BACKGROUND The response to treatment for asthma is characterized by wide interindividual variability, with a significant number of patients who have no response. We hypothesized that a genomewide association study would reveal novel pharmacogenetic determinants of the response to inhaled glucocorticoids. METHODS We analyzed a small number of statistically powerful variants selected on the basis of a family-based screening algorithm from among 534,290 single-nucleotide polymorphisms (SNPs) to determine changes in lung function in response to inhaled glucocorticoids. A significant, replicated association was found, and we characterized its functional effects. RESULTS We identified a significant pharmacogenetic association at SNP rs37972, replicated in four independent populations totaling 935 persons (P = 0.0007), which maps to the glucocorticoid-induced transcript 1 gene (GLCCI1) and is in complete linkage disequilibrium (i.e., perfectly correlated) with rs37973. Both rs37972 and rs37973 are associated with decrements in GLCCI1 expression. In isolated cell systems, the rs37973 variant is associated with significantly decreased luciferase reporter activity. Pooled data from treatment trials indicate reduced lung function in response to inhaled glucocorticoids in subjects with the variant allele (P = 0.0007 for pooled data). Overall, the mean (± SE) increase in forced expiratory volume in 1 second in the treated subjects who were homozygous for the mutant rs37973 allele was only about one third of that seen in similarly treated subjects who were homozygous for the wild-type allele (3.2 ± 1.6% vs. 9.4 ± 1.1%), and their risk of a poor response was significantly higher (odds ratio, 2.36; 95% confidence interval, 1.27 to 4.41), with genotype accounting for about 6.6% of overall inhaled glucocorticoid response variability. CONCLUSIONS A functional GLCCI1 variant is associated with substantial decrements in the response to inhaled glucocorticoids in patients with asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00000575.)
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary cancer in the liver, and its incidence is highest in the northeastern part of Thailand. ICCs in this region are known to be associated with infection with liver flukes, particularly Opisthorchis viverrini (OV), as well as nitrosamines from food. To clarify molecular mechanisms of ICC associated with or without liver flukes, we analyzed gene expression profiles of OV-associated ICCs from 20 Thai patients and compared their profiles with those of 20 Japanese ICCs that were not associated with OV, by means of laser microbeam microdissection and a cDNA microarray containing 27,648 genes. We identified 77 commonly upregulated genes and 325 commonly downregulated genes in the two ICC groups. Unsupervised hierarchical cluster analysis separated the 40 ICCs into two major branches almost completely according to the fluke status. The putative signature of OV-associated ICC exhibited elevated expression of genes involved in xenobiotic metabolism (UGT2B11, UGT1A10, CHST4, SULT1C1), whereas that of non-OV-associated ICC represented enhanced expression of genes related to growth factor signaling (TGFBI, PGF, IGFBP1, IGFBP3). Additional random permutation tests identified a total of 49 genes whose expression levels were significantly different between the two groups. We also identified genes associated with macroscopic type of ICCs. In conclusion, these data may not only contribute to clarification of common and OV-specific mechanisms underlying ICC, but also may serve as a starting point for the identification of novel diagnostic markers or therapeutic targets for the disease.
Friedreich's ataxia is an autosomal recessive disease with progressive degeneration of the central and peripheral nervous system. The biochemical abnormality underlying the disorder has not been identified. Prompted by the success in localizing the mutations causing Duchenne muscular dystrophy, Huntington's disease and cystic fibrosis, we have undertaken molecular genetic linkage studies to determine the chromosomal site of the Friedreich's ataxia mutation as an initial step towards the isolation and characterization of the defective gene. We report the assignment of the gene mutation for this disorder to chromosome 9p22-CEN by genetic linkage to an anonymous DNA marker MCT112 and the interferon-beta gene probe. In contrast to the clinical variation seen for the disorder, no evidence of genetic heterogeneity is observed.
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