A facility to search for hidden particles at the CERN SPS: the SHiP physics case

Theoretical Physic

Dog ownership in infancy is protective for persistent wheeze in 17q21 asthma-risk carriers

Background: asthma-associated SNPs from large GWAS studies only explain a fraction of genetic heritability. Likely causes of the missing heritability include broad phenotype definitions and gene-environment interactions (GxE). The mechanisms underlying GxE in asthma are poorly understood. Previous GxE studies on pet ownership showed discordant results.Objectives: to study the GxE between the 17q12-21 locus and pet ownership in infancy in relation to wheeze.Methods: wheezing classes derived from five UK-based birth cohorts (latent class analysis) were used to study GxE between the 17q12-21 asthma-risk variant rs2305480 and dog and cat ownership in infancy, using multinomial logistic regression. 9149 children had both pet ownership and genotype data available. Summary statistics from individual analyses were meta-analysed.Results: rs2305480 G allele was associated with increased risk of Persistent Wheeze (additive model OR=1.37; CI=1.25-1.51). There was no evidence of an association between dog or cat ownership and wheeze. We found significant evidence of a GxE interaction between rs2305480 and dog ownership (P=8.3e-4) on Persistent Wheeze; amongst dog owners the G allele was no longer associated with an increased risk of Persistent Wheeze (additive model OR=0.95; CI=0.73-1.24). For those without pets, G allele was associated with increased risk of Persistent Wheeze (OR=1.61; CI=1.40-1.86). Amongst cat owners no such dampening of the genetic effect was observed.Conclusions: amongst dog owners, rs2305480 G was no longer associated with an increased risk of Persistent Wheeze (or asthma). Early life environmental exposures may therefore attenuate likelihood of asthma in those carrying 17q12-21 risk alleles.</p

Opportunities for the repurposing of PARP inhibitors for the therapy of non-oncological diseases.

The recent clinical availability of the PARP inhibitor olaparib (Lynparza) opens the door for potential therapeutic repurposing for non-oncological indications. Considering (a) the preclinical efficacy data with PARP inhibitors in non-oncological diseases and (b) the risk-benefit ratio of treating patients with a compound that inhibits an enzyme that has physiological roles in the regulation of DNA repair, we have selected indications, where (a) the severity of the disease is high, (b) the available therapeutic options are limited, and (c) the duration of PARP inhibitor administration could be short, to provide first-line options for therapeutic repurposing. These indications are as follows: acute ischaemic stroke; traumatic brain injury; septic shock; acute pancreatitis; and severe asthma and severe acute lung injury. In addition, chronic, devastating diseases, where alternative therapeutic options cannot halt disease development (e.g. Parkinson's disease, progressive multiple sclerosis or severe fibrotic diseases), should also be considered. We present a preclinical and clinical action plan for the repurposing of PARP inhibitors. This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc