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.

Gender differences in platelet aggregation in healthy individuals

“…There are many genetic variations between the ethnic groups that affect the platelet function. While the ethnic differences in glycoprotein IIIa gene polymorphism remain to be established, [34] the cyclooxygenase polymorphisms are confirmed in the African-American population [35,36]. thromboxane synthase (TXS) polymorphism (TBXAS1) may have particular importance to this study, since TXS, a cytochrome P450 enzyme, converts prostaglandin H2 into thromboxane A2, a potent inducer of platelet aggregation [35,36].…”

Genetic Polymorphisms of Human Sulfate Transporters

“…(3). High K a :K s ratios (>2:1) are consistent with a strong positive selection for evolutionary change (reviewed in [Kreitman 1999]), as proposed for the thromboxane synthase (TBXAS1, K a :K s 6:1) and adipokine (ANGPTL4, K a :K s 4:1) genes [Cargill 1999;Romeo 2007;Ulrich 2005]. The high K a :K s ratio found in SLC13A1, together with the high allelic frequency (range = 22.5 to 40.4%) of N174S (Table 3) which leads to 60% loss of SO 4 2-transport function [Lee 2006], implies that reduced NaS1 function may have provided a biological benefit to human evolution and may be relevant when considering human exposure to environmental and dietary chemicals activated by sulfonation, which are implicated with certain cancers and adverse drug reactions [Gamage 2006;Glatt 2000].…”

Functional analysis of human thromboxane synthase polymorphic variants

“…Further, human TXAS mutations have been linked to a bone density disorder [14]. Fourteen non-synonymous polymorphisms in the TXAS coding region were identified in the first three reports on variations in the gene [15,16,17], with evidence for selective evolutionary pressure against genetic mutations in the gene [17]. In view of the roles of TXAS in physiology and pathology, it is important to understand the effects of human TXAS protein variants on catalytic activity.…”

“…We have developed a prokaryotic expression system that provides sufficient recombinant TXAS with ~90 % purity for enzymatic characterization [18,19]. Structural analysis based on homology modeling suggested that four of the TXAS variants (K258E, Q417E, E450K and T451N) were likely to have altered enzymatic activities [17]. In addition, the L357V variant, which has a minor allele frequency of almost 11% in African-Americans [17] was predicted to have altered catalytic activity by the PolyPhen algorithm [20].…”

“…Structural analysis based on homology modeling suggested that four of the TXAS variants (K258E, Q417E, E450K and T451N) were likely to have altered enzymatic activities [17]. In addition, the L357V variant, which has a minor allele frequency of almost 11% in African-Americans [17] was predicted to have altered catalytic activity by the PolyPhen algorithm [20]. The present report describes the results of our enzymatic characterization of the five targeted TXAS variants as purified recombinant proteins.…”