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1.
Clin J Am Soc Nephrol ; 15(3): 349-358, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32111704

RESUMO

BACKGROUND AND OBJECTIVES: eGFR and albuminuria primarily reflect glomerular function and injury, whereas tubule cell atrophy and interstitial fibrosis on kidney biopsy are important risk markers for CKD progression. Kidney tubule injury markers have primarily been studied in hospitalized AKI. Here, we examined the association between urinary kidney tubule injury markers at baseline with subsequent loss of kidney function in persons with nondiabetic CKD who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 2428 SPRINT participants with CKD (eGFR<60 ml/min per 1.73 m2) at baseline, we measured urine markers of tubule injury (IL-18, kidney injury molecule-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL]), inflammation (monocyte chemoattractant protein-1 [MCP-1]), and repair (human cartilage glycoprotein-40 [YKL-40]). Cox proportional hazards models evaluated associations of these markers with the kidney composite outcome of 50% eGFR decline or ESKD requiring dialysis or kidney transplantation, and linear mixed models evaluated annualized change in eGFR. RESULTS: Mean participant age was 73±9 (SD) years, 60% were men, 66% were white, and mean baseline eGFR was 46±11 ml/min per 1.73 m2. There were 87 kidney composite outcome events during a median follow-up of 3.8 years. Relative to the respective lowest quartiles, the highest quartiles of urinary KIM-1 (hazard ratio, 2.84; 95% confidence interval [95% CI], 1.31 to 6.17), MCP-1 (hazard ratio, 2.43; 95% CI, 1.13 to 5.23), and YKL-40 (hazard ratio, 1.95; 95% CI, 1.08 to 3.51) were associated with higher risk of the kidney composite outcome in fully adjusted models including baseline eGFR and urine albumin. In linear analysis, urinary IL-18 was the only marker associated with eGFR decline (-0.91 ml/min per 1.73 m2 per year for highest versus lowest quartile; 95% CI, -1.44 to -0.38), a finding that was stronger in the standard arm of SPRINT. CONCLUSIONS: Urine markers of tubule cell injury provide information about risk of subsequent loss of kidney function, beyond the eGFR and urine albumin.

2.
Clin Transplant ; : e13827, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080893

RESUMO

Two renal-risk variants in the apolipoprotein L1 gene (APOL1) in African American (AA) deceased donors (DD) are associated with shorter renal allograft survival after transplantation. To identify additional genes contributing to allograft survival, a genome-wide association study was performed in 532 AA DDs. Phenotypic data were obtained from the Scientific Registry of Transplant Recipients. Association and single nucleotide polymorphism (SNP)-by-APOL1 interaction tests were conducted using death-censored renal allograft survival accounting for relevant covariates. Replication and inverse-variance weighted meta-analysis were performed using data from 250 AA DD in the Genomics of Transplantation study. Accounting for APOL1, multiple SNPs near the Nudix Hydrolase 7 gene (NUDT7) showed strong independent effects (p=1.6x10-8 -2.2x10-8 ). Several SNPs in the Translocation protein SEC63 homolog (SEC63; p=2x10-9 -3.7x10-8 ) and plasmacytoma variant translocation 1 (PVT1) genes (p=4.0x10-8 -7x10-8 ) modified the effect of APOL1 on allograft survival. SEC63 is expressed in human renal tubule cells and glomeruli and PVT1 is associated with diabetic kidney disease. Overall, associations were detected for 41 SNPs (p=2x10-9 -5x10-8 ) contributing independently or interacting with APOL1 to impact renal allograft survival after transplantation from AA DD. Given the small sample size of the discovery and replication sets, independent validations and functional genomic efforts are needed to validate these results.

3.
J Electrocardiol ; 58: 150-154, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31895990

RESUMO

BACKGROUND: QRS-duration predicts mortality in patients with heart failure and, to a lesser extent, the general population. However, in patients with diabetes, its prognostic significance is unknown. To better understand how QRS-duration relates to mortality among those with diabetes, we explored survival as a function of QRS-duration in the Diabetes Heart Study. METHODS: The study population included 1335 participants. Cox proportional hazards modeling was used to evaluate the relationship between QRS-duration and all-cause mortality, comparing those with QRS-duration ≤120 vs. >120 (ms). Multivariable models adjusted for age, sex, race, hypertension, smoking, years with diabetes, BMI, systolic blood pressure, cholesterol, triglycerides, glomerular filtration rate, and hemoglobin A1c. RESULTS AND CONCLUSIONS: Participants were: mean age 61 ± 9, 55% women, 83% white; 99 participants (7.5%) had a QRS-duration >120. After 11,000 person-years of follow-up (median 8.5 years; maximum 13.9 years), 266 participants had died (20%). Participants with baseline QRS-duration >120 had an adjusted hazard ratio for all-cause mortality of 1.56 (95% CI 1.05-2.24; p = 0.027). Modeling QRS-duration as a continuous variable, we found an 11% increase in all-cause mortality for each 10 ms increase in QRS-duration. In conclusion, QRS-duration is associated with subsequent all-cause mortality among those with type 2 diabetes-participants with QRS-duration >120 ms had a 56% increase in all-cause mortality, even after adjustment for conventional risk factors. Given the ubiquitous presence of ECG data in the medical record, QRS-duration may prove to be a useful prognostic measure, especially among those with diabetes.

4.
Transplantation ; 104(1): 27-32, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31449181

RESUMO

BACKGROUND: Association between the apolipoprotein L1 gene (APOL1) and nephropathy has altered the epidemiology of chronic kidney disease. In addition, donor APOL1 genotypes play important roles in the time to allograft failure in kidneys transplanted from deceased donors and the safety of living kidney donation. METHODS: This article reviews genetic testing for inherited kidney disease in living kidney donors to improve donor safety. APOL1 genotyping in donors with recent African ancestry is considered. RESULTS: Based on current data, transplant physicians should discuss APOL1 genotyping with potential living kidney donors self-reporting recent African ancestry. Until results from APOL1 Long-term Kidney Transplant Outcomes Network ancillary studies are available, we present practical approaches from our experience for considering APOL1 genotyping in the living donor evaluation. CONCLUSIONS: Transplant physicians should inform potential living kidney donors at risk for APOL1-associated nephropathy about the gene and possibility of genetic testing early in the donor evaluation, well before scheduling the donor nephrectomy. Transplant programs must weigh risks of performing a donor nephrectomy in those with 2 APOL1 renal risk variants (high-risk genotypes), particularly younger individuals. Our program counsels kidney donors with APOL1 high-risk genotypes in the same fashion as with risk genotypes in other nephropathy genes. Because most African American kidney donor candidates lacking hypertension, proteinuria and reduced kidney function after workup will not possess APOL1 high-risk genotypes, genetic testing is unlikely to markedly increase donor declines and may reassure donors with regard to their long-term kidney outcomes, potentially increasing the number of African American donors.

5.
Ann Surg ; 271(2): 383-390, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30048305

RESUMO

OBJECTIVE: To test the hypothesis that gene expression profiling in peripheral blood from patients who have undergone kidney transplantation (KT) will provide mechanistic insights regarding graft repair and regeneration. BACKGROUND: Renal grafts obtained from living donors (LD) typically function immediately, whereas organs from donation after cardiac death (DCD) or acute kidney injury (AKI) donors may experience delayed function with eventual recovery. Thus, recipients of LD, DCD, and AKI kidneys were studied to provide a more complete understanding of the molecular basis for renal recovery. METHODS: Peripheral blood was collected from LD and DCD/AKI recipients before transplant and throughout the first 30 days thereafter. Total RNA was isolated and assayed on whole genome microarrays. RESULTS: Comparison of longitudinal gene expression between LD and AKI/DCD revealed 2 clusters, representing 141 differentially expressed transcripts. A subset of 11 transcripts was found to be differentially expressed in AKI/DCD versus LD. In all recipients, the most robust gene expression changes were observed in the first day after transplantation. After day 1, gene expression profiles differed depending upon the source of the graft. In patients receiving LD grafts, the expression of most genes did not remain markedly elevated beyond the first day post-KT. In the AKI/DCD groups, elevations in gene expression were maintained for at least 5 days post-KT. In all recipients, the pattern of coordinate gene overexpression subsided by 28 to 30 days. CONCLUSIONS: Gene expression in peripheral blood of AKI/DCD recipients offers a novel platform to understand the potential mechanisms and timing of kidney repair and regeneration after transplantation.

7.
Dig Dis Sci ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31820181

RESUMO

BACKGROUND: Although gastroparesis is seen in patients with type 2 diabetes mellitus (T2DM), the prevalence of symptoms suggestive of gastroparesis in patients with T2DM is unknown, particularly among African Americans. AIMS: To determine the prevalence of symptoms associated with gastroparesis in a large community-based population of European Americans and African Americans with T2DM. METHODS: Individuals with T2DM in the Diabetes Heart Study were asked to complete the gastroparesis cardinal symptom index (GCSI) and other GI-related questionnaires. GCSI total score ≥ 18 represented moderate or worse symptoms suggestive of gastroparesis. RESULTS: A total of 1253 participants (700 female, 553 male) completed the GCSI: 750 were European American and 503 African American. GCSI scores ≥ 18 were recorded in 72 participants: 38 (5%) of European Americans and 34 (7%) of African Americans. The average GCSI was 24.1 in European Americans and 24.6 in African Americans, indicating moderate to severe symptoms. Compared to European Americans with GCSI scores ≥ 18, African Americans were younger (59.4 vs. 53.3 years, p = 0.004), had earlier onset of T2DM (46.3 vs. 40.1 years, p = 0.01), higher HbA1c (7.6 vs. 9.1, p = 0.0009), underwent fewer upper endoscopies (55.3% vs. 26.5%, p = 0.02), and had more anxiety and depression (p < 0.001). CONCLUSIONS: Moderate or greater symptoms suggestive of gastroparesis are present in 5-7% of European and African American patients with T2DM in community-based populations. Symptoms suggestive of gastroparesis may be underappreciated in patients with T2DM and account for upper gastrointestinal symptoms, unexplained glycemic control issues, and decreased quality of life.

9.
J Rheumatol ; 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31732553

RESUMO

OBJECTIVE: Apolipoprotein L1 gene (APOL1) G1 and G2 renal-risk alleles (RRAs) are associated with end-stage renal disease (ESRD) in blacks with lupus nephritis (LN). The present study determined frequencies of APOL1 RRAs in non-white Brazilian patients with LN and controls to assess association with renal outcomes. METHODS: APOL1 RRAs were genotyped in 222 healthy blood donors (controls) and 201 cases with LN from three outpatient clinics. Two single nucleotide polymorphisms in the G1 (rs73885319; rs60910145) and an indel for the G2 (rs71785313) variant were genotyped. RESULTS: The frequency of APOL1 RRAs in non-white Brazilian LN cases did not differ significantly from healthy controls, few participants had 2 RRAs. In the sample, 84.6% of LN cases and 82.9% of controls had 0 RRAs, 13.4% and 15.3% had 1 RRA, and 2.0% and 0.4% had 2 RRAs, respectively. LN cases with >1 APOL1 RRAs had similar baseline characteristics and renal responses to treatment, yet faced higher risk for progressive chronic kidney disease (CKD) to an eGFR <30 ml/min/1.732 compared to those with 0 RRAs (11.1% with 0, 29.6% with 1; 50% with 2 RRAs, p=0.005). Although glomerular lesions and activity scores on initial kidney biopsy did not differ significantly between individuals based on APOL1 genotype, chronicity scores, tubular atrophy and interstitial fibrosis were more severe in those with >1 RRA. CONCLUSION: Although initial kidney lesions and treatment responses were similar, a single APOL1 RRA in non-white Brazilians with LN was associated with increased risk of advanced CKD and possibly more tubulo-interstitial damage.

11.
Nat Genet ; 51(11): 1580-1587, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31659325

RESUMO

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.


Assuntos
Aterosclerose/patologia , Predisposição Genética para Doença , Histona Desacetilases/metabolismo , Histona Desacetilases/fisiologia , Contração Muscular , Músculo Liso Vascular/patologia , Proteínas Repressoras/metabolismo , Proteínas Repressoras/fisiologia , Calcificação Vascular/patologia , Idoso , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Estudos de Coortes , Feminino , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Estudo de Associação Genômica Ampla , Histona Desacetilases/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Calcificação Vascular/genética , Calcificação Vascular/metabolismo
12.
Am J Nephrol ; 50(4): 303-311, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31480040

RESUMO

BACKGROUND: Apolipoprotein A1 (APOL1) gene variants occurring in people of West African descent contribute to the greater burden of kidney disease among African Americans. These variants are associated with increased risk of nondiabetic nephropathy, more rapid progression of chronic kidney disease, and shorter survival of donor kidneys after transplantation. However, only a minority of people with APOL1-associated risk develops kidney disease and specific clinical measures to address APOL1-associated risk are lacking. Given these uncertainties, we sought to engage members of the African American public in discussions with other stakeholders about the appropriate use of APOL1 testing. METHODS: Formative interviews with community members, researchers, and clinicians in Seattle WA, Nashville TN, and Jackson MS, provided baseline information about views toward APOL1 testing and informed the design of 3 community-based deliberations among African Americans. A national meeting held in March 2018 included 13 community members, 7 scientific advisors and 26 additional researchers, clinicians, bioethicists, patient advocates, and representatives from professional organizations and federal funding agencies. Using small break-out and plenary discussion, the group agreed on recommendations based on current knowledge about APOL1-associated risk. RESULTS: Meeting outcomes included recommendations to develop educational materials about APOL1 for community members and clinicians; to offer APOL1 research results to participants; and on the use of APOL1testing in kidney transplant programs. The group recommended against the routine offer of APOL1 testing in clinical care. Areas of disagreement included whether kidney transplant programs should require APOL1 testing of prospective living donors or bar individuals with APOL1 risk from donating kidneys and whether testing should be available on request in routine clinical care. CONCLUSION: We recommend continued discussion among stakeholders and concerted efforts to ensure active and informed participation of members of the affected community to guide research on APOL1 and kidney disease.

13.
J Am Soc Nephrol ; 30(10): 2027-2036, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31383730

RESUMO

BACKGROUND: Two coding variants in the apo L1 gene (APOL1) are strongly associated with kidney disease in blacks. Kidney disease itself increases the risk of cardiovascular disease, but whether these variants have an independent direct effect on the risk of cardiovascular disease is unclear. Previous studies have had inconsistent results. METHODS: We conducted a two-stage individual participant data meta-analysis to assess the association of APOL1 kidney-risk variants with adjudicated cardiovascular disease events and death, independent of kidney measures. The analysis included 21,305 blacks from eight large cohorts. RESULTS: Over 8.9±5.0 years of follow-up, 2076 incident cardiovascular disease events occurred in the 16,216 participants who did not have cardiovascular disease at study enrollment. In fully-adjusted analyses, individuals possessing two APOL1 kidney-risk variants had similar risk of incident cardiovascular disease (coronary heart disease, myocardial infarction, stroke and heart failure; hazard ratio 1.11, 95% confidence interval, 0.96 to 1.28) compared to individuals with zero or one kidney-risk variant. The risk of coronary heart disease, myocardial infarction, stroke and heart failure considered individually was also comparable by APOL1 genotype. APOL1 genotype was also not associated with death. There was no difference in adjusted associations by level of kidney function, age, diabetes status, or body-mass index. CONCLUSIONS: In this large, two-stage individual participant data meta-analysis, APOL1 kidney-risk variants were not associated with incident cardiovascular disease or death independent of kidney measures.

14.
Am J Nephrol ; 50(4): 229-239, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31461699

RESUMO

BACKGROUND: Given the increasing worldwide prevalence of chronic kidney disease (CKD), it is critical to decrease the associated risk of debilitating vascular complications, including stroke, congestive heart failure, myocardial infarction, and peripheral vascular disease. Treatment options for reducing the risk of all subtypes of stroke in patients with CKD remain limited. For patients with end-stage kidney disease (ESKD), novel applications of noninvasive imaging may help personalize the type of dialysis and dialysis prescription for patients at high-risk. SUMMARY: This manuscript reviews the heightened risk of stroke in patients with nephropathy, including ischemic and hemorrhagic subtypes. Mechanisms associated with increased risk include alterations in cardiac output, platelet function, regional cerebral perfusion, accelerated systemic atherosclerosis, altered blood brain barrier, and disordered neurovascular coupling. There is great potential for noninvasive monitoring of the cerebral vasculature using transcranial Doppler (TCD) to reduce stroke risk, particularly in patients with ESKD. Key Messages: Compared to the general population, patients with CKD are at heightened risk for all subtypes of stroke. This is due to a multitude of mechanisms linking nephropathy with altered cerebral perfusion, cerebral neurovascular coupling, and blood vessel integrity. Intracranial imaging is not currently standard of care practice in patients with CKD or ESKD. TCD may provide clinicians real-time and noninvasive measurement of brain perfusion. This could be useful for assessing risk of stroke in patients' initiating dialysis, individualizing dialysis prescriptions, and potentially reducing rates of cerebrovascular disease and stroke in high-risk patients.

15.
J Am Soc Nephrol ; 30(8): 1523-1533, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31324734

RESUMO

BACKGROUND: The Systolic BP Intervention Trial (SPRINT) found that intensive versus standard systolic BP control (targeting <120 or <140 mm Hg, respectively) reduced the risks of death and major cardiovascular events in persons with elevated cardiovascular disease risk. However, the intensive intervention was associated with an early decline in eGFR, and the clinical implications of this early decline are unclear. METHODS: In a post hoc analysis of SPRINT, we defined change in eGFR as the percentage change in eGFR at 6 months compared with baseline. We performed causal mediation analyses to separate the overall effects of the randomized systolic BP intervention on the SPRINT primary cardiovascular composite and all-cause mortality into indirect effects (mediated by percentage change in eGFR) and direct effects (mediated through pathways other than percentage change in eGFR). RESULTS: About 10.3% of the 4270 participants in the intensive group had a ≥20% eGFR decline versus 4.4% of the 4256 participants in the standard arm (P<0.001). After the 6-month visit, there were 591 cardiovascular composite events during 27,849 person-years of follow-up. The hazard ratios for total effect, direct effect, and indirect effect of the intervention on the cardiovascular composite were 0.67 (95% confidence interval [95% CI], 0.56 to 0.78), 0.68 (95% CI, 0.57 to 0.79), and 0.99 (95% CI, 0.95 to 1.03), respectively. All-cause mortality results were similar. CONCLUSIONS: Although intensive systolic BP lowering resulted in greater early decline in eGFR, there was no evidence that the reduction in eGFR owing to intensive systolic BP lowering attenuated the beneficial effects of this intervention on cardiovascular events or all-cause mortality.

16.
Med Phys ; 46(8): 3508-3519, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31228267

RESUMO

PURPOSE: 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. METHODS: 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). RESULTS: 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 < 40 HU, 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. CONCLUSIONS: 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.


Assuntos
Aprendizado Profundo , Processamento de Imagem Assistida por Computador/métodos , Fígado/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem
19.
J Lipid Res ; 60(8): 1425-1431, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31133557

RESUMO

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.

20.
Hum Genomics ; 13(1): 21, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092297

RESUMO

BACKGROUND: End-stage kidney disease (ESKD) is a significant public health concern disproportionately affecting African Americans (AAs). Type 2 diabetes (T2D) is the leading cause of ESKD in the USA, and efforts to uncover genetic susceptibility to diabetic kidney disease (DKD) have had limited success. A prior genome-wide association study (GWAS) in AAs with T2D-ESKD was expanded with additional AA cases and controls and genotypes imputed to the higher density 1000 Genomes reference panel. The discovery analysis included 3432 T2D-ESKD cases and 6977 non-diabetic non-nephropathy controls (N = 10,409), followed by a discrimination analysis in 2756 T2D non-nephropathy controls to exclude T2D-associated variants. RESULTS: Six independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1 achieved genome-wide significant association (P < 5 × 10-8) with T2D-ESKD. Following extension analyses in 1910 non-diabetic ESKD cases and 908 non-diabetic non-nephropathy controls, a meta-analysis of 5342 AA all-cause ESKD cases and 6977 AA non-diabetic non-nephropathy controls revealed an additional novel all-cause ESKD locus at EFNB2 (rs77113398; P = 9.84 × 10-9; OR = 1.94). Exclusion of APOL1 renal-risk genotype carriers identified two additional genome-wide significant T2D-ESKD-associated loci at GRAMD3 and MGAT4C. A second variant at GNG7 (rs373971520; P = 2.17 × 10-8, OR = 1.46) remained associated with all-cause ESKD in the APOL1-negative analysis. CONCLUSIONS: Findings provide further evidence for genetic factors associated with advanced kidney disease in AAs with T2D.

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