Characterization of two highly polymorphic human tryptase loci and comparison with a newly discovered monkey tryptase ortholog.
Tryptases are serine proteases involved in mast cell-mediated inflammatory responses which represent potential targets of drugs against diseases such as asthma, arthritis and inflammatory bowel disease. In order to interpret pharmacodynamic data on the tryptase inhibitors undergoing clinical trials, we defined the genetic variability of the tryptase 1 (TPS1) and tryptase 2 (TPS2) loci by screening a reference population of 32 individuals representing three major ethnic groups (Caucasian, African American, Asian). Using overlapping PCR products, we resequenced the entire tryptase genes with the only exclusion of TPS2 intron 1 and 20 bp of TPS2 5' untranslated region included in exon 1 and we identified 21 novel single nucleotide polymorphisms in TPS1 and 17 single nucleotide polymorphisms plus a large polymorphic deletion in the TPS2 gene. We also compared the type, frequency and distribution of single nucleotide polymorphisms in TPS1 and TPS2 and we observed that the polymorphism frequency within these two loci is unexpectedly high (approximately 1 SNP every 90 bp) and that some of the allele frequencies differ significantly among the three ethnic groups. Based on differences observed in preclinical studies using a cynomolgus monkey (Macaca fascicularis) asthma model system, we investigated the difference between monkey and human tryptase genes in order to better understand the mechanism of action of our tryptase inhibitors.
Guida
M
M
PPGx Incorporated, La Jolla, CA 92037, USA. marco.guida@ppgx.com
Riedy
M
M
Lee
D
D
Hall
J
J
D000595:Amino Acid Sequence; D000818:Animals; D053818:Chymases; D005819:Genetic Markers; D006801:Humans; D008252:Macaca fascicularis; D008407:Mast Cells / Q000201:enzymology*; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D012697:Serine Endopeptidases / Q000235:genetics*; D053802:Tryptases
D005819:Genetic Markers; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D053802:Tryptases