5 research outputs found
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
In vivo hemostatic efficacy of polyurethane foam compared to collagen and gelatin
<p>Topical hemostatic agents are used in all surgical disciplines. Most of these hemostats are based on animal-derived products like collagen and gelatin. They carry the potential risk of pathogen transmission. A newly developed biodegradable, fully synthetic hemostatic agent based on polyurethane foam (PU) with 55 % polyethylene glycol (PEG) would prevent these potential risks.</p><p>The hemostatic efficacy of this new agent was compared to gelatin and collagen in humans who underwent extraction of an upper and lower molar (split-mouth model). After extraction of a molar in the maxilla and mandible, a PU foam and collagen or gelatin were inserted in the extraction socket for 2 min. Hereafter, the agents were removed and stored in ethylenediaminetetraacetic acid to stop coagulation. Then, the concentration of coagulation parameters thrombin-antithrombin III (TAT) complexes, fibrinogen, and thromboxane B-2 (TxB(2)) in blood extracts from the agents was measured. The concentrations were also determined in baseline blood samples which were collected from the extraction socket.</p><p>The concentrations of TAT and TxB(2) were significantly increased, and fibrinogen concentration was significantly reduced compared to baseline wound blood concentrations indicating enhanced hemostasis. No significant differences were seen in the concentrations of these coagulation parameters in the three different hemostatic agents.</p><p>These results show that PU combined with 55 % PEG is a promising alternative for the animal-derived hemostatic agents.</p><p>The synthetic hemostatic agent could replace the animal-derived products like collagen and gelatin and therewith prevent the potential risk of pathogen transmission.</p>