In this trans-ethnic multi-omic study we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenome, and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in GWASs 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 murine renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

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.

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 (SES) in a low-income population. Methods and Results Participants were 27,078 whites and blacks recruited during 2002-2009 in the Southern Community Cohort Study, who had no history of HF and were utilizing Centers for Medicare or Medicaid services (CMS). Incident HF diagnoses through December 31, 2010 were ascertained using ICD-9 codes 428.x via linkage with CMS research files. Participant residential information was geocoded and census tract determined by a spatial join to the US Census Bureau's TIGER/Line Shapefiles. The neighborhood deprivation index (NDI) was constructed using principal components analysis based on census tract-level socioeconomic variables. Cox models with Huber-White cluster sandwich estimator of variance were utilized to investigate the association between NDI and HF risk. The study sample was predominantly middle-aged (mean 55.5 years), black (69%), female (63%), low-income (70% earned < $15,000/year), and >50% of participants lived in the most deprived neighborhoods (3rd NDI tertile). Over median follow-up of 5.2 years, 4,300 participants were diagnosed with HF. After adjustment for demographic, lifestyle and clinical factors, a 1 interquartile increase in NDI was associated with a 12% increase in risk of HF [HR= 1.12; 95% CI: 1.07-1.18], and 4.8% of the variance in HF risk [ICC = 4.8; 95% CI: 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 SES and traditional cardiovascular risk factors. Improvements in community resources may be a significant axis for curbing the burden of HF.

BackgroundCardiac 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 ResultsThe 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).ConclusionsLower 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.

Background: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 ( APOL1 ) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. Methods: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. Results: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01–1.21]; P =0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05–1.36; P =0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01–1.29l; P =0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. Conclusions: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.