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Abstract Background Community-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of infection. Here we aimed to identify genetic risk loci for CAP using a case-control genome-wide association study (GWAS). Methods We performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. We tested 7,6 million imputed genotypes using logistic regressions. UK Biobank GWAS of bacterial pneumonia were used for results validation. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association of classical HLA alleles and amino acids were also conducted. Results Six independent sentinel variants reached the genome-wide significance (p

Idiopathic pulmonary fibrosis (IPF) is a chronic, rare progressive lung disease, characterized by lung scarring and the irreversible loss of lung function. Two anti-fibrotic drugs, nintedanib and pirfenidone, have been demonstrated to slow down disease progression, although IPF mortality remains a challenge and the patients die after a few years from diagnosis. Rare pathogenic variants in genes that are involved in the surfactant metabolism and telomere maintenance, among others, have a high penetrance and tend to co-segregate with the disease in families. Common recurrent variants in the population with modest effect sizes have been also associated with the disease risk and progression. Genome-wide association studies (GWAS) support at least 23 genetic risk loci, linking the disease pathogenesis with unexpected molecular pathways including cellular adhesion and signaling, wound healing, barrier function, airway clearance, and innate immunity and host defense, besides the surfactant metabolism and telomere biology. As the cost of high-throughput genomic technologies continuously decreases and new technologies and approaches arise, their widespread use by clinicians and researchers is efficiently contributing to a better understanding of the pathogenesis of progressive pulmonary fibrosis. Here we provide an overview of the genetic factors known to be involved in IPF pathogenesis and discuss how they will continue to further advance in this field. We also discuss how genomic technologies could help to further improve IPF diagnosis and prognosis as well as for assessing genetic risk in unaffected relatives. The development and validation of evidence-based guidelines for genetic-based screening of IPF will allow redefining and classifying this disease relying on molecular characteristics and contribute to the implementation of precision medicine approaches.

Hereditary angioedema (HAE) is a rare disease where known causes involve C1 inhibitor dysfunction or dysregulation of the kinin cascade. The updated HAE management guidelines recommend performing genetic tests to reach a precise diagnosis. Unfortunately, genetic tests are still uncommon in the diagnosis routine. Here, we characterized for the first time the genetic causes of HAE in affected families from the Canary Islands (Spain). Whole-exome sequencing data was obtained from 41 affected patients and unaffected relatives from 29 unrelated families identified in the archipelago. The Hereditary Angioedema Database Annotation (HADA) tool was used for pathogenicity classification and causal variant prioritization among the genes known to cause HAE. Manual reclassification of prioritized variants was used in those families lacking known causal variants. We detected a total of eight different variants causing HAE in this patient series, affecting essentially SERPING1 and F12 genes, one of them being a novel SERPING1 variant (c.686-12A>G) with a predicted splicing effect which was reclassified as likely pathogenic in one family. Altogether, the diagnostic yield by assessing previously reported causal genes and considering variant reclassifications according to the American College of Medical Genetics guidelines reached 66.7% (95% Confidence Interval [CI]: 30.1-91.0) in families with more than one affected member and 10.0% (95% CI: 1.8-33.1) among cases without family information for the disease. Despite the genetic causes of many patients remain to be identified, our results reinforce the need of genetic tests as first-tier diagnostic tool in this disease, as recommended by the international WAO/EAACI guidelines for the management of HAE.