Lack of association between KIR and HLA-C type and susceptibility to idiopathic bronchiectasis

SummaryIntroductionIdiopathic bronchiectasis is a poorly defined disease characterised by persistent inflammation, infection and progressive lung damage. Natural killer (NK) cells provide a major defense against infection, through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin-like receptors (KIR), and human leukocyte antigens (HLA) class I molecules. Homozygosity for HLA-C has been shown in a single study to confer increased genetic susceptibility to idiopathic bronchiectasis. We aimed to assess whether the KIR and HLA repertoire, alone or in combination, may influence the risk of developing idiopathic bronchiectasis, in an independent replication study.MethodsIn this prospective, observational, case-control association study, 79 idiopathic bronchiectasis patients diagnosed following extensive aetiological investigation were compared with 98 anonymous, healthy, age, sex and ethnically-matched controls attending blood donor sessions in the same geographical location. DNA extraction was performed according to standardised techniques. Determination of presence or absence of KIR genes was performed by a sequence specific oligonucleotide probe method. Allele frequencies for the proposed KIR, HLA-B and HLA-C risk alleles both individually and in combinations were compared.ResultsWe found no significant differences in allele frequency between the idiopathic bronchiectasis and control samples, whether considering HLA-C group homozygosity alone or in combination with the KIR type.DiscussionOur results do not show an association between HLA-C and KIR and therefore do not confirm previous positive findings. This may be explained by the lower frequency of HLA-C1 group homozygosity in the control population of the previous study (27.2%), compared to 42.3% in our study, which is consistent with the genetic profiling of control groups across the UK. The previous positive association study may therefore have been driven by an anomalous control group. Further larger prospective multicentre replication studies are needed to determine if an association exists

Plasma Metabolomics Implicate Modified Transfer RNAs and Altered Bioenergetics in the Outcome of Pulmonary Arterial Hypertension.

BACKGROUND: -Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. METHODS: -We conducted a comprehensive study of plasma metabolites using ultra-performance liquid chromatography mass-spectrometry to (1) identify patients at high risk of early death, (2) identify patients who respond well to treatment and (3) provide novel molecular insights into disease pathogenesis. RESULTS: -53 circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy controls (n=121) following correction for multiple testing (p<7.3e-5) and confounding factors, including drug therapy, renal and hepatic impairment. A subset of 20/53 metabolites also discriminated PAH patients from disease controls (symptomatic patients without pulmonary hypertension, n=139). 62 metabolites were prognostic in PAH, with 36/62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), TCA cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan and polyamine metabolites and decreased levels of steroids, sphingomyelins and phosphatidylcholines distinguished patients from controls. The largest differences correlated with increased risk of death and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to healthy controls. CONCLUSIONS: -Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterisation of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients

Traffic exposures, air pollution and outcomes in pulmonary arterial hypertension: A United Kingdom cohort study analysis

While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter ≤2.5 μm3 (PM2.5), nitrogen dioxide (NO2) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK PAH national Cohort study. Associations with transplant-free survival and pulmonary hemodynamic severity at baseline were assessed, adjusting for confounding variables defined a priori.Higher estimated exposure to PM2.5 was associated with higher risk of death or lung transplant (Unadjusted hazard ratio (HR) 2.68; 95% CI 1.11-6.47 per 3 μg·m-3, p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38; 95% CI 1.44-13.36 per 3 μg·m-3, p=0.009). No associations were found between NO2 exposure or other traffic pollution indicators and transplant-free survival Conversely, indirect measures of exposure to traffic-related air pollution within the 500-1000 m buffer zones correlated with the ERS/ESC risk categories as well as pulmonary hemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM2.5 exposure may independently predict shorter transplant-free survival

Loss-of-function ABCC8 mutations in pulmonary arterial hypertension

Background: In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3, was identified as a genetic cause and pharmacological target. Methods: Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis. Results: We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)—a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide. Conclusions: Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered

Breaking down the barriers: Why the delay in referral for pulmonary arterial hypertension?

Background: Pulmonary arterial hypertension (PAH) is a rare and fatal disease. While many treatment options have been shown to improve quality of life, exercise tolerance, and hemodynamics in PAH, survival remains poor, in part due to the advanced stage at which patients present to PAH specialists. Methods: This perspective paper explores challenges related to the timing of referral, diagnosis, and initiation of therapy. Results: Multiple factors account for the delay in referral, including fallacies in physician education, commercial influence resulting in inappropriate prescribing practices, and barriers in access to care. Conclusion: Improving physician education, encouraging the prescription of PAH medications to be done predominantly by PAH specialists, overcoming barriers to care, and promoting screening for PAH will help ensure early referral, diagnosis, and treatment