Multi-trait Analysis of GWAS for circulating FGF23 Identifies Novel Network Interactions Between HRG-HMGB1 and Cardiac Disease in CKD.

Background: Genome-wide association studies (GWAS) have identified numerous genetic loci associated with mineral metabolism (MM) markers but have exclusively focused on single-trait analysis. In this study, we performed a multi-trait analysis of GWAS (MTAG) of MM, exploring overlapping genetic architecture between traits, to identify novel genetic associations for fibroblast growth factor 23 (FGF23). Methods: We applied MTAG to genetic variants common to GWAS of 5 genetically correlated MM markers (calcium, phosphorus, FGF23, 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH)) in European-ancestry subjects. We integrated information from UKBioBank GWAS for blood levels for phosphate, 25(OH)D and calcium (n=366,484), and CHARGE GWAS for PTH (n=29,155) and FGF23 (n=16,624). We then used functional genomics to model interactive and dynamic networks to identify novel associations between genetic traits and circulating FGF23. Results: MTAG increased the effective sample size for all MM markers to n=50,325 for FGF23. After clumping, MTAG identified independent genome-wide significant SNPs for all traits, including 62 loci for FGF23. Many of these loci have not been previously reported in single-trait analyses. Through functional genomics we identified Histidine-rich glycoprotein (HRG) and high mobility group box 1(HMGB1) genes as master regulators of downstream canonical pathways associated with FGF23. HRG-HMGB1 network interactions were also highly enriched in left ventricular heart tissue of a cohort of deceased hemodialysis patients. Conclusion: Our findings highlight the importance of MTAG analysis of MM markers to boost the number of genome-wide significant loci for FGF23 to identify novel genetic traits. Functional genomics revealed novel networks that inform unique cellular functions and identified HRG-HMGB1 as key master regulators of FGF23 and cardiovascular disease in CKD. Future studies will provide a deeper understanding of genetic signatures associated with FGF23 and its role in health and disease.

Mendelian Randomization Analysis of Genetic Proxies of Thiazide Diuretics and the Reduction of Kidney Stone Risk.

Importance: Clinical trial data have called into question the efficacy of thiazide diuretics for the prevention of kidney stones. Objective: To identify whether there is an association between genetic proxies of thiazide diuretics and the risk of kidney stones. Design, Setting, and Participants: This genetic association study undertook a mendelian randomization analysis of derived exposures and outcomes from genome-wide association study summary statistics. Genetic proxies of thiazide diuretics were derived from the International Consortium for Blood Pressure. Kidney stone cases and controls were derived from the Million Veteran Program, UK Biobank, and the FinnGen study. These cross-sectional designs do not report a duration of follow-up. Data analysis was performed in May 2023. Exposure: Genetic proxies of thiazide diuretics were genetic variants in the thiazide-sensitive sodium chloride cotransporter gene associated with systolic blood pressure. Genetic proxies of ß-blockers and systolic blood pressure served as negative controls. Main Outcomes and Measures: The main outcome was the odds of kidney stones. The secondary outcomes were serum laboratory values relevant to the treatment of kidney stones. Results: The main analysis included up to 1 079 657 individuals, including 50 832 kidney stone cases and 1 028 825 controls. In a meta-analysis of all cohorts, genetic proxies of thiazide diuretics were associated with a lower odds of kidney stones (OR, 0.85; 95% CI, 0.81-0.89; P < .001). Genetic proxies of ß-blockers (OR, 1.02; 95% CI, 0.96-1.07; P = .52) and systolic blood pressure (OR, 1.00; 95% CI, 1.00-1.01; P = .49) were not associated with kidney stones. Genetic proxies of thiazide diuretics were associated with higher serum calcium (ß [SE], 0.051 [0.0092]; P < .001) and total cholesterol (ß [SE], 0.065 [0.015]; P < .001), but lower serum potassium (ß [SE], -0.073 [0.022]; P < .001). Conclusions and Relevance: In this genetic association study, genetic proxies of thiazide diuretics were associated with reduced kidney stone risk. This finding reflects a drug effect over the course of a lifetime, unconstrained by the limited follow-up period of clinical trials.

Mendelian randomization and the association of fibroblast growth factor-23 with heart failure with preserved ejection fraction.

PURPOSE OF REVIEW: Observational data provide compelling evidence for elevated fibroblast growth factor-23 (FGF23) as a risk factor for heart failure (HF), particularly heart failure with preserved ejection fraction (HFpEF). Given the limitations of observational studies, uncertainties persist regarding the causal role of FGF23 in the pathogenesis of HF and HFpEF. Recently, Mendelian randomization (MR) studies have been performed to examine causal associations between FGF23 and HF phenotypes. RECENT FINDINGS: The current review describes the methodological basis of the MR techniques used to examine the causal role of FGF23 on HF phenotypes, highlighting the importance of large-scale multiomics data. The findings from most of the MR studies indicate an absence of evidence of a causal effect of FGF23 on the risk of HF in general population settings. However, analysis using individual-level data showed a strong association between genetically-predicted FGF23 and HFpEF in individuals with a genetic predisposition to low estimated glomerular filtration (eGFR). SUMMARY: Evidence from MR analysis suggests a causal role of FGF23 in the pathogenesis of HFpEF in low eGFR settings - a finding supported by experimental, clinical, and epidemiological data. While future MR studies of FGF23 and HFpEF could provide further evidence, randomized trials of FGF23-lowering agents could provide the most definitive answers on the association in chronic kidney disease populations.

Phenome-Wide Association Study of UMOD Gene Variants and Differential Associations With Clinical Outcomes Across Populations in the Million Veteran Program a Multiethnic Biobank.

Introduction: Common variants in the UMOD gene are considered an evolutionary adaptation against urinary tract infections (UTIs) and have been implicated in kidney stone formation, chronic kidney disease (CKD), and hypertension. However, differences in UMOD variant-phenotype associations across population groups are unclear. Methods: We tested associations between UMOD/PDILT variants and up to 1528 clinical diagnosis codes mapped to phenotype groups in the Million Veteran Program (MVP), using published phenome-wide association study (PheWAS) methodology. Associations were tested using logistic regression adjusted for age, sex, and 10 principal components of ancestry. Bonferroni correction for multiple comparisons was applied. Results: Among 648,593 veterans, mean (SD) age was 62 (14) years; 9% were female, 19% Black, and 8% Hispanic. In White patients, the rs4293393 UMOD risk variant associated with increased uromodulin was associated with increased odds of CKD (odds ratio [OR]: 1.22, 95% CI: 1.20-1.24, P = 5.90 × 10-111), end-stage kidney disease (OR: 1.17, 95% CI: 1.11-1.24, P = 2.40 × 10-09), and hypertension (OR: 1.03, 95% CI: 1.05-1.05, P = 2.11 × 10-06) and significantly lower odds of UTIs (OR: 0.94, 95% CI: 0.92-0.96, P = 1.21 × 10-10) and kidney calculus (OR: 0.85, 95% CI: 0.83-0.86, P = 4.27 × 10-69). Similar findings were observed across UMOD/PDILT variants. The rs77924615 PDILT variant had stronger associations with acute cystitis in White female (OR: 0.73, 95% CI: 0.59-0.91, P = 4.98 × 10-03) versus male (OR: 0.99, 95% CI: 0.89-1.11, P = 8.80 × 10-01) (P interaction = 0.01) patients. In Black patients, the rs77924615 PDILT variant was significantly associated with pyelonephritis (OR: 0.65, 95% CI: 0.54-0.79, P = 1.05 × 10-05), whereas associations with UMOD promoter variants were attenuated. Conclusion: Robust associations were observed between UMOD/PDILT variants linked with increased uromodulin expression and lower odds of UTIs and calculus and increased odds of CKD and hypertension. However, these associations varied significantly across ancestry groups and sex.

Depressive Symptoms and Incident Heart Failure Risk in the Southern Community Cohort Study.

OBJECTIVES: This study aims to examine whether greater frequency of depressive symptoms associates with increased risk of incident heart failure (HF). BACKGROUND: Depressive symptoms associate with adverse prognosis in patients with prevalent HF. Their association with incident HF is less studied, particularly in low-income and minority individuals. METHODS: We studied 23,937 Black or White Southern Community Cohort Study participants (median age: 53 years, 70% Black, 64% women) enrolled between 2002 and 2009, without prevalent HF, receiving Centers for Medicare and Medicaid Services coverage. Cox models adjusted for traditional HF risk factors, socioeconomic and behavioral factors, social support, and antidepressant medications were used to quantify the association between depressive symptoms assessed at enrollment via the Center for Epidemiologic Studies Depression Scale (CESD-10) and incident HF ascertained from Centers for Medicare and Medicaid Services International Classification of Diseases-9th Revision (ICD-9) (code: 428.x) and ICD-10 (codes: I50, I110) codes through December 31, 2016. RESULTS: The median CESD-10 score was 9 (IQR: 5 to 13). Over a median 11-year follow-up, 6,081 (25%) participants developed HF. The strongest correlates of CESD-10 score were antidepressant medication use, age, and socioeconomic factors, rather than traditional HF risk factors. Greater frequency of depressive symptoms associated with increased incident HF risk (per 8-U higher CESD-10 HR: 1.04; 95% CI: 1.00 to 1.09; P = 0.038) without variation by race or sex. The association between depressive symptoms and incident HF varied by antidepressant use (interaction-P = 0.03) with increased risk among individuals not taking antidepressants. CONCLUSIONS: In this high-risk, low-income, cohort of predominantly Black participants, greater frequency of depressive symptoms significantly associates with higher risk of incident HF.

Relation of the Dietary Approaches to Stop Hypertension Dietary Pattern to Heart Failure Risk and Socioeconomic Status (from the Southern Community Cohort Study).

The Dietary Approaches to Stop Hypertension (DASH) dietary pattern has been associated with a lower risk of incident heart failure (HF); however, previous studies were conducted in mostly middle-income White populations. The association between DASH and incident HF risk in lower income and Black individuals is less well understood. We analyzed 25,300 White and Black adults without a history of HF at enrollment (2002 to 2009) in the Southern Community Cohort Study receiving Centers for Medicare and Medicaid Services. Alignment with DASH was assessed at enrollment using a validated food frequency questionnaire. Incident HF was ascertained from Centers for Medicare and Medicaid Services claims through 2016. The association between DASH diet alignment and incident HF was examined in multivariable-adjusted Cox proportional hazards regression models, including an interaction term testing effect modification by income. The cohort was predominantly middle-aged (median 54 years), Black (68%), female (63%), and low-income (88% <$25,000/year/household). Socioeconomic factors, including education and annual income, were larger contributors to the variance in DASH score than were cardiovascular co-morbidities. The association between DASH dietary alignment and HF risk was not significant overall (hazard ratio [HR] 1.00; 95% confidence interval [CI] 0.96 to 1.04) or in race-sex groups. However, the association between alignment with the DASH diet and HF risk significantly varied by income (interaction p = 0.030), with neutral and inverse associations in lower (<$25,000/year) and higher ($≥25,000) income participants, respectively. In conclusion, income modified the association between healthier dietary patterns and risk of incident HF. In lower income participants, greater alignment with the DASH diet was not associated with lower HF risk.

Effect Modification of Body Mass Index and Kidney Function on Insulin Sensitivity Among Patients With Moderate CKD and Healthy Controls.

INTRODUCTION: Insulin resistance and obesity are prevalent in chronic kidney disease (CKD) patients. The interaction of body mass index (BMI) and kidney function across the continuum of estimated glomerular filtration rate (eGFR) is unknown. METHODS: In a cross-sectional study of 139 patients, 52 with CKD stages 3 and 4 and 87 patients with normal eGFR, we measured the insulin sensitivity index (ISI) using the hyperinsulinemic euglycemic clamp and homeostasis model assessment of insulin resistance (HOMA-IR). We investigated the interaction between eGFR and BMI in their association with ISI and HOMA-IR using linear models with robust standard errors. RESULTS: Median age was 56 (42, 66) years, 50.4% were female, and 36% were African American. Patients with low eGFR (∼30 ml/min per 1.73 m2) had low ISI (2.3 mg/min per µU/ml) regardless of BMI. Among patients with preserved eGFR (>90 ml/min per 1.73m2), BMI had a greater effect on ISI (6.3 mg/min per µU/ml at a BMI of 20 kg/m2 vs. 4.6 mg/min per µU/ml at a BMI of 30 kg/m2) (P for interaction = 0.046). In models adjusted for demographics, and log transformed interleukin-6, high-sensitivity C-reactive protein, leptin, and adiponectin, a 1-SD (28 ml/min per 1.73 m2) lower eGFR was associated with a statistically significant 1.14-unit decrease in ISI (95% confidence interval = -1.80, -0.48) among nonobese patients. Among obese patients, the effect estimate was -0.25 (95% confidence interval = -0.88, 0.39). The association between BMI and HOMA-IR was stronger in patients with lower eGFR (P for interaction = 0.005). CONCLUSION: Both eGFR and BMI are independently associated with insulin sensitivity, but the strength of the association between BMI and insulin sensitivity varies significantly across eGFR.

Association of Apparent Treatment-Resistant Hypertension With Differential Risk of End-Stage Kidney Disease Across Racial Groups in the Million Veteran Program.

[Figure: see text].

Peripheral Insulin Resistance Is Associated with Copeptin in Patients with Chronic Kidney Disease.

Background: Insulin resistance is associated with cardiovascular disease risk and worsened kidney function. Patients with CKD have higher levels of insulin resistance. Elevated levels of copeptin (a surrogate for vasopressin levels) have been associated with an increased incidence and progression of CKD, and with incident diabetes mellitus. The purpose of our study was to examine the relationship between insulin resistance, copeptin, and CKD. Methods: We performed a cross-sectional study to investigate if insulin resistance was associated with higher copeptin levels in nondiabetic patients with stage 3-4 CKD versus controls. We measured plasma copeptin levels and used data from 52 patients with stage 3-4 CKD and 85 controls (eGFR ≥60 ml/min per 1.73 m2) enrolled in the Insulin Resistance in Chronic Kidney Disease (IRCKD) study. We then used a multivariable linear-regression model to assess the independent relationship between peripheral or hepatic insulin resistance and copeptin across levels of eGFR. Results: We found that in patients with CKD (eGFR of 30-60 ml/min per 1.73 m2), but not in controls, peripheral insulin resistance was significantly correlated with higher levels of log copeptin (r=-0.21, P=0.04). In patients with CKD, when adjusted for age, sex, BMI, serum osmolality, log IL6, and log leptin/adiponectin ratio, each 1 SD decrease in insulin sensitivity was associated with a 39% increase in serum copeptin levels. The relationship between hepatic insulin resistance, copeptin, and eGFR is similar between controls and patients with reduced eGFR. Conclusion: Peripheral insulin resistance is associated with elevated copeptin levels in nondiabetic patients with stage 3-4 CKD. Further research into how the interaction between peripheral insulin resistance and elevated vasopressin affects CKD progression could be of interest.

Race and Sex Differences in Modifiable Risk Factors and Incident Heart Failure.

OBJECTIVES: The purpose of this study was to examine race- and sex-based variation in the associations between modifiable risk factors and incident heart failure (HF) among the SCCS (Southern Community Cohort Study) participants. BACKGROUND: Low-income individuals in the southeastern United States have high HF incidence rates, but relative contributions of risk factors to HF are understudied in this population. METHODS: We studied 27,078 black or white SCCS participants (mean age: 56 years, 69% black, 63% women) enrolled between 2002 and 2009, without prevalent HF, receiving Centers for Medicare and Medicaid Services. The presence of hypertension, diabetes mellitus, physical underactivity, high body mass index, smoking, high cholesterol, and poor diet was assessed at enrollment. Incident HF was ascertained using International Classification of Diseases-9th revision, codes 428.x in Centers for Medicare and Medicaid Services data through December 31, 2010. Individual risk and population attributable risk for HF for each risk factor were quantified using multivariable Cox models. RESULTS: During a median (25th, 75th percentile) 5.2 (3.1, 6.7) years, 4,341 (16%) participants developed HF. Hypertension and diabetes were associated with greatest HF risk, whereas hypertension contributed the greatest population attributable risk, 31.8% (95% confidence interval: 27.3 to 36.0). In black participants, only hypertension and diabetes associated with HF risk; in white participants, smoking and high body mass index also associated with HF risk. Physical underactivity was a risk factor only in white women. CONCLUSIONS: In this high-risk, low-income cohort, contributions of risk factors to HF varied, particularly by race. To reduce the population burden of HF, interventions tailored for specific race and sex groups may be warranted.

Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program.

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.

Racial disparities in end-stage renal disease in a high-risk population: the Southern Community Cohort Study.

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.

Association between reduced myocardial contraction fraction and cardiovascular disease outcomes: The Multi-Ethnic Study of Atherosclerosis.

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.

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.

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.

Neighborhood Deprivation Predicts Heart Failure Risk in a Low-Income Population of Blacks and Whites in the Southeastern United States.

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.

Association of Neighborhood Socioeconomic Context With Participation in Cardiac Rehabilitation.

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.

Heart Failure Incidence and Mortality in the Southern Community Cohort Study.

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.

Increased body mass index may be associated with greater risk of end-stage renal disease in whites compared to blacks: A nested case-control study.

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.

Association of HLA class II markers with autoantibody-negative ketosis-prone atypical diabetes compared to type 2 diabetes in a population of sub-Saharan African patients.

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.