Background Corin enzyme contributes to the processing of inactive natriuretic peptides to bioactive hormones. In Black individuals, Corin gene variants (rs111253292 Q568P and rs75770792 T555I) have ...been previously reported to have a modest association with blood pressure (BP) and hypertension. Methods and Results We evaluated the association of Corin genotype with BP traits, prevalent hypertension, and incident hypertension among self-identified 11 322 Black Americans in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study and the JHS (Jackson Heart Study) using multivariable-adjusted regression modeling. Multivariable-adjusted genotype-stratified differences in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and BNP (B-type natriuretic peptide) levels were assessed. Genotype-stratified
and
expression differences in healthy organ donor left atrial and left ventricular heart tissue (N=15) were also examined. The rs111253292 genotype was not associated with systolic BP (β±SE, 0.42±0.58; -1.24±0.82), diastolic BP (0.51±0.33; -0.41±0.46), mean arterial pressure (0.48±0.38; -0.68±0.51), and prevalent hypertension (odds ratio OR, 0.93 95% CI, 0.80-1.09; OR, 0.79 95% CI, 0.61-1.01) in both REGARDS and JHS, respectively. The rs75770792 genotype was not associated with systolic BP (0.48±0.58; -1.26±0.81), diastolic BP (0.52±0.33; -0.33±0.45), mean arterial pressure (0.50±0.38; -0.63±0.50), and prevalent hypertension (OR, 1.02 95% CI, 0.84-1.23; OR, 0.87 95% CI, 0.67-1.13) in both cohorts, respectively. The Corin genotype was also not associated with incident hypertension (OR, 1.35 95% CI, 0.94-1.93; OR, 0.95 95% CI, 0.64-1.39) in the study cohorts. The NT-proBNP levels in REGARDS and BNP levels in JHS were similar between the Corin genotype groups. In heart tissue, the
and
expression was similar between the genotype groups. Conclusions
gene variants observed more commonly in Black individuals are not associated with differences in NP expression, circulating NP levels, and BP or hypertension as previously reported in candidate gene studies. Understanding the genetic determinants of complex cardiovascular traits in underrepresented populations requires further evaluation.
Abstract only
Introduction:
Hypertension affects about half the US adult population with a higher prevalence in males. This study examines the contribution of the genetic architecture to the ...sex-associated differences in hypertension in a multi-ethnic US population.
Methods:
Multi-ancestry genome-wide association studies for systolic blood pressure (SBP) were conducted for each sex separately in the UK BioBank. Sex-specific SBP polygenic risk scores (SBP-PRS), comprising 1.1 million variants each, were generated from these GWASs. Sex-specific SBP-PRS was calculated in participants who underwent whole genome sequencing in the All of Us project. Based on the SBP-PRS, the cohort was stratified into low (<2.5
th
centile), low-intermediate (2.5
th
-20
th
centile), intermediate (20
th
-80
th
centile), high-intermediate (80
th
-97.5
th
centile), and high (>97.5
th
centile) genetic risk of SBP. Hypertension was defined as a BP ≥130/80 mmHg or anti-hypertensive use. Logistic regression models were used to assess the sex-stratified association of SBP-PRS with hypertension.
Results:
The All of Us cohort had 212,669 individuals median age: 54 (38, 65) years comprising 127,679 (60.0%) females and 97,600 (45.9%) non-White individuals (20.6% Black, 3.3% Asian, and 19.1% Hispanic). Hypertension was reported in 118,984 (55.9%) in the overall population and in 53,307 (62.7%) males and 65,677 (51.4%) females. Females OR
adj
: 1.29 (1.27-1.30) had higher odds of developing hypertension per SD increase in SBP PRS compared with males OR
adj
: 1.22 (1.20-1.23). (P
interaction
:2.5x10
-6
) On stratification by SBP-PRS, females in the high-risk group and the low-risk group had higher odds of developing hypertension OR
adj
: 1.81 (1.68-1.95) vs. 1.61 (1.46-1.74) and lower odds of hypertension OR
adj
: 0.52 (0.48-0.56) vs. 0.65 (0.60-0.71), respectively compared with males.
Conclusion:
The contributions of the genetic underpinnings to the development of hypertension vary by sex.
Abstract only Introduction: Pulmonary hypertension (PH) is a progressive disease characterized by adverse remodeling of the lung vasculature and right ventricular failure. While BMPR2 mutations ...account for the majority of familial pulmonary arterial hypertension (PAH), the predisposing genetic factors in non-familial PH are not well understood. Whole exome sequencing (WES) data from individuals in the UK Biobank (UKB) provides a unique opportunity to interrogate the genetic factors underlying this rare disease. Hypothesis: Rare disruptive coding variants associated with sporadic PH will provide novel mechanistic insights. Methods: Exome sequences were aligned to the GRCh38 reference genome and variants annotated using Variant Effect Predictor. We identified rare (minor allele frequency <1%) high confidence loss-of-function variants using LOFTEE and deleterious missense variants using MetaSVM. We then performed a rare variant burden association study using logistic regression in REGENIE adjusting for age, sex, array, smoking status, and principal components 1-10. These analyses were performed on unrelated individuals identified based on kinship (kinship > 0.0884). We secondarily curated a list of 58 candidate PAH genes based on recent publications of rare variants identified in PAH, as well as the ClinVar database. PH was defined utilizing ICD codes 416.0 (ICD-9), I27.0, I27.2 (ICD-10). Results: 185,586 UKB participants were included; 665 with PH (age 62 years (+/-6), 46% female) and 184,921 controls (age 56 years (+/-8), 55% female). Rare variant association testing did not identify exome-significantly associated genes (p<2.5x10 -7 ), nor nominal associations in candidate PAH genes. Four novel genes with p<0.01 were identified, which included genes important in mitochondrial function ( ACADM ), nicotinic acetylcholine receptor signaling ( MYO18A ), pulmonary surfactant metabolism ( SFTPA1 ) and smooth muscle function ( BEST2 ). Conclusions: We identified putative genes associated with PH in the population which have not been previously implicated in familial PAH. If additional evidence supports the roles of these genes in PH, these findings may provide new therapeutic insights.
Abstract only Introduction: Genome-wide association studies (GWAS) of blood lipids have yielded several translational insights for coronary artery disease. Hypothesis: We tested the hypothesis that ...novel Bayesian methods leveraging genetic correlation can improve insights from lipid genetics analyses. Methods: We used published lipids GWAS results from 297,626 participants of the Million Veterans Program (MVP), and generated summary statistics for 276,096 participants of the UK Biobank. We employed a multivariate adaptive shrinkage (mashR) model to each dataset. MashR allows the effect of a SNP to be modeled as a mixture of multivariate normal distributions across lipid levels (LDL-C, HDL-C, Total Cholesterol, and triglycerides) and an empirical Bayes approach to appropriately nudge the posterior estimates of the effect in accordance with the overall patterns observed in the data. Results: In addition to reproducing all 318 loci significantly associated with lipids in MVP, we identified 4,689 novel loci associated with lipids using mashR. We observed a high degree of agreement between MVP and UK Biobank, with over 95% of UKBB replicated in MVP and an additional 1246 identified. In genetic prioritization analyses, mashR shows improvement in the detection of known Mendelian genes and the consistency of ranks among subgroups compared with univariate results. Our approach improves the estimate of enrichment parameters of known genomic features similar to established GWAS variants. Finally, combining these joint estimates with tools for incorporating the genetic correlation structure, mashR improves the proportion of variation explained by lipid polygenic risk scores by up to 58% (se 0.015) when compared to univariate substrates across lipid traits. This improvement holds across both European and non-European individuals. We show that much of this gain in power arises from improved precision of the posterior estimates where the ratio of original standard error over posterior marginal variance reflects an increased ‘effective sample size’. Conclusions: Our framework shows that Bayesian multivariate genetic analysis markedly improves power for genomic discovery, better identifies causal genes, and improves polygenic risk prediction for complex traits.
PDF
