepatic steatosis, we propose the automatic liver attenuation ROI-based measurement (ALARM) method for automated liver attenuation estimation. The ALARM method consists of two major stages: (a) deep convolutional neural network (DCNN)-based liver segmentation and (b) automated ROI extraction. First, liver segmentation was achieved using our previously developed SS-Net. Then, a single central ROI (center-ROI) and three circles ROI (periphery-ROI) were computed based on liver segmentation and morphological operations. The ALARM method is available as an open source Docker container (https://github.com/MASILab/ALARM). Two hundred and forty-six subjects with 738 abdomen CT scans from the African American-Diabetes Heart Study (AA-DHS) were used for external validation (testing), independent from the training and validation cohort (100 clinically acquired CT abdominal scans). From the correlation analyses, the proposed ALARM method achieved Pearson correlations=0.94 with manual estimation on liver attenuation estimations. When evaluating the ALARM method for detection of nonalcoholic fatty liver disease (NAFLD) using the traditional cut point of <40HU, the center-ROI achieved substantial agreements (Kappa=0.79) with manual estimation, while the periphery-ROI method achieved "excellent" agreement (Kappa=0.88) with manual estimation. The automated ALARM method had reduced variability compared to manual measurements as indicated by a smaller standard deviation. We propose a fully automated liver attenuation estimation method termed ALARM by combining DCNN and morphological operations, which achieved "excellent" agreement with manual estimation for fatty liver detection. The entire pipeline is implemented as a Docker container which enables users to achieve liver attenuation estimation in five minutes per CT exam.

The Impact of APOL1 on Chronic Kidney Disease and Hypertension.

Essential hypertension is a clinical diagnosis based on the presence of an elevated systemic blood pressure on physical examination without a clear inciting cause. It has multiple etiologies and is not a homogeneous disorder. Hypertension contributes to the development and progression of atherosclerotic cardiovascular diseases, and antihypertensive treatment reduces the risk of fatal and nonfatal myocardial infarction, stroke, and congestive heart failure. Although hypertension is frequently present in nondiabetic individuals with low levels of proteinuria and chronic kidney disease, reducing blood pressures in this population does not reliably slow nephropathy progression. Many of these patients with recent African ancestry have the primary kidney disease "solidified glomerulosclerosis" that is strongly associated with renal-risk variants in the apolipoprotein L1 gene (APOL1). This kidney disease contributes to secondarily elevated blood pressures. The APOL1-associated spectrum of nondiabetic nephropathy also includes proteinuric kidney diseases, idiopathic focal segmental glomerulosclerosis, collapsing glomerulopathy, severe lupus nephritis, and sickle cell nephropathy. This article reviews relationships between mild to moderate essential hypertension and chronic kidney disease with a focus on the role of APOL1 in development of hypertension. Available evidence strongly supports that APOL1 renal-risk variants associate with glomerulosclerosis in African Americans, which then causes secondary hypertension, not with essential hypertension per se.

JC Viruria Is Associated With Reduced Risk of Diabetic Kidney Disease

African Americans who shed JC polyomavirus (JCV) in their urine have reduced rates of nondiabetic chronic kidney disease (CKD). We assessed the associations between urinary JCV and urine BK polyomavirus (BKV) with CKD in African Americans with diabetes mellitus. African Americans with diabetic kidney disease (DKD) and controls lacking nephropathy from the Family Investigation of Nephropathy and Diabetes Consortium (FIND) and African American-Diabetes Heart Study (AA-DHS) had urine tested for JCV and BKV using quantitative PCR. Of the 335 individuals tested, 148 had DKD and 187 were controls. JCV viruria was detected more often in the controls than in the patients with DKD (FIND: 46.6% vs 32.2%; OR, 0.52; 95% CI, 0.29 to 0.93; P = 0.03; AA-DHS: 30.4% vs 26.2%; OR, 0.63; 95% CI, 0.27 to 1.48; P = 0.29). A joint analysis adjusted for age, sex, and study revealed that JC viruria was inversely associated with DKD (OR, 0.56; 95% CI, 0.35 to 0.91; P = 0.02). Statistically significant relationships between BKV and DKD were not observed. The results from the present study extend the inverse association between urine JCV and nondiabetic nephropathy in African Americans to DKD. These results imply that common pathways likely involving the innate immune system mediate coincident chronic kidney injury and restriction of JCV replication. Future studies are needed to explore causative pathways and characterize whether the absence of JC viruria can serve as a biomarker for DKD in the African American population.

Volumetric bone mineral density of the spine predicts mortality in African-American men with type 2 diabetes.

Compared to European Americans, African Americans have lower rates of osteoporosis and higher rates of T2D. The relationships between BMD and fractures with mortality are unknown in this population. The aim of this study was to determine relationships between vertebral fractures and vertebral vBMD and mortality in African Americans with T2D. Associations between vertebral fractures and vBMD with all-cause mortality were examined in 675 participants with T2D (391 women and 284 men) in the African American-Diabetes Heart Study (AA-DHS). Lumbar and thoracic vBMD were measured using quantitative computed tomography (QCT). Vertebral fractures were assessed on sagittal CT images. Associations of vertebral fractures and vBMD with all-cause mortality were determined in sex-stratified analyses and in the full sample. Covariates in a minimally adjusted model included age, sex, BMI, smoking, and alcohol use; the full model was adjusted for those variables plus cardiovascular disease, hypertension, coronary artery calcified plaque, hormone replacement therapy (women), African ancestry proportion, and eGFR. After mean 7.6 ± 1.8-year follow-up, 59 (15.1%) of women and 58 (20.4%) of men died. In men, vBMD was inversely associated with mortality in the fully adjusted model: lumbar hazard ratio (HR) per standard deviation (SD) = 0.70 (95% CI 0.52-0.95, p = 0.02) and thoracic HR per SD = 0.71 (95% CI 0.54-0.92, p = 0.01). Only trends toward association between vBMD and mortality were observed in the combined sample of men and women, as significant associations were absent in women. Vertebral fractures were not associated with mortality in either sex. Lower vBMD was associated with increased all-cause mortality in African-American men with T2D, independent of other risk factors for mortality including subclinical atherosclerosis.

Associations of coronary artery calcified plaque density with mortality in type 2 diabetes: the Diabetes Heart Study

BackgroundCoronary artery calcified plaque (CAC) is strongly predictive of cardiovascular disease (CVD) events and mortality, both in general populations and individuals with type 2 diabetes at high risk for CVD. CAC is typically reported as an Agatston score, which is weighted for increased plaque density. However, the role of CAC density in CVD risk prediction, independently and with CAC volume, remains unclear.MethodsWe examined the role of CAC density in individuals with type 2 diabetes from the family-based Diabetes Heart Study and the African American-Diabetes Heart Study. CAC density was calculated as mass divided by volume, and associations with incident all-cause and CVD mortality [median follow-up 10.2 years European Americans (n = 902, n = 286 deceased), 5.2 years African Americans (n = 552, n = 93 deceased)] were examined using Cox proportional hazards models, independently and in models adjusted for CAC volume.ResultsIn European Americans, CAC density, like Agatston score and volume, was consistently associated with increased risk of all-cause and CVD mortality (p ≤ 0.002) in models adjusted for age, sex, statin use, total cholesterol, HDL, systolic blood pressure, high blood pressure medication use, and current smoking. However, these associations were no longer significant when models were additionally adjusted for CAC volume. CAC density was not significantly associated with mortality, either alone or adjusted for CAC volume, in African Americans.ConclusionsCAC density is not associated with mortality independent from CAC volume in European Americans and African Americans with type 2 diabetes.

Psoas and paraspinous muscle index as a predictor of mortality in African American men with type 2 diabetes mellitus

AimRecent 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. MethodsPsoas and paraspinous muscle mass index (cross sectional area/height2) 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. ResultsAfter 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). ConclusionIndependent 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.

Adipose tissue depot volume relationships with spinal trabecular bone mineral density in African Americans with diabetes.

Changes in select adipose tissue volumes may differentially impact bone mineral density. This study was performed to assess cross-sectional and longitudinal relationships between computed tomography-determined visceral (VAT), subcutaneous (SAT), inter-muscular (IMAT), and pericardial adipose tissue (PAT) volumes with respective changes in thoracic vertebral and lumbar vertebral volumetric trabecular bone mineral density (vBMD) in African Americans with type 2 diabetes. Generalized linear models were fitted to test relationships between baseline and change in adipose volumes with change in vBMD in 300 African American-Diabetes Heart Study participants; adjustment was performed for age, sex, diabetes duration, study interval, smoking, hypertension, BMI, kidney function, and medications. Participants were 50% female with mean ± SD age 55.1±9.0 years, diabetes duration 10.2±7.2 years, and BMI 34.7±7.7 kg/m2. Over 5.3 ± 1.4 years, mean vBMD decreased in thoracic/lumbar spine, while mean adipose tissue volumes increased in SAT, IMAT, and PAT, but not VAT depots. In fully-adjusted models, changes in lumbar and thoracic vBMD were positively associated with change in SAT (β[SE] 0.045[0.011], p<0.0001; 0.40[0.013], p = 0.002, respectively). Change in thoracic vBMD was positively associated with change in IMAT (p = 0.029) and VAT (p = 0.016); and change in lumbar vBMD positively associated with baseline IMAT (p<0.0001). In contrast, vBMD was not associated with change in PAT. After adjusting for BMI, baseline and change in volumes of select adipose depots were associated with increases in thoracic and lumbar trabecular vBMD in African Americans. Effects of adiposity on trabecular bone appear to be site-specific and related to factors beyond mechanical load.

Genome-wide association study of coronary artery calcified atherosclerotic plaque in African Americans with type 2 diabetes

BackgroundCoronary artery calcified atherosclerotic plaque (CAC) predicts cardiovascular disease (CVD). Despite exposure to more severe conventional CVD risk factors, African Americans (AAs) are less likely to develop CAC, and when they do, have markedly lower levels than European Americans. Genetic factors likely contribute to the observed ethnic differences. To identify genes associated with CAC in AAs with type 2 diabetes (T2D), a genome-wide association study (GWAS) was performed using the Illumina 5 M chip in 691 African American-Diabetes Heart Study participants (AA-DHS), with replication in 205 Jackson Heart Study (JHS) participants with T2D. Genetic association tests were performed on the genotyped and 1000 Genomes-imputed markers separately for each study, and combined in a meta-analysis.ResultsSingle nucleotide polymorphisms (SNPs), rs11353135 (2q22.1), rs16879003 (6p22.3), rs5014012, rs58071836 and rs10244825 (all on chromosome 7), rs10918777 (9q31.2), rs13331874 (16p13.3) and rs4459623 (18q12.1) were associated with presence and/or quantity of CAC in the AA-DHS and JHS, with meta-analysis p-values ≤8.0 × 10−7. The strongest result in AA-DHS alone was rs6491315 in the 13q32.1 region (parameter estimate (SE) = −1.14 (0.20); p-value = 9.1 × 10−9). This GWAS peak replicated a previously reported AA-DHS CAC admixture signal (rs7492028, LOD score 2.8).ConclusionsGenetic association between SNPs on chromosomes 2, 6, 7, 9, 16 and 18 and CAC were detected in AAs with T2D from AA-DHS and replicated in the JHS. These data support a role for genetic variation on these chromosomes as contributors to CAC in AAs with T2D, as well as to variation in CAC between populations of African and European ancestry.

FGF23 Concentration and APOL1 Genotype Are Novel Predictors of Mortality in African Americans With Type 2 Diabetes.

OBJECTIVECardiovascular 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 METHODSAssociations between mortality and subclinical atherosclerosis, urine albumin–to–creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), plasma fibroblast growth factor 23 (FGF23) concentration, African ancestry proportion, and apolipoprotein L1 genotypes (APOL1) were assessed in 513 African Americans with type 2 diabetes; analyses were performed using Cox proportional hazards models.RESULTSAt baseline, participants were 55.6% female with median (25th, 75th percentile) age 55 years (49.0, 62.0), diabetes duration 8 years (5.0, 13.0), glycosylated hemoglobin 60.7 mmol/mol (48.6, 76.0), eGFR 91.3 mL/min/1.73 m2 (76.4, 111.3), UACR 12.5 mg/mmol (4.2, 51.2), and coronary artery calcium 28.5 mg Ca2+ (1.0, 348.6); 11.5% had two APOL1 renal-risk variants. After 6.6-year follow-up (5.8, 7.5), 54 deaths were recorded. Higher levels of coronary artery calcified plaque, carotid artery calcified plaque, albuminuria, and FGF23 were associated with higher mortality after adjustment for age, sex, and African ancestry proportion. A penalized Cox regression that included all covariates and predictors associated with mortality identified male sex (hazard ratio [HR] 4.17 [95% CI 1.96–9.09]), higher FGF23 (HR 2.10 [95% CI 1.59–2.78]), and absence of APOL1 renal-risk genotypes (HR 0.07 [95% CI 0.01–0.69]) as the strongest predictors of mortality.CONCLUSIONSAccounting for conventional risk factors, higher FGF23 concentrations and APOL1 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.

Bone Mineral Density and Progression of Subclinical Atherosclerosis in African-Americans With Type 2 Diabetes.

Relative to European Americans, calcified atherosclerotic plaque (CP) is less prevalent and severe in African-Americans (AAs). Predictors of progression of CP in the aorta, carotid, and coronary arteries were examined in AAs over a mean 5.3 ± 1.4-year interval. This is the African American-Diabetes Heart Study. A type 2 diabetes (T2D)-affected cohort was included. A total of 300 unrelated AAs with T2D; 50% female, mean age 55 ± 9 years, baseline hemoglobin A1c 8.1 ± 1.8% was included. Glycemic control, renal parameters, vitamin D, and computed tomography-derived measures of adiposity, vascular CP, and volumetric bone mineral density (vBMD) in lumbar and thoracic vertebrae were obtained at baseline and follow-up. CP increased in incidence and quantity/mass in all three vascular beds over the 5-year study (P < .0001). Lower baseline lumbar and thoracic vBMD were associated with progression of abdominal aorta CP (P < .008), but not progression of carotid or coronary artery CP. Lower baseline estimated glomerular filtration rate was associated with progression of carotid artery CP (P = .0004), and higher baseline pericardial adipose volume was associated with progression of coronary artery (P = .001) and aorta (P = .0006) CP independent of body mass index. There was a trend for an inverse relationship between change in thoracic vBMD and change in aortic CP (P = .05). In this longitudinal study, lower baseline thoracic and lumbar vBMD and estimated glomerular filtration rate and higher pericardial adipose volumes were associated with increases in CP in AAs with T2D. Changes in these variables and baseline levels and/or changes in glycemic control, albuminuria, and vitamin D were not significantly associated with progression of CP.

APOL1 renal-risk variants associate with reduced cerebral white matter lesion volume and increased gray matter volume

To assess apolipoprotein L1 gene (APOL1) renal-risk-variant effects on the brain, magnetic resonance imaging (MRI)-based cerebral volumes and cognitive function were assessed in 517 African American-Diabetes Heart Study (AA-DHS) Memory IN Diabetes (MIND) and 2568 hypertensive African American Systolic Blood Pressure Intervention Trial (SPRINT) participants without diabetes. Within these cohorts, 483 and 197 had cerebral MRI, respectively. AA-DHS participants were characterized as follows: 60.9% female, mean age of 58.6 years, diabetes duration 13.1 years, estimated glomerular filtration rate of 88.2 ml/min/1.73 m(2), and a median spot urine albumin to creatinine ratio of 10.0 mg/g. In additive genetic models adjusting for age, sex, ancestry, scanner, intracranial volume, body mass index, hemoglobin A1c, statins, nephropathy, smoking, hypertension, and cardiovascular disease, APOL1 renal-risk-variants were positively associated with gray matter volume (β= 3.4× 10(-3)) and negatively associated with white matter lesion volume (β= -0.303) (an indicator of cerebral small vessel disease) and cerebrospinal fluid volume (β= -30707) (all significant), but not with white matter volume or cognitive function. Significant associations corresponding to adjusted effect sizes (β/SE) were observed with gray matter volume (0.16) and white matter lesion volume (-0.208), but not with cerebrospinal fluid volume (-0.251). Meta-analysis results with SPRINT Memory and Cognition in Decreased Hypertension (MIND) participants who had cerebral MRI were confirmatory. Thus, APOL1 renal-risk-variants are associated with larger gray matter volume and lower white matter lesion volume suggesting lower intracranial small vessel disease.

Admixture mapping of serum vitamin D and parathyroid hormone concentrations in the African American—Diabetes Heart Study

Vitamin D and intact parathyroid hormone (iPTH) concentrations differ between individuals of African and European descent and may play a role in observed racial differences in bone mineral density (BMD). These findings suggest that mapping by admixture linkage disequilibrium (MALD) may be informative for identifying genetic variants contributing to these ethnic disparities. Admixture mapping was performed for serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, vitamin D-binding protein (VDBP), bioavailable vitamin D, and iPTH concentrations and computed tomography measured thoracic and lumbar vertebral volumetric BMD in 552 unrelated African Americans with type 2 diabetes from the African American—Diabetes Heart Study. Genotyping was performed using a custom Illumina ancestry informative marker (AIM) panel. For each AIM, the probability of inheriting 0, 1, or 2 copies of a European-derived allele was determined. Non-parametric linkage analysis was performed by testing for association between each AIM using these probabilities among phenotypes, accounting for global ancestry, age, and gender. Fine-mapping of MALD peaks was facilitated by genome-wide association study (GWAS) data. VDBP levels were significantly linked in proximity to the protein coding locus (rs7689609, LOD=11.05). Two loci exhibited significant linkage signals for 1,25-dihydroxyvitamin D on 13q21.2 (rs1622710, LOD=3.20) and 12q13.2 (rs11171526, LOD=3.10). iPTH was significantly linked on 9q31.3 (rs7854368, LOD=3.14). Fine-mapping with GWAS data revealed significant known (rs7041 with VDBP, P=1.38×10−82) and novel (rs12741813 and rs10863774 with VDBP, P<6.43×10−5) loci with plausible biological roles. Admixture mapping in combination with fine-mapping has focused efforts to identify loci contributing to ethnic differences in vitamin D-related traits.

Plasma FGF23 and Calcified Atherosclerotic Plaque in African Americans with Type 2 Diabetes Mellitus

Background: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in disorders of serum phosphorus concentration and vitamin D. The role of FGF23 in vascular calcification remains controversial. Methods: Relationships between FGF23 and coronary artery calcified atherosclerotic plaque (CAC), aortoiliac calcified plaque (CP), carotid artery CP, volumetric bone mineral density (vBMD), albuminuria, and estimated glomerular filtration rate (eGFR) were determined in 545 African Americans with type 2 diabetes (T2D) and preserved kidney function in African American-Diabetes Heart Study participants. Generalized linear models were fitted to test associations between FGF23 and cardiovascular, bone, and renal phenotypes, and change in measurements over time, adjusting for age, gender, African ancestry proportion, body mass index, diabetes duration, hemoglobin A1c, blood pressure, renin-angiotensin-system inhibitors, statins, calcium supplements, serum calcium, and serum phosphate. Results: The sample was 56.7% female with a mean (SD) age of 55.6 (9.6) years, diabetes duration of 10.3 (8.2) years, eGFR 90.9 (22.1) ml/min/1.73 m², urine albumin:creatinine ratio (UACR) 151 (588) (median 13) mg/g, plasma FGF23 161 (157) RU/ml, and CAC 637 (1,179) mg. In fully adjusted models, FGF23 was negatively associated with eGFR (p < 0.0001) and positively associated with UACR (p < 0.0001) and CAC (p = 0.0006), but not with carotid CP or aortic CP. Baseline FGF23 concentration did not associate with changes in vBMD or CAC after a mean of 5.1 years follow-up. Conclusions: Plasma FGF23 concentrations were independently associated with subclinical coronary artery disease, albuminuria, and kidney function in the understudied African American population with T2D. Findings support relationships between FGF23 and vascular calcification, but not between FGF23 and bone mineral density, in African Americans lacking advanced nephropathy.

Effects of Type 2 Diabetes on Brain Structure and Cognitive Function: African American-Diabetes Heart Study MIND.

Rates of type 2 diabetes are higher among African Americans compared with individuals of European ancestry. The purpose of this investigation was to determine the relationship between MR imaging measures of brain structure (volume of GM, WM, WM lesions) and cognitive function in a population of African Americans with type 2 diabetes. These MR imaging measures of brain structure are affected by type 2 diabetes-associated macrovascular and microvascular disease and may be associated with performance on tasks of cognitive function in the understudied African American population. African Americans with type 2 diabetes enrolled in the African American-Diabetes Heart Study MIND study (n = 263) were evaluated across a broad range of cognitive domains and imaged with brain MR imaging. Associations between cognitive parameters and MR imaging measures of whole-brain GM, WM, and WM lesion volumes were assessed by using adjusted multivariate models. Lower GM volume was associated with poorer performance on measures of general cognitive function, working memory, and executive function. Higher WM lesion volume was associated with poorer performance on a smaller subset of cognitive domains compared with GM volume but included aspects of working memory and executive function. There were no statistically significant associations with WM volume. Markers of cortical atrophy and WM lesion volume are associated with cognitive function in African Americans with type 2 diabetes. These associations are described in an African American cohort with disease control similar to that of individuals of European ancestry, rather than underserved African Americans with poor access to health care. Interventions to reduce cortical atrophy and WM disease may improve cognitive outcomes in this understudied population.

APOL1 associations with nephropathy, atherosclerosis, and all-cause mortality in African Americans with type 2 diabetes

Albuminuria and reduced eGFR associate with two apolipoprotein L1 gene (APOL1) variants in non-diabetic African Americans. Whether APOL1 associates with subclinical atherosclerosis and survival remains unclear. To determine this, 717 African American-Diabetes Heart Study participants underwent computed tomography to determine coronary artery, carotid artery, and aorta calcified atherosclerotic plaque mass scores in addition to the urine albumin:creatinine ratio (UACR), eGFR, and C-reactive protein. Associations between mass scores and APOL1 were assessed adjusting for age, gender, African ancestry, BMI, HbA1c, smoking, hypertension, use of statins and ACE inhibitors, albuminuria, and eGFR. Participants were 58.9% female with mean age 56.5 years, eGFR 89.5 ml/min/1.73m2, UACR 169.6 mg/g, coronary artery, carotid artery and aorta calcified plaque mass scores of 610, 171 and 5378, respectively. In fully adjusted models, APOL1 risk variants were significantly associated with lower levels of carotid artery calcified plaque (β −0.42, SE 0.18, dominant model), and marginally lower coronary artery plaque (β −0.36, SE 0.21; dominant model), but not with aorta calcified plaque, C-reactive protein, UACR, or eGFR. After a mean follow-up of 5.0 years, 89 participants died. APOL1 nephropathy risk variants were significantly associated with improved survival (hazard ratio 0.67 for 1 copy; 0.44 for 2 copies). Thus, APOL1 nephropathy variants associate with lower levels of subclinical atherosclerosis and reduced risk of death in African Americans with type 2 diabetes mellitus.

Kidney Disease and Cognitive Function: African American-Diabetes Heart Study MIND

Aims: Albuminuria and reduced estimated glomerular filtration rate (eGFR) are linked with poorer cognitive performance in European-ancestry populations with advanced nephropathy; relationships in African Americans (AAs) with type 2 diabetes (T2D) are less clear. Tests of cognitive performance, urine albumin:creatinine ratio (UACR), and CKD-EPI eGFR were performed in unrelated AAs with T2D to determine relationships. Methods: Cross-sectional analysis of 263 unrelated AAs with T2D recruited in the African American-Diabetes Heart Study (AA-DHS) MIND. Global cognitive function (mini-mental state exam [3MSE] and Montreal Cognitive Assessment [MoCA]), memory (Rey Auditory Verbal Learning Test [RAVLT]), executive function (Stroop, verbal fluency for animals, and Digit Symbol Copy [DSC]), UACR, and eGFR were determined. Relationships between cognitive tests and renal parameters were assessed using multivariate models, adjusted for age, gender, body mass index, hemoglobin A1c, level of education, hypertension, and LDL cholesterol. Results: Participants had a mean ± SD age of 60.2 ± 9.7 years, 62.7% were female, T2D duration was 14.3 ± 8.9 years, eGFR 86.0 ± 23.2 ml/min/1.73 m², and UACR 155.8 ± 542.1 (median 8.1) mg/g. In adjusted models, higher UACR was associated with worse 3MSE (p = 0.014), MoCA (p = 0.0089), DSC (p = 0.0004), Stroop performance time (p = 0.003), Stroop errors (p = 0.032), and Stroop interference (p = 0.026). Higher eGFR was associated with better performance on DSC (p = 0.0071). Conclusions: In AAs with T2D, albuminuria and eGFR were associated with cognitive function, even in mild kidney disease. These data stress the need for interventions to prevent cognitive decline well before the late stages of kidney disease.