Biology subjects

Hernandez Cordero, A. I.

Publications and source records attributed to Hernandez Cordero, A. I..

4 recordsLinked to original sources

bioRxiv2026

Elexacaftor/tezacaftor/ivacaftor treatment is associated with epigenetic age deceleration in cystic fibrosis

Background: Cystic fibrosis (CF) is associated with chronic inflammation and progressive multisystem disease, which may contribute to accelerated biological aging. Elexacaftor/tezacaftor/ivacaftor (ETI) substantially improves clinical outcomes in people with CF (pwCF), but its effects on epigenetic aging and their relationship with inflammation remain poorly understood. Methods: We performed a pilot longitudinal study of 8 modulator-naive pwCF. Blood DNA methylation was profiled before ETI initiation and after 1 year of treatment. DNAmGrimAge2 age acceleration was calculated adjusting for chronological age and blood cell composition. Associations with inflammatory biomarkers and clinical measures were assessed using repeated measures correlation. Results: DNAmGrimAge2 was strongly correlated with chronological age at baseline and follow-up. DNAmGrimAge2 age acceleration decreased after ETI treatment, from a median of 1.92 years before treatment to -1.70 years after 1 year (p=0.008). Greater age acceleration was associated with higher IL-6, IL-1{beta}, and calprotectin concentrations. Higher FEV1pp was associated with lower age acceleration, whereas higher sweat chloride was associated with greater age acceleration. Conclusions: DNAmGrimAge2 age acceleration decreased following ETI initiation and was associated with markers of innate and neutrophilic inflammation and CF disease activity. These findings suggest that epigenetic aging in CF may be dynamic and responsive to improvements in CFTR function and inflammatory disease burden. Larger longitudinal studies are needed to validate these findings and determine their relationship with long-term clinical outcomes.

genetics↗

bioRxiv2020

Gene Expression Network Analysis Provides Potential Targets Against SARS-CoV-2

ABSTRACTBACKGROUND Cell entry of SARS-CoV-2, the novel coronavirus causing COVID-19, is facilitated by host cell angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We aimed to identify and characterize genes that are co-expressed with ACE2 and TMPRSS2, and to further explore their biological functions and potential as druggable targets.METHODS Using the gene expression profiles of 1,038 lung tissue samples, we performed a weighted gene correlation network analysis (WGCNA) to identify modules of co-expressed genes. We explored the biology of co-expressed genes using bioinformatics databases, and identified known drug-gene interactions.RESULTS ACE2 was in a module of 681 co-expressed genes; 12 genes with moderate-high correlation with ACE2 (r>0.3, FDR<0.05) had known interactions with existing drug compounds. TMPRSS2 was in a module of 1,086 co-expressed genes; 15 of these genes were enriched in the gene ontology biologic process ‘Entry into host cell’, and 53 TMPRSS2-correlated genes had known interactions with drug compounds.CONCLUSION Dozens of genes are co-expressed with ACE2 and TMPRSS2, many of which have plausible links to COVID-19 pathophysiology. Many of the co-expressed genes are potentially targetable with existing drugs, which may help to fast-track the development of COVID-19 therapeutics.Competing Interest StatementS.M. reports personal fees from Novartis and Boehringer-Ingelheim, outside the submitted work. W.T. reports fees to Institution from Roche-Ventana, AbbVie, Merck-Sharp-Dohme and Bristol-Myers-Squibb, outside the submitted work. M.B. reports research grants paid to University from Astra Zeneca, Novartis, outside the submitted work. D.D.S. reports research funding from AstraZeneca and received honoraria for speaking engagements from Boehringer Ingelheim and AstraZeneca over the past 36 months, outside of the submitted work.View Full Text

genomics↗

bioRxiv2019

The protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a Mendelian randomisation study

BackgroundThere are currently no robust biomarkers of chronic obstructive pulmonary disease (COPD) risk or progression. Club cell secretory protein-16 (CC-16) is associated with the clinical expression of COPD. We aimed to determine if there is a causal effect of serum CC-16 level on COPD risk and/or progression using Mendelian randomisation (MR) analysis. MethodsWe performed a genome-wide association meta-analysis for serum CC-16 in two COPD cohorts (Lung Health Study [LHS], n=3,850 and ECLIPSE, n=1,702). We then used the CC-16-associated single-nucleotide polymorphisms (SNPs) in MR analysis to estimate the causal effect of serum CC-16 on COPD risk (International COPD Genetics Consortium/UK-Biobank dataset; n=35,735 cases, n=222,076 controls) and progression (change in forced expiratory volume in 1 s [FEV1] in LHS and ECLIPSE). We also determined the associations between SNPs associated with CC-16 and gene expression using n=1,111 lung tissue samples from the Lung eQTL Study. ResultsWe identified 7 SNPs independently associated (p<5x10-8) with serum CC-16 levels; 6 of these were novel. MR analysis suggested a protective causal effect of increased serum CC-16 on COPD risk (p=0.008) and progression (LHS only, p=0.02). Five of the SNPs were also associated with gene expression in lung tissue, including that of the CC-16-encoding gene SCGB1A1 (false discovery rate<0.1). ConclusionWe have identified several novel genetic variants associated with serum CC-16 level in COPD cohorts. These genetic associations suggest a potential causal effect of serum CC-16 on COPD risk and progression. Further investigation of CC-16 as a biomarker or therapeutic target in COPD is warranted. KEY MESSAGESWhat is the key question? Can genetics help uncover a causal effect of serum CC-16 level on COPD risk and/or progression? What is the bottom line? There is a protective effect of genetically-increased serum CC-16 on both COPD risk and progression (as measured by change in FEV1 over time), which may be due to increased expression of the CC-16-encoding gene SCGB1A1 in the lung. Why read on? This is the first study to demonstrate a possible causal effect of serum CC-16 in people with COPD, and highlights the potential for CC-16 as a biomarker or therapeutic target.

genomics↗

bioRxiv2018

Genome-wide analysis in UK Biobank identifies over 100 QTLs associated with muscle mass variability in middle age individuals

Muscle bulk in adult healthy humans is highly variable even after accounting for height, age and sex. Low muscle mass, due to fewer and/or smaller constituent muscle fibers, would exacerbate the impact of muscle loss occurring in aging or disease. Genetic variability substantially influences muscle mass differences, but causative genes remain largely unknown. In a genome-wide association study (GWAS) on appendicular lean mass (ALM) in a population of 85,750 middle-age (38-49 years) individuals from the UK Biobank (UKB) we found 182 loci associated with ALM (P<5x10-8). We replicated associations for 78% of these loci (P<5x10-8) with ALM in a population of 181,862 elderly (60-74 years) individuals from UKB. We also conducted a GWAS on hindlimb skeletal muscle mass of 1,867 mice from an advanced intercross between two inbred strains (LG/J and SM/J) which identified 23 quantitative trait loci. 38 positional candidates distributed across 5 loci overlapped between the two species. In vitro studies of positional candidates confirmed CPNE1 and STC2 as modifiers of myogenesis. Collectively, these findings shed light on the genetics of muscle mass variability in humans and identify targets for the development of interventions for treatment of muscle loss. The overlapping results between humans and the mouse model GWAS point to shared genetic mechanisms across species.

genetics↗