Rationale: Limited information is available on racial/ ethnic differences in pulmonary arterial hypertension (PAH).Objectives: Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH.Methods: Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis.Measurements and Main Results: After covariate adjustment, selfreported Hispanic patients (n = 290) exhibited significantly reduced mortality versus NHW patients (n = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87]; P = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01]; P = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients (n = 1,524) versus NHW patients (n = 8,829; OR, 0.65 [95% CI, 0.50-0.84]; P = 0.001). An inpatient mortality benefit was observed for Native American patients (n = 185; OR, 0.38 [95% CI, 0.15-0.93]; P = 0.034).Conclusions: This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.

The human leukocyte antigen (HLA) system is the most polymorphic in the human genome that has been associated with protection and predisposition to a broad array of infectious, autoimmune, and malignant diseases. More recently over the last two decades, HLA class I alleles have been strongly associated with T‐cell‐mediated drug hypersensitivity reactions. In the case of abacavir hypersensitivity and HLA‐B*57:01, the 100% negative predictive value and low number needed to test to prevent a single case has led to a durable and effective global preprescription screening strategy. However, HLA associations are still undefined for most drugs clinically associated with different delayed drug hypersensitivity phenotypes, and an HLA association relevant to one population is not generalizable across ethnicities. Furthermore, while a specific risk HLA allele is necessary for drug‐induced T‐cell activation, it is not sufficient. The low and incomplete positive predictive value has hindered efforts at clinical implementation for many drugs but has provided the impetus to understand the mechanisms of HLA class I restricted T‐cell‐mediated drug hypersensitivity reactions. Current research has focused on defining the contribution of additional elements of the adaptive immune response and other genetic and ecologic risk factors that contribute to drug hypersensitivity risk. In this review we focus on new insights into immunological, pharmacological, and genetic mechanisms underpinning HLA‐associated drug reactions and the implications for future translation into clinical care.

Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. We performed a genome-wide association study with positive functional assay as the outcome in a large discovery cohort of patients divided into three groups: (1) functional assay-positive cases (n=1269), (2) antibody-positive (functional assay-negative) controls (n=1131), and (3) antibody-negative controls (n=1766). Significant associations (alpha=5x10-8) were investigated in a replication cohort (alpha=0.05) of functional assay-confirmed HIT cases (n=177), antibody-positive (function assay-negative) controls (n=258), and antibody negative controls (n=351). We observed a strong association for positive functional assay with increasing PF4/heparin IgG level (odds ratio [OR] 16.53[95% confidence interval 13.83-19.74], p=1.51x10-209) and female sex (OR 1.15[1.01-1.32], p=0.034). The rs8176719 C insertion variant in ABO was significantly associated with positive functional assay status in the discovery cohort (frequency=0.41; OR 0.751[0.682-0.828], p=7.80x10-9) and in the replication cohort (OR 0.467 [0.228-0.954], p=0.0367). The rs8176719 C insertion, which encodes all non-O blood group alleles, had a protective effect, indicating that the rs8176719 C deletion and the O blood group was a risk factor for HIT (O blood group OR 1.42 [1.26-1.61], p=3.09x10-8). Meta-analyses indicated that the ABO association was independent of PF4/heparin IgG levels and was stronger when functional assay-positive cases were compared to antibody-positive (functional assay-negative) controls than to antibody-negative controls. Sequencing and fine-mapping of ABO demonstrated that rs8176719 was the causal SNP. Our results clarify the biology underlying HIT pathogenesis with ramifications for prediction and may have important implications for related conditions, such as vaccine-induced thrombotic thrombocytopenia.

Pharmacomicrobiomic studies investigate drug‐microbiome interactions, such as the effect of microbial variation on drug response and disposition. Studying and understanding the interactions between the gut microbiome and drugs is becoming increasingly relevant to clinical practice due to its potential for avoiding adverse drug reactions or predicting variability in drug response. The highly variable nature of the human microbiome presents significant challenges to assessing microbes’ influence. Studies aiming to explore drug‐microbiome interactions should be well‐designed to account for variation in the microbiome over time and collect data on confounders such as diet, disease, concomitant drugs, and other environmental factors. Here, we assemble a set of important considerations and recommendations for the methodological features required for performing a pharmacomicrobiomic study in humans with a focus on the gut microbiome. Consideration of these factors enable discovery, reproducibility, and more accurate characterization of the relationships between a given drug and the microbiome. Furthermore, appropriate interpretation and dissemination of results from well‐designed studies will push the field closer to clinical relevance and implementation.

Response to cardiovascular drugs can vary greatly between individuals, and the role of the microbiome in this variability is being increasingly appreciated. Recent evidence indicates that bacteria and other microbes are responsible for direct and indirect effects on drug efficacy and toxicity. Pharmacomicrobiomics aims to uncover variability in drug response due to microbes in the human body, which may alter drug disposition through microbial metabolism, interference by microbial metabolites, or modification of host enzymes. In this review, we present recent advances in our understanding of the interplay between microbes, host metabolism, and cardiovascular drugs. We report numerous cardiovascular drugs with evidence of, or potential for, gut-microbe interactions. However, the effects of gut microbiota on many cardiovascular drugs are yet uninvestigated. Finally, we consider potential clinical applications for the described findings.