Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13×10– ¹⁵) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65×10– ²⁰) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69×10– ¹²; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR

Monitoring of tritium and impurities in the first wall of fusion devices using a LIBS based diagnostic

Laser-Induced Breakdown Spectroscopy (LIBS) is one of the most promising methods for quantitative in-situ determination of fuel retention in Plasma-Facing Components (PFCs) of fusion devices. The current state of understanding in LIBS development for fusion applications will be presented, based on a complete review of existing results and complemented with newly obtained data. The work has been performed as part of a research programme, set up in the EUROfusion Consortium, to address the main requirements for ITER: a) quantification of fuel from relevant surfaces with high sensitivity, b) the technical demonstration to perform LIBS with a remote handling system and c) accurate detection of fuel at ambient pressures relevant for ITER. The elemental composition of ITER-like deposits, including deuterium (D: as substitute for tritium (T)) or helium (He) containing W-Be, W, W-Al and Be-O-C coatings, was successfully determined: D surface densities below 1016 D/cm2 could be measured with an accuracy of ~30% (depth resolution 50-250 nm). A remote handling application was demonstrated inside the Frascati-Tokamak-Upgrade (FTU), where a compact, remotely controlled LIBS system was mounted on a multipurpose deployer providing an in-vessel retention monitor system. LIBS was performed at atmospheric pressure for measuring the composition and fuel content of different area of the FTU first wall and toroidal limiter. Concerning the capabilities of LIBS at pressure conditions relevant for ITER, quantitative determination of the composition of PFC materials at ambient pressures up to 100 mbar of N2, the D content could be determined with an accuracy of 25% (50% at 1 bar using single-pulse lasers). To improve the LIBS performance in atmospheric pressure conditions, a novel approach, based on an alternative LIBS detection timing scheme, is proposed. The application of double pulse LIBS at atmospheric pressure improved the distinguishability of H isotope lines significantly, but further research is required