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  • 1.
    Aithal, Guruprasad P.
    et al.
    Nottingham Univ Hosp NHS Trust, NIHR Nottingham Digest Dis Biomed Res Unit, Nottingham, England..
    Nicoletti, Paola
    Columbia Univ, New York, NY USA..
    Bjornsson, Einar
    Landspitali Univ Hosp, Reykjavik, Iceland..
    Lucena, M. I.
    CIBERehd, Madrid, Spain.;Univ Malaga, E-29071 Malaga, Spain..
    Andrade, Raul J.
    CIBERehd, Madrid, Spain.;Univ Malaga, E-29071 Malaga, Spain..
    Grove, Jane
    Nottingham Univ Hosp NHS Trust, NIHR Nottingham Digest Dis Biomed Res Unit, Nottingham, England..
    Stephens, C.
    Univ Malaga, E-29071 Malaga, Spain..
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Maitland-van der Zee, Anke H.
    Univ Utrecht, Utrecht, Netherlands..
    Martin, Jennifer H.
    Univ Queensland, Brisbane, Qld, Australia.;Princess Alexandra Hosp, Brisbane, Qld, Australia..
    Cascorbi, Ingolf
    Univ Hosp Schleswig Holstein, Kiel, Germany..
    Dillon, John F.
    Ninewells Hosp & Med Sch, Dundee, Scotland..
    Laitinen, Tarja
    Univ Helsinki, Cent Hosp, Helsinki, Finland..
    Larrey, Dominique G.
    Hop St Eloi, Montpellier, France..
    Molokhia, Mariam
    Univ London, Kings Coll London, London SW3 6LX, England..
    Kullak-Ublick, Gerd A.
    Univ Zurich, Zurich, Switzerland..
    Ibanez, Luisa
    Hosp Univ Vall Hebron, Barcelona, Spain..
    Pirmohamed, Munir
    Univ Liverpool, Liverpool L69 3BX, Merseyside, England..
    Qin, Shengying
    Shanghai Jiao Tong Univ, Shanghai 200030, Peoples R China..
    Sawle, Ashley
    Columbia Univ, New York, NY USA..
    Bessone, Fernando
    Univ Nacl Rosario, Fac Ciencias Med, RA-2000 Rosario, Argentina..
    Hernandez, Nelia
    Univ Republ, Mentevideo, Uruguay..
    Stolz, Andrew
    Univ So Calif, Los Angeles, CA USA..
    Chalasani, Naga P.
    Indiana Univ, Indianapolis, IN 46204 USA..
    Serrano, Jose
    Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA..
    Barnhart, Huiman X.
    Duke Clin Res Inst, Durham, NC USA..
    Fontana, Robert J.
    Univ Michigan, Ann Arbor, MI 48109 USA..
    Watkins, Paul
    Hamner UNC Inst Drug Safety Sci, Durham, NC USA..
    Urban, Thomas J.
    UNC Eshelman Sch Pharm, Chapel Hill, NC USA..
    Daly, Ann K.
    Newcastle Univ, Newcastle, NSW, Australia..
    HLA-A*33:01 is strongly associated with drug-induced liver injury (DILI) due to terbinafine and several other unrelated compounds2015In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 62, p. 325A-326AArticle in journal (Other academic)
  • 2.
    Alassaad, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Gillespie, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    The effects of pharmacist intervention on emergency department visits in patients 80 years and older: subgroup analyses by number of prescribed drugs and appropriate prescribing2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e111797-Article in journal (Refereed)
    Abstract [en]

    Background: Clinical pharmacist interventions have been shown to have positive effect on occurrence of drug-related issues as well as on clinical outcomes. However, evidence about which patients benefiting most from the interventions is limited. We aimed to explore whether pharmacist intervention is equally effective in preventing emergency department (ED) visits in patients with few or many prescribed drugs and in those with different levels of inappropriate prescribing. Methods: Patient and outcome data from a randomized controlled trial exploring the clinical effects of a ward-based pharmacist intervention in patients, 80 years and older, were used. The patients were divided into subgroups according to the number of prescribed drugs (< 5 or >= 5 drugs) and the level of inappropriate prescribing [using the Screening Tool Of Older People's potentially inappropriate Prescriptions (STOPP) and the Screening Tool to Alert doctors to Right Treatment (START) with a score of >= 2 (STOPP) and >= 1 (START) as cutoff points]. The effect of the intervention on the number of times the different subgroups visited the ED was analyzed. Results: The pharmacist intervention was more effective with respect to the number of subsequent ED visits in patients taking < 5 drugs on admission than in those taking >= 5 drugs. The rate ratio (RR) for a subsequent ED visit was 0.22 [95% confidence interval (CI) 0.09-0.52] for,5 drugs and 0.70 (95% CI 0.47-1.04) for >= 5 drugs (p = 0.02 for the interaction). The effect of intervention did not differ between patients with high or low STOPP or START scores. Conclusion: In this exploratory study, the pharmacist intervention appeared to be more effective in preventing visits to the ED for patients who were taking fewer drugs before the intervention. Our analysis of STOPP and START scores indicated that the level of inappropriate prescribing on admission had no effect on the outcomes of intervention with respect to ED visits.

  • 3.
    Alassaad, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Gillespie, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Prescription and transcription errors in multidose-dispensed medications on discharge from hospital: an observationaland interventional study2013In: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 19, no 1, p. 185-191Article in journal (Refereed)
    Abstract [en]

    Background 

    Medication errors frequently occur when patients are transferred between health care settings. The main objective of this study was to investigate the frequency, type and severity of prescribing and transcribing errors for drugs dispensed in multidose plastic packs when patients are discharged from the hospital. The secondary objective was to correct identified errors and suggest measures to promote safe prescribing.

    Methods 

    The drugs on the patients' multidose drug dispensing (MDD) order sheets and the medication administration records were reconciled prior to the MDD orders being sent to the pharmacy for dispensing. Discrepancies were recorded and the prescribing physician was notified and given the opportunity to change the order. Discrepancies categorized as unintentional and related to the discharge process were subject to further analysis.

    Results 

    Seventy-two (25%) of the 290 reviewed MDD orders had at least one discharge error. In total, 120 discharge errors were identified, of which 49 (41%) were assessed as being of moderate and three (3%) of major severity. Orders with a higher number of medications and orders from the orthopaedic wards had a significantly higher error rate.

    Conclusion 

    The main purpose of the MDD system is to increase patient safety by reducing medication errors. However, this study shows that prescribing and transcribing errors frequently occur when patients are hospitalized. Because the population enrolled in the MDD system is an elderly, physically vulnerable group with a high number of prescribed drugs, preventive measures to ensure safe prescribing of MDD drugs are warranted.

  • 4.
    Alassaad, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Gillespie, Ulrika
    Uppsala University Hospital, Uppsala, Sweden.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    A tool for prediction of risk of rehospitalisation and mortality in the hospitalised elderly: secondary analysis of clinical trial data2015In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 5, no 2, article id e007259Article in journal (Refereed)
    Abstract [en]

    Objectives: To construct and internally validate a risk score, the '80+ score', for revisits to hospital and mortality for older patients, incorporating aspects of pharmacotherapy. Our secondary aim was to compare the discriminatory ability of the score with that of three validated tools for measuring inappropriate prescribing: Screening Tool of Older Person's Prescriptions (STOPP), Screening Tool to Alert doctors to Right Treatment (START) and Medication Appropriateness Index (MAI). Setting: Two acute internal medicine wards at Uppsala University hospital. Patient data were used from a randomised controlled trial investigating the effects of a comprehensive clinical pharmacist intervention. Participants: Data from 368 patients, aged 80 years and older, admitted to one of the study wards. Primary outcome measure: Time to rehospitalisation or death during the year after discharge from hospital. Candidate variables were selected among a large number of clinical and drug-specific variables. After a selection process, a score for risk estimation was constructed. The 80+ score was internally validated, and the discriminatory ability of the score and of STOPP, START and MAI was assessed using C-statistics. Results: Seven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid or being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked to a lower risk of the outcome. These variables made up the components of the 80+ score. The C-statistics were 0.71 (80+), 0.57 (STOPP), 0.54 (START) and 0.63 (MAI). Conclusions: We developed and internally validated a score for prediction of risk of rehospitalisation and mortality in hospitalised older people. The score discriminated risk better than available tools for inappropriate prescribing. Pending external validation, this score can aid in clinical identification of high-risk patients and targeting of interventions.

  • 5.
    Alenius, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Hartvig, Per
    Lindström, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting2008In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, no 11, p. 884-893Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

  • 6. Alfirevic, A.
    et al.
    Neely, D.
    Armitage, J.
    Chinoy, H.
    Cooper, R. G.
    Laaksonen, R.
    Carr, D. F.
    Bloch, K. M.
    Fahy, J.
    Hanson, A.
    Yue, Q-Y
    Wadelius, Mia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Maitland-van der Zee, A. H.
    Voora, D.
    Psaty, B. M.
    Palmer, C. N. A.
    Pirmohamed, M.
    Phenotype Standardization for Statin-Induced Myotoxicity2014In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 96, no 4, p. 470-476Article, review/survey (Refereed)
    Abstract [en]

    Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.

  • 7. Aomori, Tohru
    et al.
    Yamamoto, Koujirou
    Oguchi-Katayama, Atsuko
    Kawai, Yuki
    Ishidao, Takefumi
    Mitani, Yasumasa
    Kogo, Yasushi
    Lezhava, Alexander
    Fujita, Yukiyoshi
    Obayashi, Kyoko
    Nakamura, Katsunori
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Ekström, Lena
    Skogastierna, Cristine
    Rane, Anders
    Kurabayashi, Masahiko
    Murakami, Masami
    Cizdziel, Paul E.
    Hayashizaki, Yoshihide
    Horiuchi, Ryuya
    Rapid Single-Nucleotide Polymorphism Detection of Cytochrome P450 (CYP2C9) and Vitamin K Epoxide Reductase (VKORC1) Genes for the Warfarin Dose Adjustment by the SMart-Amplification Process Version 22009In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 55, no 4, p. 804-812Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Polymorphisms of the CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) gene (CYP2C9*2, CYP2C9*3) and the VKORC1 (vitamin K epoxide reductase complex, subunit 1) gene (-1639G>A) greatly impact the maintenance dose for the drug warfarin. Prescreening patients for their genotypes before prescribing the drug facilitates a faster individualized determination of the proper maintenance dose, minimizing the risk for adverse reaction and reoccurrence of thromboembolic episodes. With current methodologies, therapy can be delayed by several hours to 1 day if genotyping is to determine the loading dose. A simpler and more rapid genotyping method is required. METHODS: We developed a single-nucleotide polymorphism (SNP)-detection assay based on the SMart Amplification Process version 2 (SMAP 2) to analyze CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A polymorphisms. Blood from consenting participants was used directly in a closed-tube real-time assay without DNA purification to obtain results within 1 h of blood collection. RESULTS: We analyzed 125 blood samples by both SMAP 2 and PCR-RFLP methods. The results showed perfect concordance. CONCLUSIONS: The results validate the accuracy of the SMAP 2 for determination of SNPs critical to personalized warfarin therapy. SMAP 2 offers speed, simplicity of sample preparation, the convenience of isothermal amplification, and assay-design flexibility, which are significant advantages over conventional genotyping technologies. In this example and other clinical scenarios in which genetic testing is required for immediate and better-informed therapeutic decisions, SMAP 2-based diagnostics have key advantages.

  • 8. Avery, P. J.
    et al.
    Jorgensen, A.
    Hamberg, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Pirmohamed, M.
    Kamali, F.
    A Proposal for an Individualized Pharmacogenetics-Based Warfarin Initiation Dose Regimen for Patients Commencing Anticoagulation Therapy2011In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 90, no 5, p. 701-706Article in journal (Refereed)
    Abstract [en]

    A significant proportion of the interindividual variability in warfarin dose requirements can be explained on the basis of CYP2C9 and VKORC1 genotypes. We report the development of a novel pharmacogenetics-based 3-day warfarin initiation dose (ID) algorithm based on the International Warfarin Pharmacogenetics Consortium (IWPC) maintenance dose algorithm and the CYP2C9 genotype-based variance in warfarin half-life. The predictive value of the pharmacogenetics-based ID was assessed in a large cohort of 671 newly diagnosed patients with thromboembolic disorders who were about to commence anticoagulation therapy in accordance with standard induction regimens. In patients with mean international normalized ratio (INR)(days 4-7)>4.0 (n = 63) after warfarin initiation, the pharmacogenetics-based ID algorithm predicted a markedly lower dose requirement (median reduction = 4.2 mg), whereas in those with mean INR(days 4-7) < 2.0 (n = 145), the predicted dose requirement was very similar to that in the standard regimen. The use of a pharmacogenetics-based ID may avoid overshooting of INR in warfarin-sensitive patients without unduly affecting the time taken to reach target range in the majority of patients.

  • 9. Becquemont, Laurent
    et al.
    Alfirevic, Ana
    Amstutz, Ursula
    Brauch, Hiltrud
    Jacqz-Aigrain, Evelyne
    Laurent-Puig, Pierre
    Molina, Miguel A
    Niemi, Mikko
    Schwab, Matthias
    Somogyi, Andrew A
    Thervet, Eric
    Maitland-van der Zee, Anke-Hilse
    van Kuilenburg, André Bp
    van Schaik, Ron Hn
    Verstuyft, Céline
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Daly, Ann K
    Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics2011In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 12, no 1, p. 113-124Article, review/survey (Refereed)
    Abstract [en]

    The present article summarizes the discussions of the 3rd European Science Foundation-University of Barcelona (ESF-UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics, which was held in June 2010 in Spain. It was focused on practical applications in routine medical practice. We provide practical recommendations for ten different clinical situations, that have either been approved or not approved by regulatory agencies. We propose some comments that might accompany the results of these tests, indicating the best drug and doses to be prescribed. The discussed examples include KRAS, cetuximab, panitumumab, EGFR-gefitinib, CYP2D6-tamoxifen, TPMT-azathioprine-6-mercaptopurine, VKORC1/CYP2C9-warfarin, CYP2C19-clopidogrel, HLA-B*5701-abacavir, HLA-B*5701-flucloxacillin, SLCO1B1-statins and CYP3A5-tacrolimus. We hope that these practical recommendations will help physicians, biologists, scientists and other healthcare professionals to prescribe, perform and interpret these genetic tests.

  • 10.
    Bejhed, Rebecca S.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Kharazmi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Cent Hosp Vasteras, Vasteras, Sweden..
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Identification of Risk Factors for Bisphosphonate-Associated Atypical Femoral Fractures and Osteonecrosis of the Jaw in a Pharmacovigilance Database2016In: The Annals of Pharmacotherapy, ISSN 1060-0280, E-ISSN 1542-6270, Vol. 50, no 8, p. 616-624Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Atypical femoral fractures (AFs) and osteonecrosis of the jaw (ONJ) are well-known adverse drug reactions (ADRs) associated with bisphosphonates. To prevent these ADRs and to aid in the search for pathogenic mechanisms, knowledge of risk factors can be helpful. Objective: To identify risk factors for bisphosphonate-related ONJ and AF. Methods: In this case-control study of reports of bisphosphonate-related ADRs from February 16, 1984, to October 16, 2013, in the Swedish national database of ADRs, we compared characteristics for cases of ONJ (n = 167) and AF (n = 55) with all other bisphosphonate-related ADRs (n = 565) with regard to demographic variables, clinical characteristics, and concomitant drug treatments. We adjusted for multiple comparisons with Bonferroni correction. Results: Time to onset of ADRs differed statistically significantly between cases of AF and controls (2156 vs 111 days). For ONJ versus controls, differences were statistically significant for time to onset (1240 vs 111 days), intravenous administration (40% vs 20%), dental procedures (49% vs 0.2%) and prostheses (5% vs 0%), cancer disease (44% vs 12%), multiple myeloma (21% vs 1%), rheumatoid arthritis (14% vs 5%), and treatment with antineoplastic agents and oxycodone. Conclusion: These results lend further evidence to previously identified risk factors for ONJthat is, intravenous bisphosphonate administration; invasive dental procedures and dental prostheses; cancer disease, in particular multiple myeloma; and possibly, long-term bisphosphonate treatment. A putative further risk factor is rheumatoid arthritis. Only long-term bisphosphonate treatment was more common among AF cases. The lack of overlap of risk factors between ONJ and AF suggests different pathogenic mechanisms.

  • 11. Bertulyte, Ilma
    et al.
    Schwan, Sofie
    Schubert, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Risk Factors for Carbamazepine Induced Serious Skin Reactions2012In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 21, no SI:3, p. 441-441Article in journal (Other academic)
  • 12. Biss, Tina
    et al.
    Hamberg, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Avery, Peter
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Kamali, Farhad
    Warfarin dose prediction in children using pharmacogenetics information2012In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 159, no 1, p. 106-109Article in journal (Refereed)
  • 13.
    Bloch, K. M.
    et al.
    Univ Liverpool, Liverpool, Merseyside, England..
    Carr, D.
    Univ Liverpool, Liverpool, Merseyside, England..
    Pirmohamed, M.
    Univ Liverpool, Liverpool, Merseyside, England..
    Morris, A.
    Univ Liverpool, Liverpool, Merseyside, England..
    Maroteau, C.
    Dundee Univ, Dundee, Scotland..
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Palmer, C.
    Dundee Univ, Dundee, Scotland..
    Alfirevic, A.
    Univ Liverpool, Liverpool, Merseyside, England..
    Whole exome sequencing in individuals with statin-induced myopathy2017In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 40, no 10, p. 1026-1026Article in journal (Other academic)
  • 14.
    Byberg, Liisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Gedeborg, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cars, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Prediction of fracture risk in men: A cohort study2012In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 27, no 4, p. 797-807Article in journal (Refereed)
    Abstract [en]

    FRAX is a tool that identifies individuals with high fracture risk who will benefit from pharmacological treatment of osteoporosis. However, a majority of fractures among elderly occur in people without osteoporosis and most occur after a fall. Our aim was to accurately identify men with a high future risk of fracture, independent of cause. In the population-based Uppsala Longitudinal Study of Adult Men (ULSAM) and using survival analysis we studied different models' prognostic values (R(2) ) for any fracture and hip fracture within 10 years from age 50 (n = 2322), 60 (n = 1852), 71 (n = 1221), and 82 (n = 526). During the total follow-up period from age 50, 897 fractures occurred in 585 individuals. Of these, 281 were hip fractures occurring in 189 individuals. The rates of any fracture were 5.7/1000 person-years at risk from age 50 and 25.9/1000 person-years at risk from age 82. Corresponding hip fractures rates were 2.9 and 11.7/1000 person-years at risk. The FRAX model included all variables in FRAX except bone mineral density. The full model combining FRAX variables, comorbidity, medications, and behavioral factors explained 25-45% of all fractures and 80-92% of hip fractures, depending on age. The corresponding prognostic values of the FRAX model were 7-17% for all fractures and 41-60% for hip fractures. Net reclassification improvement (NRI) comparing the full model with the FRAX model ranged between 40 and 53% for any fracture and between 40 and 87% for hip fracture. Within the highest quintile of predicted fracture risk with the full model, 1/3 of the men will have a fracture within 10 years after age 71 years and 2/3 after age 82 years. We conclude that the addition of comorbidity, medication and behavioral factors to the clinical components of FRAX can substantially improve the ability to identify men at high risk of fracture, especially hip fracture. 

  • 15.
    Byberg, Liisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Olsson, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Karlström, Brita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Sjögren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Reply to WB Grant2017In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 106, no 2, p. 700-701Article in journal (Other academic)
  • 16.
    Byberg, Liisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Olsson, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Karlström, Brita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Sjögren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Reply to Y Mao and H Yu.2017In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 106, no 2, p. 698-699Article in journal (Other academic)
  • 17.
    Cam, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Kempen, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Intervention fidelity within a randomised controlled trial on comprehensive medication reviews in hospitalised patients2018In: International Journal of Clinical Pharmacy, ISSN 2210-7703, E-ISSN 2210-7711, Vol. 40, no 1, p. 251-251Article in journal (Refereed)
  • 18. Caudle, Kelly E
    et al.
    Klein, Teri E
    Hoffman, James M
    Muller, Daniel J
    Whirl-Carrillo, Michelle
    Gong, Li
    McDonagh, Ellen M
    Sangkuhl, Katrin
    Thorn, Caroline F
    Schwab, Matthias
    Agundez, Jose A G
    Freimuth, Robert R
    Huser, Vojtech
    Lee, Ming Ta Michael
    Iwuchukwu, Otito F
    Crews, Kristine R
    Scott, Stuart A
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Swen, Jesse J
    Tyndale, Rachel F
    Stein, C Michael
    Roden, Dan
    Relling, Mary V
    Williams, Marc S
    Johnson, Samuel G
    Incorporation of Pharmacogenomics into Routine Clinical Practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline Development Process2014In: Current drug metabolism, ISSN 1389-2002, E-ISSN 1875-5453, Current drug metabolism, Vol. 15, no 2, p. 209-217Article in journal (Refereed)
    Abstract [en]

    The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines.

  • 19. Cavallari, Larisa H.
    et al.
    Perera, Minoli
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Deloukas, Panos
    Taube, Gelson
    Patel, Shitalben R.
    Aquino-Michaels, Keston
    Viana, Marlos A. G.
    Shapiro, Nancy L.
    Nutescu, Edith A.
    Association of the GGCX (CAA) 16/17 repeat polymorphism with higher warfarin dose requirements in African Americans2012In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 22, no 2, p. 152-158Article in journal (Refereed)
    Abstract [en]

    Objective Little is known about genetic contributors to higher than usual warfarin dose requirements, particularly for African Americans. This study tested the hypothesis that the gamma-glutamyl carboxylase (GGCX) genotype contributes to warfarin dose requirements greater than 7.5 mg/day in an African American population.

    Methods A total of 338 African Americans on a stable dose of warfarin were enrolled. The GGCX rs10654848 (CAA) n, rs12714145 (G>A), and rs699664 (p.R325Q); VKORC1 c.-1639G>A and rs61162043; and CYP2C9*2, *3, *5, *8, *11, and rs7089580 genotypes were tested for their association with dose requirements greater than 7.5mg/day alone and in the context of other variables known to influence dose variability.

    Results The GGCX rs10654848 (CAA) 16 or 17 repeat occurred at a frequency of 2.6% in African Americans and was overrepresented among patients requiring greater than 7.5 mg/day versus those who required lower doses (12 vs. 3%, P = 0.003; odds ratio 4.0, 95% confidence interval, 1.5-10.5). The GGCX rs10654848 genotype remained associated with high dose requirements on regression analysis including age, body size, and VKORC1 genotype. On linear regression, the GGCX rs10654848 genotype explained 2% of the overall variability in warfarin dose in African Americans. An examination of the GGCX rs10654848 genotype in warfarin-treated Caucasians revealed a (CAA) 16 repeat frequency of only 0.27% (P = 0.008 compared with African Americans).

    Conclusion These data support the GGCX rs10654848 genotype as a predictor of higher than usual warfarin doses in African Americans, who have a 10-fold higher frequency of the (CAA) 16/17 repeat compared with Caucasians. Pharmacogenetics and Genomics 22: 152-158 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

  • 20.
    Cavalli, Marco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pan, Gang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nord, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Novel regulatory variant detected on the VKORC1 haplotype that is associated with warfarin dose2016In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 17, no 12, p. 1305-1314Article in journal (Refereed)
    Abstract [en]

    Aim: Warfarin dose requirement is associated with VKORC1 rs9923231, and we studied whether it is a functional variant.

    Materials & methods: We selected variants in linkage disequilibrium with rs9923231 that bind transcription factors in an allele-specific way. Representative haplotypes were cloned or constructed, nuclear protein binding and transcriptional activity were evaluated.

    Results: rs56314408C>T and rs2032915C>T were detected in a liver enhancer in linkage disequilibrium with rs9923231. The rs56314408-rs2032915 C-C haplotype preferentially bound nuclear proteins and had higher transcriptional activity than T-T and the African-specific T-C. A motif for TFAP2A/C was disrupted by rs56314408T. No difference in transcriptional activity was detected for rs9923231G>A.

    Conclusion: Our results supported an activating role for rs56314408C, while rs9923231G>A had no evidence of being functional.

  • 21. Chang, Ming
    et al.
    Soderberg, Mao Mao
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Tybring, Gunnel
    Dahl, Marja-Liisa
    CYP2C19*17 affects R-warfarin plasma clearance and warfarin INR/dose ratio in patients on stable warfarin maintenance therapy2015In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, no 4, p. 433-439Article in journal (Refereed)
    Abstract [en]

    We aimed to assess the influence of CYP2C19*17 on R-warfarin clearance as well as the effect of CYP2C19, CYP2C8, CYP2C9, and VKORC1 polymorphisms together with non-genetic factors on warfarin international normalized ratio (INR)/daily dose. One hundred fifty Caucasian Italian outpatients with data on steady-state plasma concentrations of S- and R-warfarin were genotyped for CYP2C19 (*2, *3, *4, *17), CYP2C9 (*2, *3), CYP2C8*3, and VKORC1*2. The statistical analysis was performed on the effect of genotypes/haplotypes, age, sex, and body weight on the clearance of warfarin enantiomers and dose-normalized INR. R-warfarin clearance was 32 % higher in carriers of CYP2C19*17 than in carriers of CYP2C19*2 (mean 2.5 mL/min, 95 % confidence interval (CI) 2.3-2.8 vs. 1.9 mL/min, 95 % CI 1.7-2.2; P (post hoc) = 0.01). Patients with CYP2C19*1/*1 genotype had an intermediate clearance (mean 2.1 mL/min, 95 % CI 1.8-2.4). The genotypes of VKORC1, CYP2C9, and CYP2C19, together with non-genetic factors (age, sex, and body weight) explained 52 % of the variability in warfarin INR/daily dose, of which CYP2C19 genotypes accounted for 7 %. This is the first study to include the gain-of-function CYP2C19*17 allele when assessing the impact of CYP2C19 polymorphisms on the clearance of warfarin enantiomers. CYP2C19 genotypes influenced the clearance of R-warfarin and contributed significantly to the variability in INR/daily dose, indirectly indicating a clinical relevance of R-warfarin.

  • 22. Chen, Leslie Y.
    et al.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gwilliam, Rhian
    Bentley, David
    Deloukas, Panos
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Gamma-glutamyl carboxylase (GGCX) microsatellite and warfarin dosing2005In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 106, no 10, p. 3673-4Article in journal (Refereed)
  • 23.
    Cui, Tao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tsolakis, Apostolos V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Li, Su-Chen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olfactory Receptor 51E1 is a Potential Novel Tissue Biomarker for the Diagnosis of Small Intestine Neuroendocrine Tumors2013In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 42, no 2, p. 373-373Article in journal (Other academic)
  • 24.
    Cui, Tao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Tsolakis, Apostolos V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Li, Su-Chen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Cunningham, Janet L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Lind, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olfactory receptor 51E1 protein as a potential novel tissue biomarker for small intestine neuroendocrine carcinomas2013In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 168, no 2, p. 253-261Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Late diagnosis hinders proper management of small intestine neuroendocrine carcinoma (SI-NEC) patients. The olfactory receptor, family 51, subfamily E, member 1 (OR51E1) has been reported as a potential novel SI-NEC marker, without protein expression recognition. Thus, we further studied whether the encoded protein may be a novel SI-NEC clinical biomarker.

    DESIGN: OR51E1 coding sequence was cloned using total RNA from SI-NEC patient specimens. Quantitative real-time PCR analysis explored OR51E1 expression in laser capture microdissected SI-NEC cells and adjacent microenvironment cells. Moreover, immunohistochemistry investigated OR51E1 protein expression on operation and biopsy material from primary SI-NECs, mesentery, and liver metastases from 70 patients. Furthermore, double immunofluorescence studies explored the potential co-localization of the vesicular monoamine transporter 1 (SLC18A1, generally referred to as VMAT1) and OR51E1 in the neoplastic cells and in the intestinal mucosa adjacent to the tumor.

    RESULTS: OR51E1 coding sequence analysis showed absence of mutation in SI-NEC patients at different stages of disease. OR51E1 expression was higher in microdissected SI-NEC cells than in the adjacent microenvironment cells. Furthermore, both membranous and cytoplasmic OR51E1 immunostaining patterns were detected in both primary SI-NECs and metastases. Briefly, 18/43 primary tumors, 7/28 mesentery metastases, and 6/18 liver metastases were 'positive' for OR51E1 in more than 50% of the tumor cells. In addition, co-localization studies showed that OR51E1 was expressed in >50% of the VMAT1 immunoreactive tumor cells and of the enterochromaffin cells in the intestinal mucosa adjacent to the tumor.

    CONCLUSION: OR51E1 protein is a potential novel clinical tissue biomarker for SI-NECs. Moreover, we suggest its potential therapeutic molecular target development using solid tumor radioimmunotherapy.

  • 25. Dias, M M
    et al.
    Pignon, J-P
    Karapetis, C S
    Boige, V
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Kweekel, D M
    Lara, P N
    Laurent-Puig, P
    Martinez-Balibrea, E
    Páez, D
    Punt, C J A
    Redman, M W
    Toffoli, G
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    McKinnon, R A
    Sorich, M J
    The effect of the UGT1A1*28 allele on survival after irinotecan-based chemotherapy: a collaborative meta-analysis2014In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 14, no 5, p. 424-431Article in journal (Refereed)
    Abstract [en]

    To date, studies of irinotecan pharmacogenetics have mostly focused on the effect of the UGT1A1*28 allele on irinotecan-related toxicity. However, the clinical utility of routine UGT1A1*28 genotyping to pre-emptively adjust irinotecan dosage is dependent upon whether UGT1A1*28 also affects patient survival following irinotecan therapy. Previous observational studies evaluating the influence of UGT1A1*28 on survival have shown contradictory results. A systematic review and meta-analysis of both published and unpublished data were performed to summarize the available evidence of the relationship between the UGT1A1*28 allele and patient survival related to irinotecan therapy. Overall and progression-free survival meta-analysis data were available for 1524 patients and 1494 patients, respectively. The difference in the survival between patients of different UGT1A1*28 genotypes (homozygous, heterozygous or wild-type) who had received irinotecan was not found to be statistically significant. There was also no evidence of irinotecan dose, regimen or line of therapy having an impact on this association.

  • 26.
    Eriksson, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Axelsson, Tomas
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Connolly, Stuart
    Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Hamilton, ON, Canada..
    Eikelboom, John
    Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Hamilton, ON, Canada..
    Ezekowitz, Michael
    Thomas Jefferson Univ, Sidney Kimmel Med Collage, Philadelphia, PA 19107 USA..
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Pare, Guillaume
    Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Hamilton, ON, Canada..
    Reilly, Paul
    Boehringer Ingelheim Pharma Inc, Ridgefield, CT USA..
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Yusuf, Salim
    Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Hamilton, ON, Canada..
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range: a RE-LY genomics substudy2016In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 17, no 13, p. 1425-1439Article in journal (Refereed)
    Abstract [en]

    Aims: We investigated associations between genetic variation in candidate genes and on a genome-wide scale with warfarin maintenance dose, time in therapeutic range (TTR), and risk of major bleeding. Materials & methods: In total, 982 warfarin-treated patients from the RE-LY trial were studied. Results: After adjusting for SNPs in VKORC1 and CYP2C9, SNPs in DDHD1 (rs17126068) and NEDD4 (rs2288344) were associated with dose. Adding these SNPs and CYP4F2 (rs2108622) to a base model increased R-2 by 2.9%. An SNP in ASPH (rs4379440) was associated with TTR (-6.8% per minor allele). VKORC1 was associated with time less than INR 2.0. VKORC1 and CYP2C9 were associated with time more than INR 3.0, but not with major bleeding. Conclusions: We identified two novel genes associated with warfarin maintenance dose and one gene associated with TTR. These genes need to be replicated in an independent cohort.

  • 27. Eriksson, Solveig
    et al.
    Berg, Lars M.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Alderborn, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Cytochrome P450 genotyping by multiplexed real-time DNA sequencing with Pyrosequencing TM technology2002In: Assay and drug development technologies, ISSN 1540-658X, E-ISSN 1557-8127, Vol. 1, no 1, p. 49-59Article in journal (Refereed)
    Abstract [en]

    Individual differences in xenobiotic metabolism influence the therapeutic value of many drugs and are of major concern during the development of new drug candidates. A number of polymorphic cytochrome p450 enzymes account for a significant part of this variation. A better understanding of these genetic factors would be of value for drug development, as well as clinical practice. To fulfill the goal of a personalized medicine, methods for simple and accurate assessment of cytochrome p450 genes are required. We report on the development of multiplex assays for genotyping of the cytochrome p450 drug-metabolizing enzymes CYP2D6, CYP2C9, and CYP2C19 with Pyrosequencing technology. Eleven variable positions, representing 12 of the most frequent alleles, were scored: CYP2D6 alleles *2, *3, *4, *6, *7, *8, and *14, CYP2C19 alleles *2, *3, and *4, and CYP2C9 alleles *2 and *3. Four multiplex Pyrosequencing reactions per patient sample were performed to cover these positions, using either simplex or multiplex PCR for amplification of target DNA sequences. Unequivocal genotypes were obtained for all patient samples, and the results were validated by comparing with results obtained using PCR-RFLP. For positions addressed with both methods, the results were in complete agreement. Pyrosequencing technology offers a highly automated, rapid, and accurate method for identification of cytochrome p450 alleles, which is suitable for pharmacogenomic research, as well as for routine assessment of patient genotypes.

  • 28. Fall, Tove
    et al.
    Shiue, Ivy
    af Geijerstam, Per Bergea
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Relations of circulating vitamin D concentrations with left ventricular geometry and function2012In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 14, no 9, p. 985-991Article in journal (Refereed)
    Abstract [en]

    Vitamin D deficiency has been associated with risk of overt cardiovascular disease (CVD), but associations with subclinical disease are not well characterized. Hence, we examined associations of circulating vitamin D concentrations and left ventricular (LV) geometry and function by echocardiography at baseline and after 5 years in a community-based study. In the PIVUS study, we measured serum 25-dihydroxyvitamin-D (25-OH D) at age 70 and performed echocardiography including LV mass, wall thickness, end-diastolic diameter, end-systolic diameter (LVESD), left atrial diameter, fractional shortening, ejection fraction, isovolumic relaxation time, and E/A ratio at both age 70 and 75. We included 870 participants (52 women) without prior myocardial infarctions, heart failure, or prevalent valvular disease. After adjusting for potential confounders, 25-OH D at baseline was found to be significantly associated with LVESD, fractional shortening, and ejection fraction (, 0.42 mm, P 0.03; , 0.70, P 0.03; and , 0.91 P 0.01, respectively), per 1 SD increase in 25-OH D (SD 20 nmol/L) at baseline. In longitudinal analyses, vitamin D levels at baseline were not significantly associated with change in LV geometry and function after 5 years. In our community-based study among the elderly, we found higher circulating vitamin D concentrations to be associated cross-sectionally with better LV systolic function and smaller LVESD at baseline. The association persisted after adjusting for several potential confounders, including cardiovascular risk factors and calcium, phosphate, and parathyroid hormone levels. Randomized clinical trials are needed to establish firmly or refute a causal relationship between vitamin D levels and changes in LV geometry and function.

  • 29.
    Fung, P. P. L.
    et al.
    UCL, Univ Coll London Hosp, Eastman Dent Inst & Hosp, 256 Grays Inn Rd, London WC1X 8LD, England..
    Bedogni, G.
    Liver Res Ctr, Clin Epidemiol Unit, Trieste, Italy..
    Bedogni, A.
    Univ Verona, Dept Maxillofacial Surg, Verona, Italy.;Univ Padua, Dept Maxillofacial Surg, Padua, Italy..
    Petrie, A.
    UCL, Univ Coll London Hosp, Eastman Dent Inst & Hosp, 256 Grays Inn Rd, London WC1X 8LD, England..
    Porter, S.
    UCL, Univ Coll London Hosp, Eastman Dent Inst & Hosp, 256 Grays Inn Rd, London WC1X 8LD, England..
    Campisi, G.
    Univ Palermo, Dip Discipline Chirurg Oncol & Stomatol, Palermo, Italy..
    Bagan, J.
    Univ Valencia, Univ Gen Hosp, Dept Oral & Maxillofacial Surg, Oral Med, Valencia, Spain..
    Fusco, V.
    Osped SS Antonio & Biagio & C Arrigo, Med Oncol Unit, Dept Oncol & Haematol, Alessandria, Italy..
    Saia, G.
    Univ Padua, Dept Maxillofacial Surg, Padua, Italy..
    Acham, S.
    Med Univ Graz, Dept Oral Surg & Orthodont, Univ Clin Dent Hlth & Oral Med, Graz, Austria..
    Musto, P.
    IRCCS, Sci Direct, Referral Canc Ctr Basilicata, Potenza, Italy..
    Petrucci, M. T.
    Sapienza Univ, Dept Cellular Biotechnol & Haematol, Rome, Italy..
    Diz, P.
    Santiago de Compostela Univ, Sch Med & Dent, Santiago, Spain..
    Colella, G.
    Univ Naples 2, Dept Med Surg & Dent Specialties, Naples, Italy..
    Mignogna, M. D.
    Univ Naples Federico II, Dept Neurosci Reprod & Odontostomatol Sci, Head & Neck Clin Sect, Naples, Italy..
    Pentenero, M.
    Univ Turin, Oral Med & Oral Oncol Unit, Dept Oncol, Turin, Italy..
    Arduino, P.
    Univ Turin, CIR Dent Sch, Turin, Italy..
    Lodi, G.
    Univ Milan, Dipartimento Sci Biomed Chirurg & Odontoiatr, Milan, Italy..
    Maiorana, C.
    Univ Milan, Fdn IRCCS Policlin Ca Granda, Dipartimento Sci Biomed Chirurg & Odontoiatr, Osped Maggiore Policlin, Milan, Italy..
    Manfredi, M.
    Parma Univ, Dipartimento Sci Biomed Biotecnol & Translaz S Bi, Unit Odontostomatol, Parma, Italy..
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Takaoka, K.
    Hyogo Coll Med, Dept Oral & Maxillofacial Surg, Nishinomiya, Hyogo, Japan..
    Leung, Y. Y.
    Univ Hong Kong, Oral & Maxillofacial Surg, Fac Dent, Hong Kong, Hong Kong, Peoples R China..
    Bonacina, R.
    Osped Papa Giovanni XXIII, Dept Dent, Bergamo, Italy..
    Schiodt, M.
    Copenhagen Univ Hosp, Dept Oral & Maxillofacial Surg, Rigshosp, Copenhagen, Denmark..
    Lakatos, P.
    Semmelweis Univ, Dept Med 1, Sch Med, Budapest, Hungary..
    Taylor, T.
    Kings Coll Hosp London, Dept Oral Surg, London, England..
    De Riu, G.
    Univ Hosp Sassari, Dept Maxillofacial Surg, Sassari, Italy..
    Favini, G.
    San Francesco Hosp, Dept Dent, Nuoro, Italy..
    Rogers, S. N.
    Aintree Univ Hosp NHS Fdn Trust, Liverpool, Merseyside, England..
    Pirmohamed, M.
    Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England..
    Nicoletti, P.
    Columbia Univ, Dept Syst Biol, New York, NY USA..
    Fedele, S.
    UCL, Univ Coll London Hosp, Eastman Dent Inst & Hosp, 256 Grays Inn Rd, London WC1X 8LD, England.;NIHR Univ Coll London Hosp, Biomed Res Ctr, London, England..
    Time to onset of bisphosphonate-related osteonecrosis of the jaws: a multicentre retrospective cohort study2017In: Oral Diseases, ISSN 1354-523X, E-ISSN 1601-0825, Vol. 23, no 4, p. 477-483Article in journal (Refereed)
    Abstract [en]

    Objectives: Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to estimate the TTO and associated risk factors in BP-treated patients.

    Subjects and Methods: Retrospective analysis of data from 22 secondary care centres in seven countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012.

    Results: The median (95%CI) TTO was 6.0 years in patients treated with alendronate (n=88) and 2.2years in those treated with zoledronate (n=218). Multivariable Cox regression showed that dentoalveolar surgery was inversely associated, and the use of antiangiogenics directly associated, with the TTO in patients with cancer treated with zoledronate.

    Conclusions: The incidence of ONJ increases with the duration of BP therapy, with notable differences observed with respect to BP type and potency, route of administration and underlying disease. When data are stratified by BP type, a time of 6.0 and 2.2years of oral alendronate and intravenous zoledronate therapy, respectively, is required for 50% of patients to develop ONJ. After stratification by disease, a time of 5.3 and 2.2years of BP therapy is required for 50% of patients with osteoporosis and cancer, respectively, to develop ONJ. These findings have significant implications for the design of future clinical studies and the development of risk-reduction strategies aimed at either assessing or modulating the risk of ONJ associated with BP.

  • 30. Gamazon, E. R.
    et al.
    Daneshjou, R.
    Cavallari, L. H.
    Limdi, N. A.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Johnson, J. A.
    Klein, T. E.
    Scott, S.
    Tsunoda, T.
    Deloukas, P.
    Altman, R.
    Cox, N.
    Perera, M. A.
    Expression Quantitative Trait Loci Analysis of Stable Warfarin Dose Identifies Novel Associations: Finding Signal within the Noise2013In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 93, no S1, p. S27-S27Article in journal (Other academic)
  • 31.
    Garwicz, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Farmakogenetisk analys kan avslöja risk för statinbiverkningar: [Pharmacogenetic analysis can predict adverse effects of statins]2013In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 110, no 19-20, p. 951-952Article in journal (Refereed)
    Abstract [sv]

    Mer än var tionde vuxen i Sverige behandlas med statiner. 

    Muskelsvaghet, -trötthet och -värk är kända biverkningar. I sällsynta fall ses rabdomyolys, som kan leda till akut njursvikt och någon gång dödsfall. 

    Statiners kemiska egenskaper och serumkoncentration påverkar risken för allvarliga biverkningar. Serumkoncentrationen beror på dos och på patientens förmåga att omsätta läkemedlet.

    Akademiska sjukhuset har som första svenska sjukhus infört analys av en genetisk variant (SLCO1B1*5) som kan förutsäga ökad risk för sällsynta, allvarliga muskelbiverkningar vid statinbehandling.

  • 32.
    Giandomenico, V
    et al.
    IRCCS, Ist Sci Romagnolo Studio & Cura Tumori IRST, Meldola, FC, Italy..
    Li, Su-Chen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Lind, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Boccherini, M.
    IRCCS, Ist Sci Romagnolo Studio & Cura Tumori IRST, Meldola, FC, Italy..
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology. Uppsala Univ Hosp, Uppsala, Sweden..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology. Uppsala Univ Hosp, Uppsala, Sweden..
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Paganelli, G.
    IRCCS, Ist Sci Romagnolo Studio & Cura Tumori IRST, Meldola, FC, Italy..
    miR-196a Is Specifically Regulated in FDG-PET Positive and Negative Small Intestinal Neuroendocrine Tumor Patients at Late Stage of Disease2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, p. 115-115Article in journal (Refereed)
  • 33.
    Gillespie, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alassaad, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Morlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Effects of Pharmacists' Interventions on Appropriateness of Prescribing and Evaluation of the Instruments' (MAI, STOPP and STARTs') Ability to Predict Hospitalization-Analyses from a Randomized Controlled Trial2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, p. e62401-Article in journal (Refereed)
    Abstract [en]

    Background: Appropriateness of prescribing can be assessed by various measures and screening instruments. The aims of this study were to investigate the effects of pharmacists' interventions on appropriateness of prescribing in elderly patients, and to explore the relationship between these results and hospital care utilization during a 12-month follow-up period. Methods: The study population from a previous randomized controlled study, in which the effects of a comprehensive pharmacist intervention on re-hospitalization was investigated, was used. The criteria from the instruments MAI, STOPP and START were applied retrospectively to the 368 study patients (intervention group (I) n = 182, control group (C) n = 186). The assessments were done on admission and at discharge to detect differences over time and between the groups. Hospital care consumption was recorded and the association between scores for appropriateness, and hospitalization was analysed. Results: The number of Potentially Inappropriate Medicines (PIMs) per patient as identified by STOPP was reduced for I but not for C (1.42 to 0.93 vs. 1.46 to 1.66 respectively, p<0.01). The number of Potential Prescription Omissions (PPOs) per patient as identified by START was reduced for I but not for C (0.36 to 0.09 vs. 0.42 to 0.45 respectively, p<0.001). The summated score for MAI was reduced for I but not for C (8.5 to 5.0 and 8.7 to 10.0 respectively, p<0.001). There was a positive association between scores for MAI and STOPP and drug-related readmissions (RR 8-9% and 30-34% respectively). No association was detected between the scores of the tools and total re-visits to hospital. Conclusion: The interventions significantly improved the appropriateness of prescribing for patients in the intervention group as evaluated by the instruments MAI, STOPP and START. High scores in MAI and STOPP were associated with a higher number of drug-related readmissions.

  • 34.
    Gillespie, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alassaad, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Mörlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effects of pharmacists’ interventions on appropriateness of prescribing for elderly and exploration of a possible correlation between scores for appropriateness and clinical outcomes: analyses from a randomized controlled trialManuscript (preprint) (Other academic)
    Abstract [en]

    Background:

    Inappropriate prescribing can cause substantial morbidity and represents a clinical and economic burden for patients and society. Appropriateness of prescribing can be assessed by various measures and screening tools, however, for a tool to be valid there should be casual links to important clinical health outcomes. The aim of this study was to investigate the effect of a pharmacist intervention on appropriateness of prescribing, and to explore the relationship between these results and clinical health outcomes defined as re-visits to hospital.

    Methods:

    The study population from a previous randomized controlled study, in which the effects of a comprehensive pharmacist intervention on re-hospitalisation was investigated, was used. The criteria from the validated instruments STOPP, START and MAI were applied retrospectively to the study patients (368 patients; intervention group n=182, control group n=186). The quality assessments were done on admission and at discharge to detect differences over time between the control- and the intervention group. Hospital care consumption one year after admission was recorded and the correlation between scores for appropriateness, as well as number of drugs at discharge, and hospital visits was analysed.

    Results:

    The number of Potentially Inappropriate Medicines (PIMs) per patient as identified by STOPP was reduced for the intervention group but not for the control group (1.42 and 0.93 vs. 1.46 and 1.66 respectively, p<0.01) The number of Potential Prescription Omissions (PPOs) per patient as identified by START was reduced for the intervention group but not for the control group (0.36 and 0.09 vs. 0.42 and 0.45 respectively, p<0.001). The summated score for MAI was reduced for the intervention group but not for the control group (8.5 to 5.0 and 8.7 to 10.0 respectively, p< 0.001). There was no correlation between the scores of the tools and total visits to hospital. Number of drugs (unadjusted) correlated with visits to hospital and the rate ratio was 4%. For readmissions to hospital, MAI (unadjusted) and the number of drugs showed a positive correlation. There was a correlation between MAI and STOPP and drug-related readmissions (RR 8-9% and 30-34% respectively).

    Conclusion:

    The addition of a comprehensive pharmacist service to standard care significantly improved the appropriateness of prescribing for patients in the intervention group that participated in the randomized controlled trial, as evaluated by all three instruments used; STOPP, START and MAI. However, the results on correlation between the tools and re-visits to hospital were inconclusive.

  • 35.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Garmo, Hans
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Fredriksson, L. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Byström, P.
    Sørbye, H.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer2011In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 11, no 1, p. 61-71Article in journal (Refereed)
    Abstract [en]

    Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).

  • 36. Gottlieb, Assaf
    et al.
    Daneshjou, Roxana
    DeGorter, M
    Bourgeois, S
    Svensson, PJ
    Wadelius, Mia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Deloukas, P
    Montgomery, SB
    Altman, RB
    Cohort-specific imputation of gene expression improves prediction of warfarin dose for African Americans2017In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 9, no 1, article id 98Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Genome-wide association studies are useful for discovering genotype-phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power and allows the effects of both protein-coding variation as well as variation in expression to be combined into "gene level" effects.

    METHODS: Previous work has shown that warfarin dose can be predicted using information from genetic variation that affects protein-coding regions. Here, we introduce a method that improves dose prediction by integrating tissue-specific gene expression. In particular, we use drug pathways and expression quantitative trait loci knowledge to impute gene expression-on the assumption that differential expression of key pathway genes may impact dose requirement. We focus on 116 genes from the pharmacokinetic and pharmacodynamic pathways of warfarin within training and validation sets comprising both European and African-descent individuals.

    RESULTS: We build gene-tissue signatures associated with warfarin dose in a cohort-specific manner and identify a signature of 11 gene-tissue pairs that significantly augments the International Warfarin Pharmacogenetics Consortium dosage-prediction algorithm in both populations.

    CONCLUSIONS: Our results demonstrate that imputed expression can improve dose prediction and bridge population-specific compositions.

    MATLAB code is available at https://github.com/assafgo/warfarin-cohort.

  • 37.
    Grybauskas, Simonas
    et al.
    Vilnius Implantol Ctr, LT-01205 Vilnius, Lithuania..
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Razukevicius, Dainius
    Kaunas Implantol Ctr, Kalnieciu 247, Kaunas, Lithuania..
    Kharazmi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Cent Hosp Vasteras, Dept Oral & Maxillofacial Surg, SE-72189 Vasteras, Sweden..
    Entrapment of soft tissue: a new technique to improve the stability of malar augmentation with hydroxyapatite2016In: British Journal of Oral & Maxillofacial Surgery, ISSN 0266-4356, E-ISSN 1532-1940, Vol. 54, no 7, p. 826-827Article in journal (Refereed)
  • 38.
    Hagström, Emil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ahlström, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Parathyroid hormone and calcium are independently associated with subclinical vascular disease in a community-based cohort2015In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 238, no 2, p. 420-426Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Diseases with abnormal levels of parathyroid hormone (PTH) and calcium, such as primary and secondary hyperparathyroidism, are associated with an increased risk of cardiovascular morbidity and mortality. However, there is paucity on the association between calcium, PTH and abnormalities in the vascular system in the general population.

    METHODS:

    In the PIVUS study (Prospective Investigation of the Vasculature in Uppsala Seniors), a community based cohort of 70-year old men and women (n = 1016), the associations between s-calcium, p-PTH and endothelial function, arterial stiffness and blood pressures were investigated, adjusting for cardiovascular risk factors and mineral metabolism.

    RESULTS:

    In multivariable linear regression models 1 SD increase in calcium was associated with 1.1 units decrease in the stroke volume/pulse pressure ratio and 0.06 decrease in common carotid artery distensibility (p < 0.001) indicative of increased arterial stiffness. Further, calcium was associated with increasing calculated central pulse pressure with 1.3 mmHg elevation per 1 SD increase in calcium (p < 0.05). 1 SD increase in PTH was associated with 1.9 and 1.0 mmHg increase in intra-arterially measured brachial artery systolic and diastolic blood pressures, respectively (p < 0.01), as well as 1.6 and 0.9 mmHg increase in calculated central systolic and diastolic blood pressures (p < 0.05). PTH was not associated with arterial stiffness, endothelial function or pulse pressure.

    CONCLUSION:

    In a large community-based sample of elderly, calcium was independently associated with increased arterial stiffness, and PTH independently to intra-arterial peripheral and calculated central blood pressures. The findings indicate a possible link between the vasculature and mineral metabolism.

  • 39.
    Hagström, Emil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nylander, Ruta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Arnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Plasma Parathyroid Hormone Is Associated with Vascular Dementia and Cerebral Hyperintensities in Two Community-Based Cohorts2014In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 11, p. 4181-4189Article in journal (Refereed)
    Abstract [en]

    Context:

    In diseases with increased PTH such as hyperparathyroidism and chronic renal failure, dementia is common. Little is known of PTH and dementia in the community.

    Objective:

    We sought to investigate relations between PTH, clinical dementia and cerebral micro-vascular disease.

    Setting and Design:

    The Uppsala Longitudinal Study Of Adult Men (ULSAM) was prospective, baseline, 1991-1995; followup, 15.8 years. The Prospective Investigation Of The Vasculature In Uppsala Seniors (PIVUS) was cross-sectional, baseline, 2001. Both settings were community based.

    Participants and Main Outcome Measure:

    In the ULSAM study of 998 men (age 71) the association between PTH and dementia was investigated. In the PIVUS study of 406 men and women (age 70) the relation between PTH and magnetic resonance imaging signs of cerebral small vascular disease was investigated.

    Results:

    During followup, 56 individuals were diagnosed with vascular, 91 with Alzheimer's, and 59 with other dementias. In Cox-regression analyses, higher PTH was associated with vascular dementia (hazard ratio per 1 SD increase of PTH, 1.41; P < .01), but not with other dementias. The top tertile of PTH accounted for 18.5% of the population-attributable risk for vascular dementia, exceeding all other risk factors. In linear regression analysis in PIVUS, PTH was associated with increasing white matter hyperintensities (WMHI), reflecting increasing burden of cerebral small vessel disease (1 SD PTH increase, 0.31 higher category of WMHI; P = .016). All models were adjusted for vascular risk factors and mineral metabolism.

    Conclusions:

    In two community-based samples, PTH predicted clinically diagnosed and neuroimaging indices of vascular dementia and cerebral small vessel disease. Our data suggest a role for PTH in the development of vascular dementia.

  • 40.
    Hagström, Emil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hansen, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Arnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Plasma-Parathyroid Hormone Is Associated With Subclinical and Clinical Atherosclerotic Disease in 2 Community-Based Cohorts2014In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 34, no 7, p. 1567-73Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Cardiovascular risk factors have different impact on different arterial territories. Diseases with elevated circulating parathyroid hormone (PTH) such as primary hyperparathyroidism and chronic renal failure have been shown to be associated with an increased risk of cardiovascular disease, predominantly heart or cerebrovascular diseases. However, data on the associations between circulating PTH and peripheral atherosclerosis are limited.

    APPROACH AND RESULTS: Two prospective, community-based studies were used. In 306 men and women, who were 70 years old, from the Prospective investigation of the vasculature in Uppsala seniors (PIVUS) study, cross-sectional relations between PTH and atherosclerotic burden assessed by whole-body magnetic resonance angiography were investigated. In 998 men, who were 71 years old, from the Uppsala longitudinal study of adult men (ULSAM) study, the association between PTH concentration and risk of subsequent nonfatal atherosclerotic disease (excluding coronary or cerebrovascular disease) was investigated. Adjusting for established vascular risk factors, PTH was associated with burden of atherosclerosis (increase in total atherosclerotic score per SD PTH increase: 0.04, 0.003-0.08; P=0.03) in the PIVUS study. During follow-up in the ULSAM study (median 16.7 years), 89 men were diagnosed with nonfatal atherosclerotic disease. In Cox-regression analyses adjusting for established vascular risk factors and mineral metabolism, higher PTH was associated with an increased risk of nonfatal atherosclerotic disease (hazard ratio for 1 SD increase of PTH: 1.55, 1.33-1.88; P<0.0001). Results were similar when including fatal atherosclerotic disease in the outcome.

    CONCLUSIONS: In 2 independent community-based cohorts, PTH was associated to the degree of atherosclerosis and risk of clinically overt atherosclerotic disease, respectively. Our data confirm and extend previous studies supporting a role for PTH in the development of atherosclerotic disease.

  • 41.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Collin, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Preventivt arbete kan minska läkemedelsbiverkningar2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, article id ERYWArticle in journal (Other academic)
  • 42.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ibanez, Luisa
    Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Fundacio Inst Catala Farmacol, E-08193 Barcelona, Spain..
    Bondon-Guitton, Emmanuelle
    Univ Toulouse, Serv Pharmacol Med & Clin, Ctr Hosp Univ, Fac Med, Toulouse, France..
    Kreutz, Reinhold
    Charite, Inst Klin Pharmakol & Toxikol, D-13353 Berlin, Germany..
    Carvajal, Alfonso
    Univ Valladolid, Ctr Estudios Seguridad Medicamentos, Valladolid, Spain..
    Isabel Lucena, M.
    Univ Malaga, Hosp Univ Virgen de la Victoria, Inst Invest Biomed Malaga, Farmacol Clin S, E-29071 Malaga, Spain.;Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain..
    Sancho Ponce, Esther
    Hosp Gen Cataluna, Serv Hematol & Banc Sang, Sant Cugat Del Valles, Spain..
    Molokhia, Mariam
    Guys & St Thomas NHS Fdn Trust, Res Biomed Res Ctr, Natl Inst Hlth, Dept Primary Care & Publ Hlth Sci, London, England.;Kings Coll London, London WC2R 2LS, England..
    Martin, Javier
    CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain..
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yue, Qun-Ying
    Med Prod Agcy, Uppsala, Sweden..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Swedish Twin Registry, Stockholm, Sweden..
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic variants associated with antithyroid drug-induced agranulocytosis: a genome-wide association study in a European population2016In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 4, no 6, p. 507-516Article in journal (Refereed)
    Abstract [en]

    Background: Drug-induced agranulocytosis is a potentially life-threatening adverse reaction. Genome-wide association studies (GWASs) in ethnic Chinese people in Taiwan and Hong Kong have shown an association between agranulocytosis induced by antithyroid drugs and the HLA alleles HLA-B*38:02 and HLA-DRB1*08:03. We aimed to identify genetic variants associated with antithyroid drug-induced agranulocytosis in a white European population.

    Methods: We did a GWAS in 234 European adults with any non-chemotherapy drug-induced agranulocytosis (absolute neutrophil count <= 0.5 x 10(9)/L [<= 500/mu L]) and 5170 population controls. 39 of the 234 patients had agranulocytosis that was induced by antithyroid drugs (thiamazole [methimazole], carbimazole, or propylthiouracil). After imputation and HLA allele prediction, 9 380 034 single nucleotide polymorphisms (SNPs) and 180 HLA alleles were tested for association. The genome-wide significance threshold was p<5 x 10(-8).

    Findings: Agranulocytosis induced by non-chemotherapy drugs in general was significantly associated with the HLA region on chromosome 6, with odds ratios (ORs) of 3.24 (95% CI 2.31-4.55, p = 1.20 x 10(-11)) for HLA-B*27:05 and 3.57 (2.61-4.90, p = 2.32 x 10(-15)) for the top SNP (rs114291795). Drug-specific analysis showed that the association with HLA-B*27: 05 was largely driven by cases induced by antithyroid drugs. In a multiple logistic regression model, the OR for HLA-B*27: 05 was 7.30 (3.81-13.96) when antithyroid drug-induced agranulocytosis was compared with population controls (p= 1.91 x 10(-9)) and 16.91 (3.44-83.17) when compared with a small group of hyperthyroid controls (p = 5.04 x 10(-4)). Three SNPs were strongly associated with antithyroid drug-induced agranulocytosis: rs652888 (OR 4.73, 95% CI 3.00-7.44, p= 1.92 x 10(-11)) and rs199564443 (17.42, 7.38-41.12, p = 7.04 x 10(-11)), which were independent of HLA-B*27:05, and rs1071816 (5.27, 3.06-9.10, p = 2.35 x 10(-9)) which was in moderate linkage disequilibrium with HLA-B*27:05. In heterozygous carriers of all three SNPs, the predicted probability of antithyroid drug-induced agranulocytosis was about 30% (OR 753, 95% CI 105-6812). To avoid one case of agranulocytosis, based on the possible risk reduction if all three SNPs are genotyped and carriers are treated or monitored differently from non-carriers, roughly 238 patients would need to be genotyped.

    Interpretation: In white European people, antithyroid drug-induced agranulocytosis was associated with HLA-B* 27: 05 and with other SNPs on chromosome 6. In the future, carriers of these variants could be placed under intensified monitoring or offered alternative treatment for hyperthyroidism.

  • 43.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Martén, Leif
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Possible fluconazole-fentanyl interaction: a case report2006In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 62, no 6, p. 491-2Article in journal (Refereed)
  • 44.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Nagy, Julia
    Karawajczyk, Malgorzata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordang, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.