Genetic factors in end-stage renal disease

Genetic factors in end-stage renal disease. Despite more aggressive treatment of diabetes, hypertension, and hyperlipidemia, the incidence and prevalence rates of end-stage renal disease (ESRD) continue to increase worldwide. The likelihood of developing chronic kidney disease in an individual is determined by interactions between genes and the environment. Familial clustering of nephropathy has repeatedly been observed in all population groups studied and for multiple etiologies of kidney disease. A three- to nine-fold greater risk of ESRD is observed in individuals with a family history of ESRD. Marked racial variation in the familial aggregation of kidney disease exists, with high rates in African American, Native American, and Hispanic American families. Disparate etiologies of nephropathy aggregate within African American families, as well. These data have led several investigators to search for genes linked to diabetic and other forms of nephropathy. Evidence for linkage to kidney disease has been detected and replicated at several loci on chromosomes 3q (types 1 and 2 diabetic nephropathy), 10q (diabetic and nondiabetic kidney disease), and 18q (type 2 diabetic nephropathy). Multicenter consortia are currently recruiting large numbers of multiplex diabetic families with index cases having nephropathy for linkage and association analyses. In addition, large-scale screening studies are underway, with the goals of better defining the overall prevalence of chronic kidney disease, as well as educating the population about risk factors for nephropathy, including family history. Given the overwhelming burden of kidney disease worldwide, it is imperative that we develop a clearer understanding of the pathogenesis of nephropathy so that individuals at risk can be identified and treated at earlier, potentially reversible, stages of their illness

Blood-based bioenergetic profiling is related to differences in brain morphology in African Americans with Type 2 diabetes.

Blood-based bioenergetic profiling has promising applications as a minimally invasive biomarker of systemic bioenergetic capacity. In the present study, we examined peripheral blood mononuclear cell (PBMC) mitochondrial function and brain morphology in a cohort of African Americans with long-standing Type 2 diabetes. Key parameters of PBMC respiration were correlated with white matter, gray matter, and total intracranial volumes. Our analyses indicate that these relationships are primarily driven by the relationship of systemic bioenergetic capacity with total intracranial volume, suggesting that systemic differences in mitochondrial function may play a role in overall brain morphology

Normative Values for Electrochemical Skin Conductances and Impact of Ethnicity on Quantitative Assessment of Sudomotor Function

Background: Sudomotor dysfunction is one of the earliest pathophysiologic abnormalities in diabetes. Sudoscan? (Impeto Medical, Paris, France) was developed as a noninvasive, rapid, and quantitative assessment of sudomotor function and has been shown to be sensitive in the detection of neuropathy. This global collaborative analysis aimed to establish reference values in healthy subjects of different ethnic groups, age, and gender, to define factors potentially affecting results, and to provide standardization of the methodology. Materials and Methods: Data from 1,350 generally healthy study participants who underwent sudomotor function testing were collected and analyzed. The relationship between age, height, weight, gender, glycemic and lipid profiles, ethnicity, and hand and foot electrochemical skin conductance (ESC) was assessed among subgroups of participants. Results: Lower mean hands and feet ESC values were observed in African American, Indian, and Chinese subjects (P?Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140359/1/dia.2015.0396.pd

Renal artery calcified plaque associations with subclinical renal and cardiovascular disease

Renal artery calcified plaque associations with subclinical renal and cardiovascular disease.BackgroundThe prognostic significance of renal artery calcified plaque (RAC) and its relationship with renal function, albuminuria, and systemic atherosclerosis are unknown.MethodsCalcified atherosclerotic plaque was measured in the renal arteries of 96 unrelated Caucasian subjects with type 2 diabetes mellitus (DM) using four-channel multidetector–row computed tomography (MDCT4). Renal artery calcium was measured as the sum of ostial and main renal artery calcium scores. Participants also underwent MDCT scanning to measure coronary artery calcium (CAC), carotid artery calcium, common iliac artery calcium, infra-renal aorta calcium, and B-mode ultrasound to measure carotid artery intima-medial thickness (IMT). Spearman's rank correlation coefficients were used to assess associations between RAC and measures of subclinical renal and cardiovascular disease. Partial correlation coefficients were computed to adjust for the potential confounding effects of age, gender, body mass index (BMI), DM duration, smoking, and serum cholesterol and triglyceride levels.ResultsCharacteristics of the study group were 54% (52/96) female with a mean ± SD (median) age 62.8 ± 8.4 (62.5) years, DM duration 10.6 ± 6.3 (8.0) years, hemoglobin A1C 7.5 ± 1.5 (7.2)%, BMI 32.1 ± 6.3 (31.1) kg/m2, serum creatinine concentration 1.11 ± 0.18 (1.10) mg/dL, urine albumin:creatinine ratio (ACR) 105.3 ± 423.1 (17.6) mg/g, modified MDRD equation glomerular filtration rate (GFR) 64.3 ± 12.6 (63.6) mL/min, RAC 372 ± 799 (101), CAC 1819 ± 2594 (622), carotid artery calcium 264 ± 451 (72), and B-mode ultrasound carotid IMT 0.70 ± 0.12 (0.69) mm. Sixty-five percent of subjects (62/96) had detectable RAC. Renal artery calcium was significantly associated with CAC (r = 0.50, P < 0.0001), carotid artery calcium (r = 0.58, P < 0.0001), common iliac artery calcium (r = 0.45, P < 0.0001), infra-renal aorta calcium (r = 0.70, P < 0.0001), IMT (r = 0.40, P = 0.0004), diastolic blood pressure (r=-0.33, P = 0.0009), BMI (r=-0.19, P = 0.0573), and age (r = 0.54, P < 0.0001). There was no association between RAC and GFR (r=-0.15, P = 0.1637) or between RAC and urine ACR (r = 0.07, P = 0.5083).ConclusionRenal artery calcium is strongly associated with older age, diastolic blood pressure, BMI, carotid artery IMT, and coronary, carotid, common iliac artery, and infra-renal aorta calcium in Caucasians with type 2 diabetes mellitus. Renal artery calcium, similar to CAC and IMT, appears to be a useful noninvasive marker of subclinical atherosclerosis. However, RAC is not significantly associated with either GFR or albuminuria

Dense mapping of MYH9 localizes the strongest kidney disease associations to the region of introns 13 to 15

Admixture mapping recently identified MYH9 as a susceptibility gene for idiopathic focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy (HIVAN) and end-stage kidney disease attributed to hypertension (H-ESKD) in African Americans (AA). MYH9 encodes the heavy chain of non-muscle myosin IIA, a cellular motor involved in motility. A haplotype and its tagging SNPs spanning introns 12–23 were most strongly associated with kidney disease (OR 2–7; P < 10−8, recessive). To narrow the region of association and identify potential causal variation, we performed a dense-mapping study using 79 MYH9 SNPs in AA populations with FSGS, HIVAN and H-ESKD (typed for a subset of 46 SNPs), for a total of 2496 cases and controls. The strongest associations were for correlated SNPs rs5750250, rs2413396 and rs5750248 in introns 13, 14 and 15, a region of 5.6 kb. Rs5750250 showed OR 5.0, 8.0 and 2.8; P = 2 × 10−17, 2 × 10−10 and 3 × 10−22, respectively, for FSGS, HIVAN and H-ESKD; OR 5.7; P = 9 × 10−27 for combined FSGS and HIVAN, recessive. An independent association was observed for rs11912763 in intron 33. Neither the highly associated SNPs nor the results of resequencing MYH9 in 40 HIVAN or FSGS cases and controls revealed non-synonymous changes that could account for the disease associations. Rs2413396 and one of the highly associated SNPs in intron 23, rs4821480, are predicted splicing motif modifiers. Rs5750250 combined with rs11912763 had receiver operator characteristic (ROC) C statistics of 0.80, 0.73 and 0.65 for HIVAN, FSGS and H-ESKD, respectively, allowing prediction of genetic risk by typing two SNPs

Neighborhood Socioeconomic Deprivation and Mortality: NIH-AARP Diet and Health Study

Residing in deprived areas may increase risk of mortality beyond that explained by a person's own SES-related factors and lifestyle. The aim of this study was to examine the relation between neighborhood socioeconomic deprivation and all-cause, cancer- and cardiovascular disease (CVD)-specific mortality for men and women after accounting for education and other important person-level risk factors.In the longitudinal NIH-AARP Study, we analyzed data from healthy participants, ages 50-71 years at study baseline (1995-1996). Deaths (n = 33831) were identified through December 2005. Information on census tracts was obtained from the 2000 US Census. Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for quintiles of neighborhood deprivation.Participants in the highest quintile of deprivation had elevated risks for overall mortality (HR(men) = 1.17, 95% CI: 1.10, 1.24; HR(women) = 1.13, 95% CI: 1.05, 1.22) and marginally increased risk for cancer deaths (HR(men) = 1.09, 95% CI: 1.00, 1.20; HR(women) = 1.09, 95% CI: 0.99, 1.22). CVD mortality associations appeared stronger in men (HR = 1.33, 95% CI: 1.19, 1.49) than women (HR = 1.18, 95% CI: 1.01, 1.38). There was no evidence of an effect modification by education.Higher neighborhood deprivation was associated with modest increases in all-cause, cancer- and CVD-mortality after accounting for many established risk factors

The Carnegie Supernova Project: The Low-Redshift Survey

Supernovae are essential to understanding the chemical evolution of the Universe. Type Ia supernovae also provide the most powerful observational tool currently available for studying the expansion history of the Universe and the nature of dark energy. Our basic knowledge of supernovae comes from the study of their photometric and spectroscopic properties. However, the presently available data sets of optical and near-infrared light curves of supernovae are rather small and/or heterogeneous, and employ photometric systems that are poorly characterized. Similarly, there are relatively few supernovae whose spectral evolution has been well sampled, both in wavelength and phase, with precise spectrophotometric observations. The low-redshift portion of the Carnegie Supernova Project (CSP) seeks to remedy this situation by providing photometry and spectrophotometry of a large sample of supernovae taken on telescope/filter/detector systems that are well understood and well characterized. During a five-year program which began in September 2004, we expect to obtain high-precision u'g'r'i'BVYJHKs light curves and optical spectrophotometry for about 250 supernovae of all types. In this paper we provide a detailed description of the CSP survey observing and data reduction methodology. In addition, we present preliminary photometry and spectra obtained for a few representative supernovae during the first observing campaign.Comment: 45 pages, 13 figures, 3 tables, accepted by PAS

Apolipoprotein L1 gene variants associate with prevalent kidney but not prevalent cardiovascular disease in the Systolic Blood Pressure Intervention Trial.

Apolipoprotein L1 gene (APOL1) G1 and G2 coding variants are strongly associated with chronic kidney disease (CKD) in African Americans (AAs). Here APOL1 association was tested with baseline estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (UACR), and prevalent cardiovascular disease (CVD) in 2571 AAs from the Systolic Blood Pressure Intervention Trial (SPRINT), a trial assessing effects of systolic blood pressure reduction on renal and CVD outcomes. Logistic regression models that adjusted for potentially important confounders tested for association between APOL1 risk variants and baseline clinical CVD (myocardial infarction, coronary, or carotid artery revascularization) and CKD (eGFR under 60 ml/min per 1.73 m(2) and/or UACR over 30 mg/g). AA SPRINT participants were 45.3% female with a mean (median) age of 64.3 (63) years, mean arterial pressure 100.7 (100) mm Hg, eGFR 76.3 (77.1) ml/min per 1.73 m(2), and UACR 49.9 (9.2) mg/g, and 8.2% had clinical CVD. APOL1 (recessive inheritance) was positively associated with CKD (odds ratio 1.37, 95% confidence interval 1.08-1.73) and log UACR estimated slope (β) 0.33) and negatively associated with eGFR (β -3.58), all significant. APOL1 risk variants were not significantly associated with prevalent CVD (1.02, 0.82-1.27). Thus, SPRINT data show that APOL1 risk variants are associated with mild CKD but not with prevalent CVD in AAs with a UACR under 1000 mg/g