Jeffrey Mclean posted an update 3 months, 1 week ago
Thus, although neutrophils are the cells that increase in the bronchoalveolar lavage after ozone, it is tissue eosinophils around airway nerves that mediate ozone-induced hyperreactivity. In eosinophils, eotaxin and IL-5 signal through both ERK and p38 MAPK activation. Inhibition of p38 reduces eosinophil degranulation as measured by decreased eosinophil cationic protein release. Major basic protein has also been shown to alter smooth muscle contractility. Thus, while not tested directly in this study, blocking eosinophil degranulation with MAPK inhibitors could also contribute to preventing smooth muscle hyperreactivity. Thus, p38 and JNK MAPK inhibitors inhibit ozone-induced hyperreactivity by multiple mechanisms. Exposure to high levels of environmental ozone increases hospitalizations from asthma exacerbations. Over 4 million children and 10 million adults with asthma live in counties with unhealthy levels of ozone, and those with asthma are an especially susceptible population to the adverse health effects of ozone. Our data show that treatment with p38 and JNK inhibitors, immediately prior to ozone exposure prevented subsequent development of airway hyperreactivity. Currently there is no specific therapy for ozone related asthma complications and our data suggest both p38 and JNK are potential targets for additional therapeutic candidates; and that inhibitors could be tested as prophylactic treatment for asthma exacerbations on days with anticipated high ozone. Several recent studies on PD have focused on genetic variations. Myles et al. attempted to identify SNPs accounting for disease-associated PD. However, they found no diseaseassociated SNPs that were more significantly differentiated than randomly selected SNPs in the genome among populations. Nevertheless, the frequencies of risk alleles for disease-associated SNPs showed substantial variation across human populations. Barreiro et al. analyzed the degree of PD with 2.8 million SNPs and discovered the role of natural selection in shaping PD. Wu and Zhang also performed a genome-wide study of PD and found that many groups of genes had higher degrees of PD. Specifically, PD existed on some loci associated with phenotypes that are well known to vary across populations. PD has also been investigated in pharmacogenomic studies. For example, the response to warfarin, one of the most widely studied drugs, depends not only on genetic variants but also on population. As a result, some authors have suggested that warfarin be dosed according to the patient’s race. In fact, Pavani et al. suggested a linear model for optimizing populationspecific warfarin dose. Huang et al. identified SNPs contributing to etoposide-induced cytotoxicity in a genome-wide association study using International HapMap cell lines, and they demonstrated different genotypes associated with cytotoxicity between two populations. In order to investigate PD of DR genes, we analyzed data from two databases: International Hap- Map release 27 and Pharmacogenomics Knowledge Base, the most widely used DR database. Originally, HapMap release 27 contained 11 subpopulations. However, the allele frequencies of populations in the same ethnic groups are highly correlated, and there is lack of genotypic information in some populations. Therefore, we used the following subpopulations: European, African, and Asian from Japan and China. There are several measures for determining the distance among populations. Among them, Fst is the most widely used measure to determine PD. Akey et al. and Barreiro et al. used Weir and Cockerham’s estimate, an unbiased estimate of Fst. Casto et al. used four measures: δ, the difference in allele frequency between two groups; integrated haplotype score, which characterizes the lengths of the haplotypes surrounding each allele of a SNP ; latitude/longitude correlation, which describes how closely changes in a SNP’s allele frequency follow geographical coordinates; and Fst, which shows variation in allele frequency among populations. Park et al. used the Nearest Shrunken Centroid Method, which was originally designed for clustering of microarray data. NSCM has been proposed for solving the classification problem with a large number of features and it was also applied to the analysis of population differentiation in SNPs via Hapmap data. Han et al. modified Fst for use with allele frequency data with unbalanced sample sizes. In order to investigate PD of DR genes, we first compared four measures for assessing population differentiation: the chi-square test, the ANOVA F-test, Fst, and NSCM. Fst showed high sensitivity with stable SM-21 maleate specificity among varying sample sizes; thus, we selected Fst for determining population differentiation.We then divided DR genes from PharmGKB into two groups based on the degree of population differentiation as assessed by Fst: genes with high a level of differentiation and genes with a low level of differentiation. Finally, we conducted a gene ontology analysis and pathway analysis.