{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:00:54Z","timestamp":1790359254256,"version":"4.1.0"},"reference-count":28,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Human PTGS1 and PTGS2 encode cyclooxygenase paralogs that regulate prostaglandin biosynthesis and are major targets of nonsteroidal anti-inflammatory drugs (NSAIDs). Interpreting population-differentiated PTGS variation requires integration of allele-frequency structure with transcript consequence, protein topology, splice-prediction evidence and structural context. This study integrated allele-resolved population differentiation, transcript-aware consequence annotation, splice-prediction boundary checks, protein-domain mapping, direct leader-sequence property calculations and controlled structural analyses. Candidate classes distinguished high-FST synonymous contextual markers, N-terminal PTGS1 leader-sequence missense variants, splice-region candidates and PTGS2 p.Val511Ala. Web-based SpliceAI\/Pangolin evaluation of seven splice-relevant or comparator variants provided limited support for splice alteration. A retrospective comparison of 31 missense candidates showed that Val511Ala was not the most differentiated missense variant overall, but ranked first by allele frequency, allele-frequency range and maximum pairwise FST within four channel-context candidates; FST was used only to describe population differentiation. Canonical Val511 mapped to 5KIR Val525, a second-shell position adjacent to the rofecoxib-contact network. Controlled docking-score, contact and direct-frame pose analyses detected no systematic variant-associated shift under the tested conditions. PTGS1 p.Trp8Arg and p.Pro17Leu produced distinct directly calculated changes in net-charge proxy, hydrophobic-residue count, mean Kyte-Doolittle hydropathy, aromatic-residue count and proline count across the 23-residue leader sequence and descriptive H-region. No signal-peptide predictor output was used, and effects on SRP recognition, ER targeting, translocation, cleavage, membrane insertion, maturation, abundance, localization, enzyme activity or drug response were not demonstrated. These results support a calibrated prioritisation framework in which population differentiation identifies structured variation, while transcript consequence, protein context and reproducible quantitative analyses define experimentally testable candidates.<\/jats:p>","DOI":"10.1371\/journal.pone.0358222","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:32:46Z","timestamp":1790357566000},"page":"e0358222","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparative evolutionary pharmacogenomics of human prostaglandin-endoperoxide synthase paralogs identifies population-structured coding variation and protein-contextual candidates in N-terminal leader-sequence and catalytic-channel regions"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2453-5993","authenticated-orcid":true,"given":"Reuben S.","family":"Maghembe","sequence":"first","affiliation":[{"name":"St. Francis University College of Health and Allied Sciences (SFUCHAS)","place":["Ifakara, Tanzania"],"department":["Department of Microbiology and Parasitology, Faculty of Medicine"]},{"name":"AfroBiomics Co. Ltd.","place":["Dar es Salaam, Tanzania"],"department":["Department of Omics and Computational Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"issue":"8","key":"pone.0358222.ref001","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0071126","article-title":"A meta-analysis of PTGS1 and PTGS2 polymorphisms and NSAID intake on the risk of developing cancer","volume":"8","author":"M Nagao","year":"2013","journal-title":"PLoS One"},{"key":"pone.0358222.ref002","first-page":"14843","article-title":"Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2","volume":"270","author":"WL Smith","year":"1995","journal-title":"J Biol Chem"},{"issue":"7","key":"pone.0358222.ref003","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1021\/jm0613166","article-title":"Structural and functional basis of cyclooxygenase inhibition","volume":"50","author":"AL 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