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Sökning: WFRF:(Palotie Aarno) > (2020-2024) > Functional characte...

Functional characterization of six SLCO1B1 (OATP1B1) variants observed in Finnish individuals with a psychotic disorder

Häkkinen, Katja (författare)
Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
Kiander, Wilma (författare)
Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
Kidron, Heidi (författare)
Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
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Lähteenvuo, Markku (författare)
Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland
Urpa, Lea (författare)
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
Lintunen, Jonne (författare)
Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland
Vellonen, Kati-Sisko (författare)
School of Pharmacy, University of Eastern Finland, Kuopio, Finland
Auriola, Seppo (författare)
School of Pharmacy, University of Eastern Finland, Kuopio, Finland
Holm, Minna (författare)
Mental Health Team, Finnish Institute for Health and Welfare, Helsinki, Finland
Lahdensuo, Kaisla (författare)
Mehiläinen Ltd, Helsinki, Finland
Kampman, Olli (författare)
Umeå universitet,Psykiatri,Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Department of Psychiatry, Pirkanmaa Hospital District, Tampere, Finland; Department of Clinical Medicine (Psychiatry), Faculty of Medicine, University of Turku, Turku, Finland; Department of Psychiatry, The Wellbeing Services County of Ostrobothnia, Vaasa, Finland
Isometsä, Erkki (författare)
Department of Psychiatry, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
Kieseppä, Tuula (författare)
Mental Health Team, Finnish Institute for Health and Welfare, Helsinki, Finland; Department of Psychiatry, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
Lönnqvist, Jouko (författare)
Mental Health Team, Finnish Institute for Health and Welfare, Helsinki, Finland; Department of Psychiatry, University of Helsinki, Helsinki, Finland
Suvisaari, Jaana (författare)
Mental Health Team, Finnish Institute for Health and Welfare, Helsinki, Finland
Hietala, Jarmo (författare)
Department of Psychiatry, University of Turku, Turku University Hospital, Turku, Finland
Tiihonen, Jari (författare)
Karolinska Institutet
Palotie, Aarno (författare)
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, MA, Cambridge, United States; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, United States
Ahola-Olli, Ari V. (författare)
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, MA, Cambridge, United States; Department of Internal Medicine, Satasairaala Hospital, Pori, Finland
Niemi, Mikko (författare)
Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
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 (creator_code:org_t)
2023-02-13
2023
Engelska.
Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 20:3, s. 1500-1508
Relaterad länk:
https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
https://urn.kb.se/re...
https://doi.org/10.1...
http://kipublication...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • Variants in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene encoding the OATP1B1 (organic anion transporting polypeptide 1B1) protein are associated with altered transporter function that can predispose patients to adverse drug effects with statin treatment. We explored the effect of six rare SLCO1B1 single nucleotide variants (SNVs) occurring in Finnish individuals with a psychotic disorder on expression and functionality of the OATP1B1 protein. The SUPER-Finland study has performed exome sequencing on 9381 individuals with at least one psychotic episode during their lifetime. SLCO1B1 SNVs were annotated with PHRED-scaled combined annotation-dependent (CADD) scores and the Ensembl variant effect predictor. In vitro functionality studies were conducted for the SNVs with a PHRED-scaled CADD score of >10 and predicted to be missense. To estimate possible changes in transport activity caused by the variants, transport of 2′,7′-dichlorofluorescein (DCF) in OATP1B1-expressing HEK293 cells was measured. According to the findings, additional tests with rosuvastatin and estrone sulfate were conducted. The amount of OATP1B1 in crude membrane fractions was quantified using a liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomics analysis. Six rare missense variants of SLCO1B1 were identified in the study population, located in transmembrane helix 3: c.317T>C (p.106I>T), intracellular loop 2: c.629G>T (p.210G>V), c.633A>G (p.211I>M), c.639T>A (p.213N>L), transmembrane helix 6: 820A>G (p.274I>V), and the C-terminal end: 2005A>C (p.669N>H). Of these variants, SLCO1B1 c.629G>T (p.210G>V) resulted in the loss of in vitro function, abolishing the uptake of DCF, estrone sulfate, and rosuvastatin and reducing the membrane protein expression to 31% of reference OATP1B1. Of the six rare missense variants, SLCO1B1 c.629G>T (p.210G>V) causes a loss of function of OATP1B1 transport in vitro and severely decreases membrane protein abundance. Carriers of SLCO1B1 c.629G>T might be susceptible to altered pharmacokinetics of OATP1B1 substrate drugs and might have increased likelihood of adverse drug effects such as statin-associated musculoskeletal symptoms.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)

Nyckelord

drug transporter
OATP1B1
organic anion transporting polypeptide 1B1
pharmacogenetics
SLCO1B1

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