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

Programa de Promoción de Salud en la Escuela : área 1

En esta publicación se expone el Programa de Promoción de Salud en la Escuela llevado a cabo en los colegios madrileños del Área Sanitaria 1, con la colaboración del Ministerio de Educación y Cultura, el Ayuntamiento y la Comunidad de Madrid, y el Instituto Nacional de la Salud. Los objetivos principales son fomentar la adquisición de conocimientos, actitudes y hábitos saludables en la comunidad escolar; contribuir a la prevención de enfermedades; favorecer la detección y atención de patologías; apoyar a los profesores en el desarrollo de la Educación para la Salud como tema transversal; contribuir a la integración de niños en situación de riesgo social y facilitarles una atención socio-sanitaria adecuada; y apoyar la coordinación entre instituciones en este ámbito. El programa contempla varias actividades: prevención y control de enfermedades transmisibles; salud buco dental; detección de desviaciones en la columna vertebral y de alteraciones de la visión; preparación para la atención de urgencias; eliminación de conductas de riesgo; y detección y prevención de las situaciones de riesgo social en la infancia. Se incluye en anexos documentación para el desarrollo del programa, además de una relación de materiales divulgativos y bibliografía de interés.MadridMadrid (Comunidad Autónoma). Servicio de Formación del Profesorado. CRIF Las Acacias; General Ricardos 179 - 28025; Madrid; +34915250893; +34914660991; [email protected]

Approach to the Spanish continental Neogene synthesis and palaeoclimatic interpretation.

Peer reviewe

Approach to the Spanish continental Neogene synthesis and paleoclimatic interpretation

Peer reviewe

Memorias IX Congreso Geológico Venezolano (3)

Memorias IX Congreso Geológico Venezolano (3