ABSTRACT
AIMS/HYPOTHESIS: The association between IL4R and type 1 diabetes has been tested in many studies in recent years, with contradictory results. The aim of this study was to re-evaluate the genetic association in type 1 diabetic nuclear families of mixed European background. SUBJECTS, MATERIALS AND METHODS: We genotyped six non-synonymous single-nucleotide polymorphisms (SNPs) of the IL4R gene in 830 nuclear families as specified above, including a French Canadian subset. RESULTS: No association between type 1 diabetes and any SNP or haplotype was found by the transmission disequilibrium test. CONCLUSIONS/INTERPRETATION: Previous positive reports may be due to population stratification as, according to HapMap data, allele frequencies in the IL4R region vary considerably by ethnicity.
Subject(s)
Diabetes Mellitus, Type 1/genetics , Polymorphism, Single Nucleotide , Receptors, Interleukin-4/genetics , Canada , Diabetes Mellitus, Type 1/immunology , Female , France/ethnology , Genotype , Humans , Linkage Disequilibrium , Male , Nuclear Family , White PeopleABSTRACT
BACKGROUND: The 2',5'-oligoadenylate synthetase genes (OAS1, OAS2, and OAS3) map to human chromosome 12q24 and encode a family of enzymes pivotal to innate antiviral defence. Recently, the minor allele of an OAS1 single nucleotide polymorphism (SNP) that alters splicing (rs10774671) was found to be associated with increased enzymatic activity and, in a case-sibling control study, with type 1 diabetes (T1D). METHODS: We have confirmed this T1D association in 784 nuclear families (two parents and at least one affected offspring) by the transmission disequilibrium test (TDT; G:A = 386:329, p = 0.033). However, because of linkage disequilibrium within OAS1 and with the other two OAS genes, functional attribution of the association to this SNP cannot be assumed. To help answer this question, we also genotyped two non-synonymous SNPs in OAS1 exons 3 and 7. RESULTS: All three SNPs showed significant transmission distortion. Three of the eight possible haplotypes accounted for 98.4% of parental chromosomes and two of them carried the non-predisposing A allele at rs10774671. Parents heterozygous for these two haplotypes showed significant transmission distortion (p = 0.009) despite being homozygous at rs10774671. CONCLUSIONS: We confirm the T1D association with rs10774671, but we conclude that it cannot be attributed (solely) to the splicing variant rs10774671. A serine/glycine substitution in OAS1 exon 3 is more likely a functional variant.
Subject(s)
2',5'-Oligoadenylate Synthetase/genetics , Diabetes Mellitus, Type 1/genetics , Haplotypes/genetics , Multigene Family/genetics , Polymorphism, Genetic/genetics , RNA Splicing/genetics , Adolescent , Genetic Predisposition to Disease , Humans , Linkage DisequilibriumABSTRACT
Toyama and Bristol-Myers Squibb (BMS) are developing the des-F(6)-quinolone T-3811 (BMS-284756) as a potential treatment for bacterial infections, including respiratory and urinary tract infections, and skin and soft tissue infections. The drug is in phase II trials in the US and Europe, and an injectable formulation began phase I trials in the US in April 2000. Phase I trials commenced in Japan in September 1999. Phase III trials were expected to begin outside Japan in 2000. T-3811 is expected to be administered as an oral or injectable once-a-day formulation. Preclinical studies suggests it has a better side-effect profile than commonly associated with other quinolones on the market. Bristol-Myers Squibb has acquired worldwide development and marketing rights, with the exception of Japan, South Korea, Taiwan and China. In December 2001, Morgan Stanley predicted that T-3811 could have peak sales potential exceeding $500 million if the positive clinical data released at this year's ICAAC continued, and that BMS was on track for filing in 3Q02.
Subject(s)
Anti-Infective Agents/therapeutic use , Bacteria/drug effects , Bacterial Infections/drug therapy , Indoles/therapeutic use , Quinolones/therapeutic use , Animals , Anti-Infective Agents/pharmacology , Bacterial Infections/microbiology , Clinical Trials, Phase I as Topic , Humans , Indoles/metabolism , Indoles/pharmacology , Indoles/toxicity , Isoindoles , Quinolones/metabolism , Quinolones/pharmacology , Quinolones/toxicity , Structure-Activity RelationshipABSTRACT
A class of antibacterials has been discovered that inhibits the growth of Gram-positive pathogenic bacteria. RWJ-49815, a representative of a family of hydrophobic tyramines, in addition to being a potent bactericidal Gram-positive antibacterial, inhibits the autophosphorylation of kinase A of the KinA::Spo0F two-component signal transduction system in vitro. Analogs of RWJ-49815 vary greatly in their ability to inhibit growth of bacteria and this ability correlates directly with their activity as kinase A inhibitors. Compared with the potent quinolone, ciprofloxacin, RWJ-49815 exhibits reduced resistance emergence in a laboratory passage experiment. Inhibition of the histidine protein kinase::response regulator two-component signal transduction pathways may present an opportunity to depress chromosomal resistance emergence by targeting multiple proteins with a single inhibitor in a single bacterium. Such inhibitors may represent a class of antibacterials that potentially may represent a breakthrough in antibacterial therapy.
