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1.
Nat Commun ; 10(1): 3842, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451708

RESUMO

Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.

2.
BMC Nephrol ; 20(1): 308, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31390993

RESUMO

INTRODUCTION: The Southern Community Cohort Study is a prospective study of low socioeconomic status (SES) blacks and whites from the southeastern US, where the burden of end-stage renal disease (ESRD) and its risk factors are high. We tested whether the 2.4-fold elevated risk of ESRD we previously observed in blacks compared to whites was explained by differences in baseline kidney function. METHODS: We conducted a case-cohort study of incident ESRD cases (n = 737) with stored blood and a probability sampled subcohort (n = 4238) and calculated estimated glomerular filtration rate (eGFR) from serum creatinine. 86% of participants were enrolled from community health centers in medically underserved areas and 14% from the general population in 12 states in the southeastern United States. Incident ESRD after entry into the cohort was ascertained by linkage of the cohort with the US Renal Data System (USRDS). RESULTS: Median (25th, 75th percentile) eGFR at baseline was 63.3 (36.0, 98.2) ml/min/1.73m2 for ESRD cases and 103.2 (86.0, 117.9) for subcohort. Black ESRD cases had higher median (25th, 75th) eGFR [63.3 (35.9, 95.9)] compared to whites [59.1 (39.4, 99.2)]. In multivariable Cox models accounting for sampling weights, baseline eGFR was a strong predictor of ESRD risk, and an interaction with race was detected (P = 0.029). The higher ESRD risk among blacks relative to whites persisted (hazard ratio: 2.58; 95% confidence interval: 1.65, 4.03) after adjustment for eGFR. CONCLUSION: In this predominantly lower SES cohort, the racial disparity in ESRD risk is not explained by differences in baseline kidney function.

3.
Int J Cardiol ; 293: 10-16, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31327521

RESUMO

BACKGROUND: The myocardial contraction fraction (MCF: stroke volume to myocardial volume) is a volumetric measure of left ventricular myocardial shortening. We examined the relationship of MCF, measured by cardiac magnetic resonance imaging (cMRI), to incident cardiovascular (CV) events within the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: Participants (n = 5000, aged 45-84 years) underwent cMRI. PRIMARY OUTCOME: CVD events (myocardial infarction, resuscitated cardiac arrest, stroke, coronary heart disease: CHD death, and stroke death). SECONDARY OUTCOMES: CHD and heart failure (HF) events. Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for outcomes. RESULTS: There were 299 incident CVD, 188 CHD, and 151 HF events over 10.2 years. The lowest MCF quartile was associated with an increased risk for incident CVD [HR 2.42, CI: 1.58-3.72], CHD [HR 2.32, CI: 1.36-3.96] and HF events [HR 1.99, CI: 1.15-3.44]. In a model adjusted for demographics, CV risk factors, antihypertensive and lipid-lowering medication use, each standard deviation decrease in MCF was associated with incident CVD [HR 1.42, CI: 1.23-1.64], CHD [HR 1.40, CI: 1.17-1.67] and HF [HR 1.58, CI: 1.30-1.94]. In a subgroup analysis of participants with preserved ejection fraction and without left ventricular hypertrophy, the lowest MCF quartile and each standard deviation decrease in MCF was also associated with an increased risk for incident CVD in fully-adjusted analyses. CONCLUSIONS: MCF is a novel measure that can be measured using cMRI. In this multi-ethnic cohort, MCF is a measure that can be used to predict incident CVD events.

4.
Nat Genet ; 51(1): 51-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578418

RESUMO

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.


Assuntos
Pressão Sanguínea/genética , Grupos Étnicos/genética , Adolescente , Animais , Feminino , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Túbulos Renais/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Regulação para Cima/genética
5.
Circ Cardiovasc Qual Outcomes ; 11(1): e004052, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29317456

RESUMO

BACKGROUND: Recent data suggest that neighborhood socioeconomic environment predicts heart failure (HF) hospital readmissions. We investigated whether neighborhood deprivation predicts risk of incident HF beyond individual socioeconomic status in a low-income population. METHODS AND RESULTS: Participants were 27 078 whites and blacks recruited during 2002 to 2009 in the SCCS (Southern Community Cohort Study), who had no history of HF and were using Centers for Medicare or Medicaid Services. Incident HF diagnoses through December 31, 2010, were ascertained using International Classification of Diseases, Ninth Revision, codes 428.x via linkage with Centers for Medicare or Medicaid Services research files. Participant residential information was geocoded and census tract determined by a spatial join to the US Census Bureau TIGER/Line Shapefiles. The neighborhood deprivation index was constructed using principal components analysis based on census tract-level socioeconomic variables. Cox models with Huber-White cluster sandwich estimator of variance were used to investigate the association between neighborhood deprivation index and HF risk. The study sample was predominantly middle aged (mean, 55.5 years), black (69%), female (63%), low income (70% earned <$15 000/y), and >50% of participants lived in the most deprived neighborhoods (third neighborhood deprivation index tertile). Over median follow-up of 5.2 years, 4300 participants were diagnosed with HF. After adjustment for demographic, lifestyle, and clinical factors, a 1 interquartile increase in neighborhood deprivation index was associated with a 12% increase in risk of HF (hazard ratio, 1.12; 95% confidence interval, 1.07-1.18), and 4.8% of the variance in HF risk (intraclass correlation coefficient, 4.8; 95% confidence interval, 3.6-6.4) was explained by neighborhood deprivation. CONCLUSIONS: In this low-income population, scant neighborhood resources compound the risk of HF above and beyond individual socioeconomic status and traditional cardiovascular risk factors. Improvements in community resources may be a significant axis for curbing the burden of HF.

6.
J Am Heart Assoc ; 6(10)2017 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-29021267

RESUMO

BACKGROUND: Cardiac rehabilitation (CR) is underutilized in the United States, with fewer than 20% of eligible patients participating in CR programs. Individual socioeconomic status is associated with CR utilization, but data regarding neighborhood characteristics and CR are sparse. We investigated the association of neighborhood socioeconomic context with CR participation in the SCCS (Southern Community Cohort Study). METHODS AND RESULTS: The SCCS is a prospective cohort study of 84 569 adults in the southeastern United States from 2002 to 2009, 52 117 of whom have Medicare or Medicaid claims. Using these data, we identified participants with hospitalizations for myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery and ascertained their CR utilization. Neighborhood socioeconomic context was assessed using a neighborhood deprivation index derived from 11 census-tract level variables. We analyzed the association of CR utilization with neighborhood deprivation after adjusting for individual socioeconomic status. A total of 4096 SCCS participants (55% female, 57% black) with claims data were eligible for CR. CR utilization was low, with 340 subjects (8%) participating in CR programs. Study participants residing in the most deprived communities (highest quintile of neighborhood deprivation) were less than half as likely to initiate CR (odds ratio 0.42, 95% confidence interval, 0.27-0.66, P<0.001) as those in the lowest quintile. CR participation was inversely associated with all-cause mortality (hazard ratio 0.77, 95% confidence interval, 0.60-0.996, P<0.05). CONCLUSIONS: Lower neighborhood socioeconomic context was associated with decreased CR participation independent of individual socioeconomic status. These data invite research on interventions to increase CR access in deprived communities.


Assuntos
Área Programática (Saúde) , Disparidades em Assistência à Saúde , Cardiopatias/reabilitação , Fatores Socioeconômicos , Demandas Administrativas em Assistência à Saúde , Idoso , Reabilitação Cardíaca/efeitos adversos , Reabilitação Cardíaca/economia , Reabilitação Cardíaca/mortalidade , Distribuição de Qui-Quadrado , Comorbidade , Bases de Dados Factuais , Feminino , Pesquisa sobre Serviços de Saúde , Disparidades em Assistência à Saúde/economia , Cardiopatias/diagnóstico , Cardiopatias/economia , Cardiopatias/mortalidade , Humanos , Renda , Estimativa de Kaplan-Meier , Masculino , Medicaid , Medicare , Pessoa de Meia-Idade , Razão de Chances , Pobreza , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia
7.
Circ Heart Fail ; 10(3)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28255010

RESUMO

BACKGROUND: There is a paucity of data on heart failure (HF) incidence among low-income and minority populations. Our objective was to investigate HF incidence and post-HF survival by race and sex among low-income adults in the southeastern United States. METHODS AND RESULTS: Participants were 27 078 white and black men and women enrolled during 2002 to 2009 in the SCCS (Southern Community Cohort Study) who had no history of HF and were receiving Centers for Medicare and Medicaid Services. Incident HF diagnoses through December 31, 2010 were ascertained using International Classification of Diseases 9th Revision codes 428.x via linkage with Centers for Medicare and Medicaid Services research files. Most participants were black (68.8%), women (62.6%), and earned <$15 000/y (69.7%); mean age was 55.5 (10.4) years. Risk factors for HF were common: hypertension (62.5%), diabetes mellitus (26.5%), myocardial infarction (8.6%), and obesity (44.8%). Over a median follow-up of 5.2 years, 4341 participants were diagnosed with HF. The age-standardized incidence rates were 34.8, 37.3, 34.9, and 35.6 /1000 person-years in white women, white men, black men, and black women, respectively, remarkably higher than previously reported. Among HF cases, 952 deaths occurred over a median follow-up of 2.3 years. Men had lower survival; hazard ratios and 95% confidence intervals were 1.63 (1.27-2.08), 1.38 (1.11-1.72), and 0.90 (0.73-1.12) for white men, black men, and black women compared with white women. CONCLUSIONS: In this low-income population, HF incidence was higher for all race-sex groups than previously reported in other cohorts. The SCCS is a unique resource to investigate determinants of HF risk in a segment of the population underrepresented in other existing cohorts.


Assuntos
Insuficiência Cardíaca/epidemiologia , Adulto , Afro-Americanos , Idoso , Comorbidade , Grupo com Ancestrais do Continente Europeu , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pobreza , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Distribuição por Sexo , Sudeste dos Estados Unidos/epidemiologia , Fatores de Tempo
8.
BMC Nutr ; 12015.
Artigo em Inglês | MEDLINE | ID: mdl-27239330

RESUMO

BACKGROUND: The relationship between body mass index (BMI) and end-stage renal disease (ESRD) may differ between blacks and whites due to underlying metabolic differences. METHODS: We conducted a nested case-control study of 631 incident ESRD cases and 1,897 matched controls within the Southern Community Cohort Study. Current weight, height, and weight at age 21 were reported at enrollment. Occurrence of ESRD was ascertained by linkage with the United States Renal Data System. With normal BMI (18.5-24.9 kg/m2) as reference, conditional logistic regression was used to calculate adjusted odds ratios (OR) and corresponding 95% confidence intervals (CI) for ESRD across other BMI categories by race. In subsequent analysis, BMI at age 21 was modeled using restricted cubic splines with 5 knots. Predicted probabilities of incident ESRD were computed from the multivariable logistic models and plotted against BMI at age 21. RESULTS: Among blacks, odds of ESRD were significantly increased among those who were overweight (OR: 1.41; 95%CI: 1.09, 1.83) or obese (OR: 2.56; 95%CI: 1.88, 3.47) at age 21. Among whites, the association between ESRD and BMI at age 21 was more pronounced, with corresponding ORs of 2.13 (95%CI: 0.92, 4.93) and 7.46 (95%CI: 2.90, 19.21; p-interaction 0.05). Only among whites was high BMI at enrollment associated with ESRD risk; OR for BMI≥40 kg/m2, was 3.31 (95%CI: 1.08, 10.12). The plot of the predicted probabilities of incident ESRD vs BMI at age 21 showed a monotonic increase in the probability of ESRD after a BMI cutoff ≈ 25Kg/m2 in both whites and blacks but the slope of the curve for whites appeared greater. CONCLUSIONS: Our results suggest racial differences in the relationship between BMI, both in early adulthood and middle age, and ESRD. These findings warrant further research into understanding the underlying metabolic differences that may explain these differences.

9.
Diabetes Res Clin Pract ; 107(1): 31-6, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25511714

RESUMO

AIM: We investigated the association of HLA DRB1 and DQB1 alleles, haplotypes and genotypes with unprovoked antibody-negative ketosis-prone atypical diabetes (A(-) KPD) in comparison to type 2 diabetes (T2D). METHODS: A(-) KPD and T2D sub-Saharan African patients aged 19-63 years were consecutively recruited. Patients positive for cytoplasmic islet cell, insulin, glutamic acid decarboxylase or islet antigen-2 autoantibodies were excluded. Odds ratios were obtained via logistic regression after considering alleles with a minimum frequency of 5% in the study population. Bonferroni correction was used in the case of multiple comparisons. RESULTS: Among the 130 participants, 35 (27%) were women and 57 (44%) were A(-) KPD. DRB1 and DQB1 allele frequencies were similar for both A(-) KPD and T2D patients; they did not confer any substantial risk even after considering type 1 diabetes susceptibility and resistance alleles. We found no association between A(-) KPD and the derived DRB1*07-DQB1*02:02 (OR: 0.55 [95%CI: 0.17-1.85], P=0.336); DRB1*11-DQB1*03:01 (OR: 2.42 [95%CI: 0.79-7.42], P=0.123); DRB1*15-DQB1*06:02 (OR: 0.87 [95%CI: 0.39-1.95], P=0.731) and DRB1*03:01-DQB1*02:01 (OR: 1.48 [95%CI: 0.55-3.96], P=0.437) haplotypes. Overall, we did not find any evidence of susceptibility to ketosis associated with DRB1 and DQB1 genotypes (all P>0.05) in A(-) KPD compared to T2D. Similar results were obtained after adjusting the analysis for age and sex. CONCLUSION: Factors other than DRB1 and DQB1 genotype could explain the propensity to ketosis in A(-) KPD. These results need to be confirmed in a larger population with the perspective of improving the classification and understanding of the pathophysiology of A(-) KPD.


Assuntos
Autoanticorpos/imunologia , Diabetes Mellitus Tipo 2/imunologia , Cadeias beta de HLA-DQ/imunologia , Cadeias HLA-DRB1/imunologia , Cetose/imunologia , Adulto , África ao Sul do Saara , Grupo com Ancestrais do Continente Africano , Autoanticorpos/genética , Estudos Transversais , Diabetes Mellitus Tipo 2/genética , Feminino , Frequência do Gene , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Humanos , Cetose/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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