Publications (8)5.24 Total impact
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Article: Optimization of phenylacetic acid derivatives for balanced CRTH2 and DP dual antagonists.
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ABSTRACT: Our first generation CRTH2 and DP dual antagonists, represented by AMG 009, are more potent toward the CRTH2 receptor than to the DP receptor. Here we report our efforts in the discovery of CRTH2 and DP dual antagonists with more balanced potencies to both receptors, such as compound 15.Bioorganic & medicinal chemistry letters 02/2012; 22(4):1686-9. · 2.65 Impact Factor -
Article: Non-invasive visualisation and volume estimation of maggot masses using computed tomography scanning.
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ABSTRACT: There is limited understanding of the actual temperatures that maggots experience during growth. The impact of maggot mass heating on their growth rates cannot be properly factored into maggot growth rate models, thus limiting the accuracy of forensic entomology estimates. One of the major factors contributing to mass heating is the mass size; however, measuring mass volume is problematic as masses quickly become disturbed when probing them to measure their depth and width. Furthermore, many masses are deep within the body cavity and are inaccessible. This study examined the development of a non-invasive means for measuring mass volume using computed tomography (CT) scanning. It was found that CT can be used to visualise and measure the volume of maggot masses, and a series of rules for doing so were established. The level of agreement between mass measurements made by four 'judges' using CT volumetric analysis tools produced excellent reliability (ICC > 0.95). This high level of reliability was maintained when applied to masses of different sizes in experimental cups of meat and natural masses of mixed species on human bodies. Entomological features of mortuary CT scans are now routinely reported in forensic entomology casework in Victoria, Australia, as a result of our work.Deutsche Zeitschrift für die Gesamte Gerichtliche Medizin 02/2012; · 2.59 Impact Factor -
Article: Discovery of AMG 853, a CRTH2 and DP Dual Antagonist
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ABSTRACT: Prostaglandin D2 (PGD2) plays a key role in mediating allergic reactions seen in asthma, allergic rhinitis, and atopic dermatitis. PGD2 exerts its activity through two G protein-coupled receptors (GPCRs), prostanoid D receptor (DP or DP1), and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2). We report the optimization of a series of phenylacetic acid derivatives in an effort to improve the dual activity of AMG 009 against DP and CRTH2. These efforts led to the discovery of AMG 853 (2-(4-(4-(tert-butylcarbamoyl)-2-(2-chloro-4-cyclopropylphenyl sulfonamido)phenoxy)-5-chloro-2-fluorophenyl)acetic acid), which is being evaluated in human clinical trials for asthma.Keywords: AMG 853; CRTH2 receptor; DP receptor; prostaglandin D2; antagonist; asthma03/2011; -
Article: Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship
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ABSTRACT: Background & Aims: Identifying shared and disease-specific susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD. Methods: We analyzed 45 single nucleotide polymorphisms, tagging 29 of the loci recently associated with CD in 2527 UC cases and 4070 population controls. We also genotyped the UC-associated ECM1 variant rs11205387 in 1560 CD patients and 3028 controls. Results: Nine regions showed association with UC at a threshold corrected for the 29 loci tested (P < .0017). The strongest association (P = 4.13 × 10−8; odds ratio = 1.27) was identified with a 170-kilobase region on chromosome 1q32 that contains 3 genes. We also found association with JAK2 and replicated a recently reported association with STAT3, further implicating the role of this signaling pathway in inflammatory bowel disease. Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD. ECM1 variation was not associated with CD. Conclusions: Collectively, these data help define the genetic relationship between CD and UC and characterize common, as well as disease-specific mechanisms of pathogenesis. -
Article: New susceptibility locus for coronary artery disease on chromosome 3q22.3
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ABSTRACT: We present a three-stage analysis of genome-wide SNP data in 1,222 German individuals with myocardial infarction and 1,298 controls, in silico replication in three additional genome-wide datasets of coronary artery disease (CAD) and subsequent replication in approx25,000 subjects. We identified one new CAD risk locus on 3q22.3 in MRAS (P = 7.44 times 10-13; OR = 1.15, 95% CI = 1.11–1.19), and suggestive association with a locus on 12q24.31 near HNF1A-C12orf43 (P = 4.81 times 10-7; OR = 1.08, 95% CI = 1.05–1.11). -
Article: Association of novel genetic loci with circulating fibrinogen levels: A genome-wide association study in 6 population-based cohorts
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ABSTRACT: Background— Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels. Methods and Results— We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0x10–8). These included a single-nucleotide polymorphism located in the fibrinogen β chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8x10–30), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3x10–15), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9x10–10), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04x10–8). Conclusions— Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease. -
Article: Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor
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ABSTRACT: In a recent genome-wide association study (GWAS) based on 12 374 non-synonymous single nucleotide polymorphisms we identified a number of candidate multiple sclerosis susceptibility genes. Here, we describe the extended analysis of 17 of these loci undertaken using an additional 4234 patients, 2983 controls and 2053 trio families. In the final analysis combining all available data, we found that evidence for association was substantially increased for one of the 17 loci, rs34536443 from the tyrosine kinase 2 (TYK2) gene (P=2.7 × 10−6, odds ratio=1.32 (1.17–1.47)). This single nucleotide polymorphism results in an amino acid substitution (proline to alanine) in the kinase domain of TYK2, which is predicted to influence the levels of phosphorylation and therefore activity of the protein and so is likely to have a functional role in multiple sclerosis. -
Article: Origins and functional impact of copy number variation in the human genome
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ABSTRACT: Structural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotide microarrays, comprising 42 million probes, to generate a comprehensive map of 11,700 copy number variations (CNVs) greater than 443 base pairs, of which most (8,599) have been validated independently. For 4,978 of these CNVs, we generated reference genotypes from 450 individuals of European, African or East Asian ancestry. The predominant mutational mechanisms differ among CNV size classes. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. Furthermore, by correlation with known trait-associated single nucleotide polymorphisms (SNPs), we identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Despite this, having assessed the completeness of our map and the patterns of linkage disequilibrium between CNVs and SNPs, we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs.
