👤 Luis Ángel Villar

Acute respiratory distress syndrome (ARDS) is a severe inflammatory process of the lung, often due to sepsis, and poses significant mortality burden in intensive care units. Here we conducted a genome-wide association study (GWAS) of ARDS to identify genetic risk loci that can help guide the development of new therapeutic options. We performed a case-control GWAS in 716 cases with ARDS, mainly associated with severe infections, and 4399 at-risk controls from three independent studies. Results were meta-analysed across the three studies, with significance set at p < 5 × 10 We identified a variant near HMGCR that showed genome-wide significant association with ARDS and had been previously linked to cholesterol metabolism. This locus was associated with ANKDD1B expression in artery. The rare exonic variant analysis showed associations between HMGCR and ARDS at nominal level (p < 0.05). While no nominal significance was achieved in the two additional validation cohorts, this variant exhibited a consistent direction of effects across all 5 studies. A common variant near HMGCR was associated with ARDS risk, suggesting a link between cholesterol metabolism and ARDS risk. Validation in independent studies is needed. Wellcome Trust, National Institute for Health Research Leicester Biomedical Research Centre, National Heart, Lung, and Blood Institute, ATS Research Program, Gobierno de Canarias, Fundación Canaria Instituto de Investigación Sanitaria de Canarias, Instituto Tecnológico y de Energías Renovables, Cabildo Insular de Tenerife, Instituto de Salud Carlos III, Agencia Estatal de Investigación, German Ministry of Education and Research, Thuringian Ministry of Education, Science and Culture, the Thuringian Foundation for Technology, Innovation, and Research, German Sepsis Society. Show less

Early biomarkers are needed to predict the long-term persistence of rheumatical symptoms in patients infected with Chikungunya virus (CHIKV). This nested case-control study aimed to assess immunological factors during the early phases of CHIKV infection to predict the risk of post-CHIK chronic rheumatism (pCHIK-CR) in adult patients of two prospective cohorts. We evaluated 46 febrile patients (median age: 33.5 years; IQR: 19 years; women: 50.0%) with CHIKV infection confirmed during the 2014-2015 outbreak in Santander, Colombia. The participants were classified by a rheumatologist as either cases (pCHIK-CR) or controls (WoRM, without rheumatical manifestations). We quantified serum levels of IL-4, IL-6, IL-8/CXCL-8, IL-27, CCL-2, CXCL-9, CXCL-10, and IgG using Luminex and ELISA assays during the acute and subacute phases of infection. Then, we evaluated the association of these immune factors with the case-control status using piecewise logistic regression adjusted for age and sex. There were non-linear associations between IL-8/CXCL-8, CXCL-9, and CXCL-10 with pCHIK-CR. Increases in the levels of IL-8/CXCL-8 (<35.7 pg/mL), CXCL-9 (≥6000 pg/mL), and CXCL-10 (≥36,800 pg/mL) were significantly associated with a reduced risk of pCHIK-CR (adjusted ORs: 0.85, 0.96, and 0.94, respectively). These results suggest that increases in IL-8/CXCL-8, CXCL-9, and CXCL-10 levels, measured in the early stages of CHIKV infection, may predict a chronic disease risk. This suggests the possibility that an early and strong immune response could contribute to enhancing CHIKV control and potentially reduce the risk of persistent joint symptoms. Given their expression patterns and timing, these three immune factors may be considered promising biomarker candidates for assessing the risk of chronic rheumatologic disease. These findings should be considered as exploratory and validated in additional cohort studies. Show less

The epigenetic mechanisms of asthma remain largely understudied in African Americans and Hispanics/Latinos, two populations disproportionately affected by asthma. We aimed to identify markers, regions and processes with differential patterns of DNA methylation (DNAm) in whole blood by asthma status in ethnically diverse children and youth, and to assess their functional consequences. DNAm levels were profiled with the Infinium MethylationEPIC or HumanMethylation450 BeadChip arrays among 1226 African Americans or Hispanics/Latinos and assessed for differential methylation per asthma status at the CpG and region (differentially methylated region (DMR)) level. Novel associations were validated in blood and/or nasal epithelium from ethnically diverse children and youth. The functional and biological implications of the markers identified were investigated by combining epigenomics with transcriptomics from study participants. 128 CpGs and 196 DMRs were differentially methylated after multiple testing corrections, including 92.3% and 92.8% novel associations, respectively. 41 CpGs were replicated in other Hispanics/Latinos, prioritising cg17647904 ( We report novel whole-blood DNAm markers for asthma underlying key processes of the disease pathophysiology and confirm the transferability of previous asthma DNAm associations to ethnically diverse populations. Show less