Barry I Freedman

Wake Forest School of Medicine, Winston-Salem, North Carolina, United States

Are you Barry I Freedman?

Claim your profile

Publications (428)2515.02 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Despite evidence of an association between variants at the apolipoprotein L1 gene (APOL1) locus and a spectrum of related kidney diseases, underlying biological mechanisms remain unknown. An earlier preliminary study published by our group showed that an APOL1 variant (rs73885319) modified the association between high-density lipoprotein cholesterol (HDLC) and estimated glomerular filtration rate (eGFR) in African Americans. To further understand this relationship, we evaluated the interaction in two additional large cohorts of African Americans for a total of 3,592 unrelated individuals from the Howard University Family Study (HUFS), the Natural History of APOL1-Associated Nephropathy Study (NHAAN), and the Atherosclerosis Risk in Communities Study (ARIC). The association between HDLC and eGFR was determined using linear mixed models, and the interaction between rs73885319 genotype and HDLC was evaluated using a multiplicative term. Results: Among individuals homozygous for the risk genotype, a strong inverse HDLC-eGFR association was observed, with a positive association in others (p for the interaction of the rs73885319 × HDLC =0.0001). The interaction was similar in HUFS and NHAAN, and attenuated in ARIC. Given that ARIC participants were older, we investigated an age effect; age was a significant modifier of the observed interaction. When older individuals were excluded, the interaction in ARIC was similar to that in the other studies. Conclusions: Based on these findings, it is clear that the relationship between HDLC and eGFR is strongly influenced by the APOL1 rs73885319 kidney risk genotype. Moreover, the degree to which this variant modifies the association may depend on the age of the individual. More detailed physiological studies are warranted to understand how rs73885319 may affect the relationship between HDLC and eGFR in individuals with and without disease and across the lifespan.
    BMC Genomics 12/2015; 16(1). DOI:10.1186/s12864-015-1645-7 · 3.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Apolipoprotein L1 gene (APOL1) renal-risk variants are associated with nephropathy and cardiovascular disease (CVD) in African Americans; however, little is known about the circulating APOL1 variant proteins which reportedly bind to HDL. We examined whether APOL1 G1 and G2 renal-risk variant serum concentrations or lipoprotein distributions differed from non-risk G0 APOL1 in African Americans without nephropathy. Serum APOL1 protein concentrations were similar regardless of APOL1 genotype. In addition, serum APOL1 protein was bound to protein complexes in two non-overlapping peaks, herein referred to as APOL1 complex A (12.2 nm diameter) and complex B (20.0 nm diameter). Neither of these protein complexes associated with HDL or LDL. Proteomic analysis revealed that complex A was composed of APOA1, haptoglobin-related protein (HPR), and complement C3, whereas complex B contained APOA1, HPR, IgM, and fibronectin. Serum HPR was less abundant on complex B in individuals with G1 and G2 renal-risk variant genotypes, relative to G0 (p=0.0002-0.002). These circulating complexes may play roles in HDL metabolism and susceptibility to CVD.
    The Journal of Lipid Research 11/2015; DOI:10.1194/jlr.M063453 · 4.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Two apolipoprotein L1 gene (APOL1) renal-risk variants in donors and African American (AA) recipient race are associated with worse allograft survival in deceased-donor kidney transplantation (DDKT) from AA donors. To detect other factors impacting allograft survival from deceased AA kidney donors, APOL1 renal-risk variants were genotyped in additional AA kidney donors. Methods: The APOL1 genotypes were linked to outcomes in 478 newly analyzed DDKTs in the Scientific Registry of Transplant Recipients. Multivariate analyses accounting for recipient age, sex, race, panel-reactive antibody level, HLA match, cold ischemia time, donor age, and expanded criteria donation were performed. These 478 transplantations and 675 DDKTs from a prior report were jointly analyzed. Results: Fully adjusted analyses limited to the new 478 DDKTs replicated shorter renal allograft survival in recipients of APOL1 2-renal-risk-variant kidneys (hazard ratio [HR], 2.00; P = 0.03). Combined analysis of 1153 DDKTs from AA donors revealed donor APOL1 high-risk genotype (HR, 2.05; P = 3 × 10), older donor age (HR, 1.18; P = 0.05), and younger recipient age (HR, 0.70; P = 0.001) adversely impacted allograft survival. Although prolonged allograft survival was seen in many recipients of APOL1 2-renal-risk-variant kidneys, follow-up serum creatinine concentrations were higher than that in recipients of 0/1 APOL1 renal-risk-variant kidneys. A competing risk analysis revealed that APOL1 impacted renal allograft survival, but not recipient survival. Interactions between donor age and APOL1 genotype on renal allograft survival were nonsignificant. Conclusions: Shorter renal allograft survival is reproducibly observed after DDKT from APOL1 2-renal-risk-variant donors. Younger recipient age and older donor age have independent adverse effects on renal allograft survival.
    Transplantation 11/2015; DOI:10.1097/TP.0000000000000969 · 3.83 Impact Factor
  • Karl L Skorecki · Barry I Freedman ·
    [Show abstract] [Hide abstract]
    ABSTRACT: The worldwide epidemic of chronic kidney disease - an insidious illness that manifests with asymptomatic reductions in the estimated glomerular filtration rate (eGFR) to less than 60 ml per minute per 1.73 m(2) of body-surface area, excessive urinary excretion of protein, or both - afflicts an estimated 600 million people.(1) Many will have progression to end-stage kidney disease and require dialysis or kidney transplantation for survival or succumb to related cardiovascular complications, even while taking antihypertensive agents and medications to lower blood glucose levels.(2),(3) Chronic kidney disease shortens survival, reduces the quality of life remaining to these patients, and . . .
    New England Journal of Medicine 11/2015; DOI:10.1056/NEJMe1512997 · 55.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims: To examine the relationships between type 2 diabetes (T2D) status, glycemic control, and T2D duration with magnetic resonance imaging (MRI)-derived neuroimaging measures in European Americans from the Diabetes Heart Study (DHS) Mind cohort. Methods: Relationships were examined using marginal models with generalized estimating equations in 784 participants from 514 DHS Mind families. Fasting plasma glucose, glycated hemoglobin, and diabetes duration were analyzed in 682 participants with T2D. Models were adjusted for potential confounders, including age, sex, history of cardiovascular disease, smoking, educational attainment, and use of statins or blood pressure medications. Association was tested with gray and white matter volume, white matter lesion volume, gray matter cerebral blood flow, and white and gray matter fractional anisotropy and mean diffusivity. Results: Adjusting for multiple comparisons, T2D status was associated with reduced white matter volume (p = 2.48 × 10(-6)) and reduced gray and white matter fractional anisotropy (p ≤ 0.001) in fully adjusted models, with a trend toward increased white matter lesion volume (p = 0.008) and increased gray and white matter mean diffusivity (p ≤ 0.031). Among T2D-affected participants, neither fasting glucose, glycated hemoglobin, nor diabetes duration were associated with the neuroimaging measures assessed (p > 0.05). Conclusions: While T2D was significantly associated with MRI-derived neuroimaging measures, differences in glycemic control in T2D-affected individuals in the DHS Mind study do not appear to significantly contribute to variation in these measures. This supports the idea that the presence or absence of T2D, not fine gradations of glycemic control, may be more significantly associated with age-related changes in the brain.
    Acta Diabetologica 11/2015; DOI:10.1007/s00592-015-0815-z · 2.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: The reticulon 1 gene (RTN1) encodes reticulons, endoplasmic reticulum stress proteins recently implicated in kidney disease progression. Methods: RTN1 single nucleotide polymorphisms (SNPs) were tested for association with type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) in African Americans (AAs) and European Americans (EAs), and AAs with non-diabetic ESKD. RTN1 SNPs that were associated with T2D-ESKD in AA cases compared to non-nephropathy controls were identified from a discovery genome-wide association study (n = 1,797), then tested for replication in 1,847 additional AA T2D-ESKD cases and controls. Results: Three intronic RTN1 variants were nominally associated with T2D-ESKD in both discovery and replication analyses: rs1952034, rs12431381 and rs12434215 (additive models); combined T2D-ESKD (discovery + replication) p values were 0.015-3.0 × 10-4 (ORs 0.67-0.77; minor alleles protective). In addition, rs12434215 was weakly associated with T2D-ESKD in 557 EA T2D-ESKD cases contrasted with 753 EA non-nephropathy controls (p = 0.019; OR 0.69, dominant model). Nominal association extended to non-diabetic causes of ESKD in 1,459 additional AA cases (rs12431381 and rs12434215 p values 0.014-0.015; OR 0.77). An all-cause ESKD association analysis contrasted the 3,594 AA ESKD cases with 1,489 AA non-nephropathy controls and detected association with rs12434215 (p = 6.7 × 10-4, OR 0.73) and rs12431381 (p = 7.5 × 10-4, OR 0.75) in dominant models. Of the 3 SNPs, only rs12434215 was weakly associated with T2D per se when contrasting T2D non-nephropathy cases with non-diabetic controls (additive model p = 0.032 AAs; p = 0.048 EAs). Conclusions: These results suggest evidence of genetic association between common variants in RTN1 and ESKD in AAs and EAs.
    American Journal of Nephrology 10/2015; 42(4):259-264. DOI:10.1159/000441199 · 2.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.
    Clinical Immunology 09/2015; 161(2). DOI:10.1016/j.clim.2015.09.007 · 3.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: Relative to European Americans, African Americans manifest lower levels of computed tomography-based calcified atherosclerotic plaque (CP), a measure of subclinical cardiovascular disease (CVD). Potential relationships between CP and cerebral structure are poorly defined in the African American population. We assessed associations among glycemic control, inflammation, and CP with cerebral structure on MRI and with cognitive performance in 268 high-risk African Americans with type 2 diabetes. Research design and methods: Associations among hemoglobin A1c (HbA1c), C-reactive protein (CRP), and CP in coronary arteries, carotid arteries, and the aorta with MRI volumetric analysis (white matter volume, gray matter volume [GMV], cerebrospinal fluid volume, and white matter lesion volume) were assessed using generalized linear models adjusted for age, sex, African ancestry proportion, smoking, BMI, use of statins, HbA1c level, hypertension, and prior CVD. Results: Participants were 63.4% female with mean (SD) age of 59.8 years (9.2 years), diabetes duration of 14.5 years (7.6 years), HbA1c level of 7.95% (1.9%), estimated glomerular filtration rate of 86.7 mL/min/1.73 m(2) (24.6 mL/min/1.73 m(2)), and coronary artery CP mass score of 215 mg (502 mg). In fully adjusted models, GMV was inversely associated with coronary artery CP (parameter estimate [β] -0.47 [SE 0.15], P = 0.002; carotid artery CP (β -1.92 [SE 0.62], P = 0.002; and aorta CP [β -0.10 [SE 0.03] P = 0.002); whereas HbA1c and CRP levels did not associate with cerebral volumes. Coronary artery CP also associated with poorer global cognitive function on the Montreal Cognitive Assessment. Conclusions: Subclinical atherosclerosis was associated with smaller GMV and poorer cognitive performance in African Americans with diabetes. Cardioprotective strategies could preserve GMV and cognitive function in high-risk African Americans with diabetes.
    Diabetes care 09/2015; DOI:10.2337/dc15-1035 · 8.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: In African Americans (AAs), APOL1 G1 and G2 nephropathy risk variants are associated with non-diabetic end-stage kidney disease (ESKD) in an autosomal recessive pattern. Additional risk and protective genetic variants may be present near the APOL1 loci, since earlier age ESKD is observed in some AAs with one APOL1 renal-risk variant, and because the adjacent gene MYH9 is associated with nephropathy in populations lacking G1 and G2 variants. Methods: Re-sequencing was performed across a ∼275 kb region encompassing the APOL1-APOL4 and MYH9 genes in 154 AA cases with non-diabetic ESKD and 38 controls without nephropathy who were heterozygous for a single APOL1 G1 or G2 risk variant. Results: Sequencing identified 3,246 non-coding single nucleotide polymorphisms (SNPs), 55 coding SNPs, and 246 insertion/deletions. No new coding variations were identified. Eleven variants, including a rare APOL3 Gln58Ter null variant (rs11089781), were genotyped in a replication panel of 1,571 AA ESKD cases and 1,334 controls. After adjusting for APOL1 G1 and G2 risk effects, these variations were not significantly associated with ESKD. In subjects with <2 APOL1 G1 and/or G2 alleles (849 cases; 1,139 controls), the APOL3 null variant was nominally associated with ESKD (recessive model, OR 1.81; p = 0.026); however, analysis in 807 AA cases and 634 controls from the Family Investigation of Nephropathy and Diabetes did not replicate this association. Conclusion: Additional common variants in the APOL1-APOL4-MYH9 region do not contribute significantly to ESKD risk beyond the APOL1 G1 and G2 alleles.
    American Journal of Nephrology 09/2015; 42(2):99-106. DOI:10.1159/000439448 · 2.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims: Anxiety, depression, accelerated cognitive decline, and increased risk of dementia are observed in individuals with type 2 diabetes. Anxiety and depression may contribute to lower performance on cognitive tests and differences in neuroimaging observed in individuals with type 2 diabetes. Methods: These relationships were assessed in 655 European Americans with type 2 diabetes from 504 Diabetes Heart Study families. Participants completed cognitive testing, brain magnetic resonance imaging, the Brief Symptom Inventory Anxiety subscale, and the Center for Epidemiologic Studies Depression-10. Results: In analyses adjusted for age, sex, educational attainment, and use of psychotropic medications, individuals with comorbid anxiety and depression symptoms had lower performance on all cognitive testing measures assessed (p≤0.005). Those with both anxiety and depression also had increased white matter lesion volume (p=0.015), decreased gray matter cerebral blood flow (p=4.43×10(-6)), decreased gray matter volume (p=0.002), increased white and gray matter mean diffusivity (p≤0.001), and decreased white matter fractional anisotropy (p=7.79×10(-4)). These associations were somewhat attenuated upon further adjustment for health status related covariates. Conclusions: Comorbid anxiety and depression symptoms were associated with cognitive performance and brain structure in a European American cohort with type 2 diabetes.
    Journal of diabetes and its complications 09/2015; DOI:10.1016/j.jdiacomp.2015.09.010 · 3.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.
    PLoS Genetics 08/2015; 11(8):e1005352. DOI:10.1371/journal.pgen.1005352 · 7.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There is a need to identify patients with diabetic kidney disease (DKD) using noninvasive, cost-effective screening tests. Sudoscan®, a device using electrochemical skin conductance (ESC) to measure sweat gland dysfunction, is valuable for detecting peripheral neuropathy. ESC was tested for association with DKD (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2)) in 383 type 2 diabetes mellitus (T2D)-affected patients; diagnostic thresholds were determined in 540 patients. Relationships between ESC with eGFR and urine albumin:creatinine ratio (UACR) were assessed in 202 European Americans and 181 African Americans with T2D. In 92 European American DKD cases and 110 T2D non-nephropathy controls, respectively, mean (SD) ages were 69 (9.7) and 61 (10.8) years, hemoglobin A1c (HbA1c) 7.4 (1.2) and 7.4 (1.3)%, eGFR 29.6 (12.2) and 87.8 (14.2) ml/min/1.73 m(2), and UACR 1,214 (1,705) and 7.5 (5.8) mg/g. In 57 African American cases and 124 controls, respectively, mean (SD) ages were 64.0 (11.9) and 59.5 (9.7) years, HbA1c 7.4 (1.3) and 7.5 (1.7)%, eGFR 29.6 (13.3) and 90.2 (16.2) ml/min/1.73 m(2), and UACR 1,172 (1,564) and 7.8 (7.1) mg/g. Mean (SD) ESC (μS) was lower in cases than controls (European Americans: case/control hands 49.5 (18.5)/62.3 (16.2); feet 62.1 (17.9)/73.6 (13.8), both p < 1.3 × 10(-6); African Americans: case/control hands 39.8 (19.0)/48.5 (17.1); feet 53.2 (21.3)/63.5 (19.4), both p ≤ 0.01). Adjusting for age, sex, body mass index and HbA1c, hands and feet ESC associated with eGFR <60 ml/min/1.73 m(2) (p ≤ 7.2 × 10(-3)), UACR >30 mg/g (p ≤ 7.0 × 10(-3)), UACR >300 mg/g (p ≤ 8.1 × 10(-3)), and continuous traits eGFR and UACR (both p ≤ 5.0 × 10(-9)). HbA1c values were not useful for risk stratification. ESC measured using Sudoscan® is strongly associated with DKD in African Americans and European Americans. ESC is a useful screening test to identify DKD in patients with T2D. © 2015 S. Karger AG, Basel.
    American Journal of Nephrology 07/2015; 41(6):438-447. DOI:10.1159/000437342 · 2.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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. © 2015 American Society of Neuroradiology.
    American Journal of Neuroradiology 07/2015; 36(9). DOI:10.3174/ajnr.A4321 · 3.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Vitamin D binding protein (DBP) is an important determinant of bioavailable vitamin D (BAVD) and may provide clues to racial variation in osteoporosis and atherosclerosis. Assess relationships between DBP, BAVD, 25-hydroxyvitamin D (25OHD), and 1,25 di-hydroxyvitamin D (1,25OH2D) with kidney, bone, adipose, and atherosclerosis phenotypes in African Americans with type 2 diabetes. Cross-sectional (N=545) and longitudinal (N=288; mean 5.1±0.9 year follow-up) relationships between vitamin D concentrations with renal phenotypes, vertebral bone mineral density (BMD), aorto-iliac, coronary artery, and carotid artery calcified plaque (CP), and adipose tissue volumes. African American-Diabetes Heart Study. Participants were 56.7% female with mean±SD age 55.6±9.6 years, diabetes duration 10.3±8.2 years, and eGFR 90.9±22.1 ml/min/1.73m(2). None. Associations tested between vitamin D and aforementioned phenotypes adjusting for age, sex, African ancestry proportion, diabetes duration, statins, smoking, changes in eGFR, BMI, hemoglobin A1c, and blood pressure. 1,25OH2D was inversely associated with change in coronary artery CP (parameter estimate [β] -0.005, SE 0.002; p=0.037), with a trend for change in carotid artery CP (β -0.007, SE 0.004; p=0.074). Further adjustment for renin-aldosterone-system blockade revealed inverse association between 1,25OH2D and change in albuminuria (β -0.004, SE 0.002; p=0.037). DBP, BAVD, and 25OHD did not associate significantly with changes in albuminuria, CP, or BMD. BAVD was inversely associated with visceral, subcutaneous, intermuscular, and pericardial adipose volumes. In contrast to BAVD and 25OHD, only 1,25OH2D levels were significantly and inversely associated with changes in subclinical atherosclerosis and albuminuria in African Americans, suggesting potential beneficial effects.
    The Journal of Clinical Endocrinology and Metabolism 07/2015; 100(10):jc20152167. DOI:10.1210/jc.2015-2167 · 6.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Type 2 diabetes mellitus increases the risk of cognitive decline and dementia, and elevated burdens of vascular disease are hypothesized to contribute to this risk. These relationships were examined in the Diabetes Heart Study-MIND using a battery of cognitive tests, neuroimaging measures and subclinical cardiovascular disease (CVD) burden assessed by coronary artery calcified (CAC) plaque. We hypothesized that CAC would attenuate the association between neuroimaging measures and cognition performance. Associations were examined using marginal models in this family-based cohort of 572 European Americans from 263 families. All models were adjusted for age, gender, education, type 2 diabetes and hypertension, with some neuroimaging measures additionally adjusted for intracranial volume. Higher total brain volume was associated with better performance on the Digit Symbol Substitution Task and Semantic Fluency (both p ≤ 7.0 × 10(-4)). Higher gray matter volume was associated with better performance on the Modified Mini-Mental State Examination and Semantic Fluency (both p ≤ 9.0 × 10(-4)). Adjusting for CAC caused minimal changes to the results. Relationships exist between neuroimaging measures and cognitive performance in a type 2 diabetes-enriched European American cohort. Associations were minimally attenuated after adjusting for subclinical CVD. Additional work is needed to understand how subclinical CVD burden interacts with other factors and impacts relationships between neuroimaging and cognitive testing measures. © 2015 S. Karger AG, Basel.
    Neuroepidemiology 07/2015; 45(1):1-11. DOI:10.1159/000435775 · 2.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Two independent coding variants in the apolipoprotein L1 gene (APOL1), G1 and G2, strongly associate with nephropathy in African Americans; associations with cardiovascular disease are more controversial. Although APOL1 binds plasma high-density lipoproteins (HDLs), data on APOL1 risk variant associations with HDL subfractions are sparse. Two APOL1 G1 single nucleotide polymorphisms and the G2 insertion/deletion polymorphism were genotyped in 2010 Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study participants with nuclear magnetic resonance spectroscopy-based lipoprotein subfraction measurements. Linear regression was used to model associations between numbers of APOL1 G1/G2 risk variants and HDL subfractions, adjusting for demographic, clinical and ancestral covariates. Female sex and higher percentage of African ancestry were positively associated with the number of APOL1 G1/G2 risk alleles. In the unadjusted analysis, mean (standard error) small HDL concentrations (μmol/L) for participants with zero, one and two G1/G2 risk alleles were 19.0 (0.2), 19.7 (0.2) and 19.9 (0.4), respectively (P = 0.02). Adjustment for age, sex, diabetes and African ancestry did not change the results but strengthened the statistical significance (P = 0.004). No significant differences in large or medium HDL, very low-density lipoprotein or low-density lipoprotein particle concentrations were observed by APOL1 genotype. Greater numbers of APOL1 G1/G2 risk alleles were associated with higher small HDL particle concentrations in African Americans. These results may suggest novel areas of investigation to uncover reasons for the association between APOL1 risk variants with adverse outcomes in African Americans. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
    Nephrology Dialysis Transplantation 07/2015; DOI:10.1093/ndt/gfv229 · 3.58 Impact Factor
  • Barry I Freedman ·

    American Journal of Kidney Diseases 07/2015; 66(1):9-11. DOI:10.1053/j.ajkd.2015.05.005 · 5.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Two apolipoprotein L1 (APOL1) gene variants, which likely evolved to protect individuals from African sleeping sickness, are strongly associated with non-diabetic kidney disease in individuals with recent African ancestry. Consistent with its role in trypanosome killing, the pro-death APOL1 protein is toxic to most cells, but its mechanism of cell death is poorly understood and little is known regarding its intracellular trafficking and secretion. Because liver appears to be the main source of circulating APOL1, we examined its secretory behavior and mechanism of toxicity in hepatoma cells and primary human hepatocytes. APOL1 is poorly secreted in vitro, even in the presence of chemical chaperones; however, it is efficiently secreted in wild-type transgenic mice, suggesting that APOL1 secretion has specialized requirements that cultured cells fail to support. In hepatoma cells, inducible expression of APOL1 and its risk variants promoted cell death, with the G1 variant displaying the highest degree of toxicity. To explore the basis for APOL1-mediated cell toxicity, ER stress, pyroptosis, autophagy, and apoptosis were examined. Our results suggest that autophagy represents the predominant mechanism of APOL1-mediated cell death. Overall, these results increase our understanding of the basic biology and trafficking behavior of circulating APOL1 from the liver. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    The Journal of Lipid Research 06/2015; 56(8). DOI:10.1194/jlr.M059733 · 4.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Many studies evaluated the best predictors for cardiovascular disease (CVD) events in individuals with type 2 diabetes (T2D), but few studies examined the factors most strongly associated with mortality in T2D. The Diabetes Heart Study (DHS), an intensively phenotyped family-based cohort enriched for T2D, provided an opportunity to address this question. Associations with mortality were examined in 1022 European Americans affected by T2D from 476 DHS families. All-cause mortality was 31.2 % over an average 9.6 years of follow-up. Cox proportional hazards models with sandwich-based variance estimation were used to evaluate associations between all-cause and CVD mortality and 24 demographic and clinical factors, including coronary artery calcified plaque (CAC), carotid artery intima-media thickness, medications, body mass index, waist hip ratio, lipids, blood pressure, kidney function, QT interval, educational attainment, and glycemic control. Nominally significant factors (p < 0.25) from univariate analyses were included in model selection (backward elimination, forward selection, and stepwise selection). Age and sex were included in all models. The all-cause mortality model selected from the full DHS sample included age, sex, CAC, urine albumin: creatinine ratio (UACR), insulin use, current smoking, and educational attainment. The CVD mortality model selected from the full sample included age, sex, CAC, UACR, triglycerides, and history of CVD events. Beyond age, the most significant associations for both mortality models were CAC (2.03 × 10(-4) ≤ p ≤ 0.001) and UACR (1.99 × 10(-8) ≤ p ≤ 2.23 × 10(-8)). To confirm the validity of the main predictors identified with model selection using the full sample, a two-fold cross-validation approach was used, and similar results were observed. This analysis highlights important demographic and clinical factors, notably CAC and albuminuria, which predict mortality in the general population of patients with T2D.
    Diabetology and Metabolic Syndrome 06/2015; 7(1):58. DOI:10.1186/s13098-015-0055-y · 2.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We report the rare occurrence of donor-derived myeloid sarcoma in two kidney transplant patients who received organs from a single deceased donor. There was no evidence of preexisting hematologic malignancy in the donor at the time of organ recovery. Both recipients developed leukemic involvement that appeared to be limited to the transplanted organ. Fluorescence in situ hybridization (FISH) and molecular genotyping analyses confirmed that the malignant cells were of donor origin in each patient. Allograft nephrectomy and immediate withdrawal of immunosuppression were performed in both cases; systemic chemotherapy was subsequently administered to one patient. Both recipients were in remission at least one year following the diagnosis of donor-derived myeloid sarcoma. These cases suggest that restoration of the immune system after withdrawal of immunosuppressive therapy and allograft nephrectomy may be sufficient to control HLA-mismatched donor-derived myeloid sarcoma without systemic involvement.
    05/2015; 2015:1-5. DOI:10.1155/2015/821346

Publication Stats

13k Citations
2,515.02 Total Impact Points


  • 1999-2015
    • Wake Forest School of Medicine
      • • Section of Nephrology
      • • Center for Diabetes Research
      • • Department of Internal Medicine
      • • Department of Biochemistry
      Winston-Salem, North Carolina, United States
  • 2014
    • University of Bristol
      Bristol, England, United Kingdom
  • 2013
    • University of California, Los Angeles
      • Division of Rheumatology
      Los Angeles, California, United States
  • 1989-2013
    • Wake Forest University
      • • Department of Internal Medicine
      • • Department of Public Health Sciences
      • • Department of Biochemistry
      • • School of Medicine
      Winston-Salem, North Carolina, United States
  • 2012
    • Washington University in St. Louis
      • Division of Biostatistics
      Saint Louis, MO, United States
  • 2010-2011
    • Winston-Salem State University
      Winston-Salem, North Carolina, United States
  • 2007
    • Pennsylvania State University
      University Park, Maryland, United States
    • Boston University
      Boston, Massachusetts, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2006
    • University of Virginia
      Charlottesville, Virginia, United States
  • 1999-2006
    • Emory University
      • Department of Epidemiology
      Atlanta, Georgia, United States
  • 2005
    • University of Missouri
      • Department of Radiology
      Columbia, MO, United States
  • 1994
    • Highland Hospital
      Oakland, California, United States