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

Ability of pulse contour and esophageal Doppler to estimate rapid changes in stroke volume

Objective: Two technologies to acquire beat-to-beat stroke volume values exist, pulse contour analysis and esophageal Doppler monitoring. Pulse contour analysis assumes fixed aortic impedance. Esophageal Doppler assumes a constant proportional descending aortic flow and diameter. These assumptions may not be correct as arterial tone or myocardial contractility vary. We tested these relationships in the setting of rapidly changing stroke volumes and different cardiovascular states over a period of 10-15 cardiac cycles. Design and setting: In a university research facility we compared beat-to-beat changes in stroke volume as measure by aortic root flow probe or conductance catheter to pulse contour analysis and stroke distance as measured by esophageal Doppler. Subjects: Five purpose-bred research hounds. Interventions: To obtain a wide range of rapidly changing stroke volumes measurements were made during transient inferior vena cava occlusion. Data were gathered under baseline conditions and during norepinephrine, nitroprusside, and dobutamine infusions. Measurements and results: The pulse contour stroke volumes and esophageal Doppler stroke distance paralleled flow probe stroke volumes under all conditions (R 2 = 0.89 for all measures). However, the absolute changes and proportional changes and the absolute values for both surrogate measures differed from absolute stroke volumes. Bland-Altman analysis showed no consistent bias or degree of precision across all animals under any given cardiovascular state. Conclusions: Both pulse contour stroke volumes and esophageal Doppler derived stroke distance estimates yield significant correlations with aortic root flow probe. However, the absolute values, absolute changes, or proportional changes may not reflect actual stroke volumes as cardiovascular state varies, making their use in estimating absolute changes in stroke volume potentially inaccurate. © 2006 Springer-Verlag