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A comprehensive pharmacogenomic study indicates roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics

Taskinen Suvi; Viinamäki Jenni; Tarkiainen E Katriina; Tapaninen Tuija; Tornio Aleksi; Paile-Hyvarinen Maria; Backman Janne T; Neuvonen Mikko; Niemi Mikko; Lilius Tuomas O; Lehtisalo Minna

dc.contributor.authorTaskinen Suvi
dc.contributor.authorViinamäki Jenni
dc.contributor.authorTarkiainen E Katriina
dc.contributor.authorTapaninen Tuija
dc.contributor.authorTornio Aleksi
dc.contributor.authorPaile-Hyvarinen Maria
dc.contributor.authorBackman Janne T
dc.contributor.authorNeuvonen Mikko
dc.contributor.authorNiemi Mikko
dc.contributor.authorLilius Tuomas O
dc.contributor.authorLehtisalo Minna
dc.date.accessioned2022-10-27T12:23:49Z
dc.date.available2022-10-27T12:23:49Z
dc.identifier.urihttps://www.utupub.fi/handle/10024/158318
dc.description.abstract<h3>Aims</h3><p>The aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin.</p><h3>Methods</h3><p>We conducted a genome-wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (<em>n =</em> 159) and a cohort of previously published studies (<em>n =</em> 88).</p><h3>Results</h3><p>In a genome-wide association meta-analysis of the prospective study and the cohort of previously published studies, the <em>SLCO1B1</em> c.521 T > C (rs4149056) single nucleotide variation (SNV) associated with increased area under the plasma concentration–time curve (AUC) and peak plasma concentration of rosuvastatin (<em>P</em> = 1.8 × 10<sup>−12</sup> and <em>P</em> = 3.2 × 10<sup>−15</sup>). The candidate gene analysis suggested that the <em>ABCG2</em> c.421C > A (rs2231142) SNV associates with increased rosuvastatin AUC (<em>P</em> = .0079), while the <em>SLCO1B1</em> c.388A > G (rs2306283) and <em>SLCO2B1</em> c.1457C > T (rs2306168) SNVs associate with decreased rosuvastatin AUC (<em>P</em> = .0041 and <em>P</em> = .0076). Based on <em>SLCO1B1</em> genotypes, we stratified the participants into poor, decreased, normal, increased and highly increased organic anion transporting polypeptide (OATP) 1B1 function groups. The OATP1B1 poor function phenotype associated with 2.1-fold (90% confidence interval 1.6–2.8, <em>P =</em> 4.69 × 10<sup>−5</sup>) increased AUC of rosuvastatin, whereas the OATP1B1 highly increased function phenotype associated with a 44% (16–62%; <em>P</em> = .019) decreased rosuvastatin AUC. The <em>ABCG2</em> c.421A/A genotype associated with 2.2-fold (1.5–3.0; <em>P =</em> 2.6 × 10<sup>−4</sup>) increased AUC of rosuvastatin. The <em>SLCO2B1</em> c.1457C/T genotype associated with 28% decreased rosuvastatin AUC (11–42%; <em>P =</em> .01).</p><h3>Conclusion</h3><p>These data suggest roles for <em>SLCO1B1</em>, <em>ABCG2</em> and <em>SLCO2B1</em> in rosuvastatin pharmacokinetics. Poor <em>SLCO1B1</em> or <em>ABCG2</em> function genotypes may increase the risk of rosuvastatin-induced myotoxicity. Reduced doses of rosuvastatin are advisable for patients with these genotypes.</p>
dc.language.isoen
dc.publisherWILEY
dc.titleA comprehensive pharmacogenomic study indicates roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics
dc.identifier.urlhttps://doi.org/10.1111/bcp.15485
dc.identifier.urnURN:NBN:fi-fe2022091258507
dc.contributor.organizationfi=tyks, vsshp|en=tyks, vsshp|
dc.contributor.organizationfi=biolääketieteen laitos, yhteiset|en=Institute of Biomedicine|
dc.contributor.organization-code2607100
dc.converis.publication-id176232622
dc.converis.urlhttps://research.utu.fi/converis/portal/Publication/176232622
dc.identifier.jour-issn0306-5251
dc.okm.affiliatedauthorTornio, Aleksi
dc.okm.affiliatedauthorDataimport, tyks, vsshp
dc.okm.discipline3111 Biolääketieteetfi_FI
dc.okm.discipline3111 Biomedicineen_GB
dc.okm.internationalcopublicationnot an international co-publication
dc.okm.internationalityInternational publication
dc.okm.typeJournal article
dc.publisher.countryUnited Statesen_GB
dc.publisher.countryYhdysvallat (USA)fi_FI
dc.publisher.country-codeUS
dc.publisher.placeHoboken
dc.relation.doi10.1111/bcp.15485
dc.relation.ispartofjournalBritish Journal of Clinical Pharmacology
dc.year.issued2022


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