Recent genome-wide association studies (GWAs) have identified several new genetic risk factors for asthma; however, their influence on disease behavior and treatment response is still unclear. The aim of our study was the association analysis of the most significant single nucleotide polymorphisms (SNPs) recently reported by GWAs in different phenotypes of childhood asthma and analysis of correlation between these SNPs and clinical parameters. We have genotyped 288 children with asthma and 276 healthy controls. We provided here first replication of bivariate associations between CA10 (p = 0.001) and SGK493 (p = 0.011) with asthma. In addition, we have identified new correlation between SNPs in CA10, SGK493, and CTNNA3 with asthma behavior and glucocorticoid treatment response. Asthma patients who carried G allele in SNP rs967676 in gene CA10 were associated with more pronounced airway obstruction, higher bronchial hyper-reactivity, and increased inflammation. Higher bronchial hyper-reactivity was also associated with C allele in SNP rs1440095 in gene SGK493 but only in nonatopic asthmatics. In addition, we found that patients who carried at least one T allele in SNP rs1786929 in CTNNA3 (p = 0.022) and atopic patients who carried at least one G allele in SNP rs967676 in gene CA10 (p = 0.034) had higher increase in pulmonary function after glucocorticoid therapy. Our results suggest genetic heterogeneity between atopic and nonatopic asthma. We provided further evidence that treatment response in childhood asthma is genetically predisposed, and we report here two novel SNPs in genes CA10 and CTNNA3 as potential pharmacogenetic biomarkers that could be used in personalized treatment in childhood asthma.
COBISS.SI-ID: 17472790
Understanding the links between genetic, epigenetic and non-genetic factors throughout the lifespan and across generations and their role in disease susceptibility and disease progression offer entirely new avenues and solutions to major problems in our society. To overcome the numerous challenges, we have come up with nine major conclusions to set the vision for future policies and research agendas at the European level.
COBISS.SI-ID: 512412216
TAR DNA-binding protein (TDP-43, also known as TARDBP) is the major pathological protein in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Large TDP-43 aggregates that are decorated with degradation adaptor proteins are seen in the cytoplasm of remaining neurons in ALS and FTD patients post mortem. TDP-43 accumulation and ALS-linked mutations within degradation pathways implicate failed TDP-43 clearance as a primary disease mechanism. Here, we report the differing roles of the ubiquitin proteasome system (UPS) and autophagy in the clearance of TDP-43. We have investigated the effects of inhibitors of the UPS and autophagy on the degradation, localisation and mobility of soluble and insoluble TDP-43. We find that soluble TDP-43 is degraded primarily by the UPS, whereas the clearance of aggregated TDP-43 requires autophagy. Cellular macroaggregates, which recapitulate many of the pathological features of the aggregates in patients, are reversible when both the UPS and autophagy are functional. Their clearance involves the autophagic removal of oligomeric TDP-43. We speculate that, in addition to an age-related decline in pathway activity, a second hit in either the UPS or the autophagy pathway drives the accumulation of TDP-43 in ALS and FTD. Therapies for clearing excess TDP-43 should therefore target a combination of these pathways.
COBISS.SI-ID: 27414567