title: Thromboxane synthase (TBXAS1) polymorphisms in African-American and Caucasian populations: evidence for selective pressure.
abstract: Thromboxane synthase (TBXAS1), a cytochrome P450 enzyme, converts prostaglandin H2 into thromboxane A2, a potent vasoconstrictor and inducer of platelet aggregation. Thromboxane A2 has been implicated in modulating cell cytotoxicity and in tumor growth and metastasis. Twelve coding-region variants were identified in the human TBXAS1 gene in 48 African-American and 46 Caucasian individuals, of which eight were amino-acid substitutions. The latter were confirmed in an independent Caucasian population (n=94 unrelated individuals). We performed an evolutionary analysis of patterns of nucleotide diversity and identified patterns of amino acid replacement in human-mouse comparisons consistent with purifying selection on an inter-species time scale using the McDonald-Kreitman test. We also observed patterns of nucleotide diversity within humans consistent with purifying selection acting on existing polymorphism using Tajima's D within coding regions. These evolutionary tests suggest that some of the rare coding variations observed in the human population are deleterious. We used two sequence-homology-based software programs and molecular modeling to predict the potential impact of these polymorphisms on TBXAS1 function. The c.772C>T (p.Lys258Glu), c.1249C>G (p.Gln417Glu), and c.1348G>A (p.Glu450Lys) substitutions are predicted as most likely to alter protein function; another, c.1352C>A (p.Thr451Asn), may also affect function. Given the evolutionary evidence, these variants may be functional and therefore of relevance for disease endpoints related to inflammation and angiogenesis, as well as for the pharmacogenetics of non-steroidal anti-inflammatory drugs.
authors.affiliation: Fred Hutchinson Cancer Research Center, Cancer Prevention Program, University of Washington, Seattle, Washington 98109-1024, USA. nulrich@fhcrc.org
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Carlson
authors.forename: Justin
authors.initials: J
authors.lastname: Sibert
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Poole
authors.forename: Joon-Ho
authors.initials: JH
authors.lastname: Yu
authors.forename: Lee-Ho
authors.initials: LH
authors.lastname: Wang
authors.forename: Rachel
authors.initials: R
authors.lastname: Sparks
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Jeannette
authors.initials: J
authors.lastname: Bigler
mesh_terms: D001741:Black or African American / Q000235:genetics*; D019943:Amino Acid Substitution / Q000235:genetics; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D013930:Thromboxane-A Synthase / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: D013930:Thromboxane-A Synthase