One‐seventh of the world's adult population, or approximately one billion people, are estimated to have OSA. Over the past four decades, obesity, the main risk factor for OSA, has risen in striking proportion worldwide. In the past 5 years, the WHO estimates global obesity to affect almost two billion adults. A second major risk factor for OSA is advanced age. As the prevalence of the ageing population and obesity increases, the vulnerability towards having OSA increases. In addition to these traditional OSA risk factors, studies of the global population reveal select contributing features and phenotypes, including extreme phenotypes and symptom clusters that deserve further examination. Untreated OSA is associated with significant comorbidities and mortality. These represent a tremendous threat to the individual and global health. Beyond the personal toll, the economic costs of OSA are far‐reaching, affecting the individual, family and society directly and indirectly, in terms of productivity and public safety. A better understanding of the pathophysiology, individual and ethnic similarities and differences is needed to better facilitate management of this chronic disease. In some countries, measures of the OSA disease burden are sparse. As the global burden of OSA and its associated comorbidities are projected to further increase, the infrastructure to diagnose and manage OSA will need to adapt. The use of novel approaches (electronic health records and artificial intelligence) to stratify risk, diagnose and affect treatment are necessary. Together, a unified multi‐disciplinary, multi‐organizational, global approach will be needed to manage this disease.

Summary 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 11 744 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 ...

A number of inflammatory cytokines and growth factors promote monocyte survival; however, the biochemical events stimulated by these factors are poorly defined. We previously showed that the monocyte survival factor macrophage colony-stimulating factor (M-CSF) activated monocyte survival through a PI 3-kinase-dependent pathway resulting in the phosphorylation of Akt and the suppression of the activation of caspase-3. Because other cytokines and bacterial cell wall products also induce monocyte survival, we hypothesized that these factors may also suppress caspase-3 and caspase-9 activation and activate Akt in human monocytes. To test this hypothesis, we found that interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, lipopolysaccharide (LPS), granulocyte macrophage-colony-stimulating factor (GM-CSF), and IL-18 appeared to suppress DNA fragmentation, caspase-9, and caspase-3 activation in human monocytes. Moreover, these stimuli appeared to induce the serine and threonine phosphorylation of Akt, which was reduced by the PI 3-kinase inhibitor LY294002. Using in vitro kinase assays, M-CSF appeared to induce more Akt activity than did the other survival factors. Treatment of monocytes with either LY294002 or wortmannin resulted in caspase-3 activation in the presence of these survival factors. These results suggest that monocyte survival factors may suppress DNA fragmentation, caspase-9, and caspase-3 activation in a PI 3-kinase-dependent manner, perhaps through the activation of Akt.

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