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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. 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)
  • 3.
    Englund, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. klin farm.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring2004In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 2, p. 8-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The ABC transporter P-glycoprotein (P-gp) is recognized as a site for drug-drug interactions and provides a mechanistic explanation for clinically relevant pharmacokinetic interactions with digoxin. The question of whether several P-gp inhibitors may have additive effects has not yet been addressed. METHODS: We evaluated the effects on serum concentrations of digoxin (S-digoxin) in 618 patients undergoing therapeutic drug monitoring. P-gp inhibitors were classified as Class I, with a known effect on digoxin kinetics, or Class II, showing inhibition in vitro but no documented effect on digoxin kinetics in humans. Mean S-digoxin values were compared between groups of patients with different numbers of coadministered P-gp inhibitors by a univariate and a multivariate model, including the potential covariates age, sex, digoxin dose and total number of prescribed drugs. RESULTS: A large proportion (47%) of the digoxin patients undergoing therapeutic drug monitoring had one or more P-gp inhibitor prescribed. In both univariate and multivariate analysis, S-digoxin increased in a stepwise fashion according to the number of coadministered P-gp inhibitors (all P values < 0.01 compared with no P-gp inhibitor). In multivariate analysis, S-digoxin levels were 1.26 +/- 0.04, 1.51 +/- 0.05, 1.59 +/- 0.08 and 2.00 +/- 0.25 nmol/L for zero, one, two and three P-gp inhibitors, respectively. The results were even more pronounced when we analyzed only Class I P-gp inhibitors (1.65 +/- 0.07 for one and 1.83 +/- 0.07 nmol/L for two). CONCLUSIONS: Polypharmacy may lead to multiple drug-drug interactions at the same site, in this case P-gp. The S-digoxin levels increased in a stepwise fashion with an increasing number of coadministered P-gp inhibitors in patients taking P-gp inhibitors and digoxin concomitantly. As coadministration of digoxin and P-gp inhibitors is common, it is important to increase awareness about P-gp interactions among prescribing clinicians.

  • 4.
    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.

  • 5. Grudén, Sofie
    et al.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Är något SSRI-preparat att föredra vad gäller sexuella biverkningar?2008In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, no 26, p. 1949-1949Article in journal (Other academic)
  • 6.
    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)
  • 7.
    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.

  • 8.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hallberg, Ebba
    Amini, Hashem
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Acute pancreatitis following medical abortion: Case report2004In: BMC Women's Health, ISSN 1472-6874, E-ISSN 1472-6874, Vol. 4, no 1, p. 1-Article in journal (Other academic)
    Abstract [en]

    BACKGROUND: Acute pancreatitis rarely complicates pregnancy. Although most pregnant women with acute pancreatitis have associated gallstones, less common causes such as drugs have been reported. CASE PRESENTATION: We report the case of a 34-year-old woman who underwent medical abortion with mifepristone and gemeprost and received codeine as pain-relief during the induction of abortion. She developed a severe acute necrotizing pancreatitis which required 14 days of intensive care. Other possible etiological factors, i.e. gallstone, alcohol intake and hyperlipidemia, were excluded. CONCLUSIONS: The reported case of acute pancreatitis was most likely drug-induced.

  • 9.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlsson, Julia
    Kurland, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Kahan, Thomas
    Malmqvist, Karin
    Öhman, K. Peter
    Nyström, Fredrik
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The CYP2C9 genotype predicts the blood pressure response to irbesartan: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial2002In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 20, no 10, p. 2089-2093Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The cytochrome P450 CYP2C9 enzyme (CYP2C9) metabolizes many clinically important drugs, for example, phenytoin, warfarin and the angiotensin II type 1 (AT(1)) receptor antagonists, losartan and irbesartan. Single nucleotide polymorphisms in the CYP2C9 gene result in the expression of three important variants, CYP2C9*1(wild-type), CYP2C9*2 and CYP2C9*3, the last two exhibiting reduced catalytic activity compared with the wild-type. The CYP2C9 genotype is known to determine sensitivity to and dose requirements for both warfarin and phenytoin, and also the rate of metabolism of losartan. However, its influence on clinical response to treatment with the AT(1) receptor antagonist, irbesartan, has not been investigated. OBJECTIVE: To determine whether the CYP2C9genotype influences the blood pressure-decreasing response to antihypertensive treatment with irbesartan. DESIGN AND METHODS: One hundred and two patients with essential hypertension and left ventricular hypertrophy were allocated randomly to groups to receive double-blind treatment with either irbesartan (n = 49) or the beta(1)-adrenergic receptor blocker, atenolol ( n= 53). Blood pressure was measured before and after 12 weeks of treatment. genotyping was performed using solid-phase minisequencing. RESULTS: The diastolic blood pressure (DBP) response differed in relation to the CYP2C9 genotype in patients given irbesartan: the reduction in patients with genotype CYP2C9*1/CYP2C9*1 (n = 33) was 7.5% and that with CYP2C9*1/CYP2C9*2 (n = 12) was 14.4% ( P= 0.036). A similar trend was seen for systolic blood pressure. In contrast, no relation was seen between the CYP2C9 genotype and blood pressure response to atenolol, a drug not metabolized via CYP2C9. CONCLUSIONS: The CYP2C9 genotype seems to predict the DBP response to irbesartan, but not to atenolol, in patients with essential hypertension.

  • 10.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Billberger, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Karlsson, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kurland, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kahan, Thomas
    Malmqvist, Karin
    Öhman, K. Peter
    Nyström, Fredrik
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christne
    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.
    Transforming growth factor beta1 genotype and change in left ventricular mass during antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA)2004In: Clinical Cardiology, ISSN 0160-9289, E-ISSN 1932-8737, Vol. 27, no 3, p. 169-73Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Angiotensin II, via the angiotensin II type 1 (AT1) receptor, may mediate myocardial fibrosis and myocyte hypertrophy seen in hypertensive left ventricular (LV) hypertrophy through production of transforming growth factor beta1 (TGF-beta1); AT1-receptor antagonists reverse these changes. The TGF-beta1 G + 915C polymorphism is associated with interindividual variation in TGF-beta1 production. No study has yet determined the impact of this polymorphism on the response to antihypertensive treatment. HYPOTHESIS: We aimed to determine whether the TGF-beta1 G + 915C polymorphism was related to change in LV mass during antihypertensive treatment with either an AT1-receptor antagonists or a beta1-adrenoceptor blocker. The polymorphism was hypothesized to have an impact mainly on the irbesartan group. METHODS: We determined the association between the TGF-beta1 genotype and regression of LV mass in 90 patients with essential hypertension and echocardiographically diagnosed LV hypertrophy, randomized in a double-blind study to receive treatment for 48 weeks with either the AT1-receptor antagonist irbesartan or the beta1-adrenoceptor blocker atenolol. RESULTS: Irbesartan-treated patients who were carriers of the C-allele, which is associated with low expression of TGF-beta1, responded with a markedly greater decrease in LV mass index (LVMI) than subjects with the G/G genotype (adjusted mean change in LVMI -44.7 g/m2 vs. -22.2 g/m2, p = 0.007), independent of blood pressure reduction. No association between genotype and change in LVMI was observed in the atenolol group. CONCLUSIONS: The TGF-beta1 G + 915C polymorphism is related to the change in LVMI in response to antihypertensive treatment with the AT1-receptor antagonist irbesartan.

  • 11.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Karlsson, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kurland, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kahan, Thomas
    Malmqvist, Karin
    Öhman, K. Peter
    Nyström, Fredrik
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    B2 bradykinin receptor (B2BKR) polymorphism and change in left ventricular mass in response to antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial2003In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 21, no 3, p. 621-4Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Hypertension is associated with a number of adverse morphologic and functional changes in the cardiovascular system, including left ventricular (LV) hypertrophy. Studies have demonstrated that bradykinin, through the B2 bradykinin receptor (B2BKR), mediates important cardiovascular effects that may protect against LV hypertrophy. Recently, a +9/-9 exon 1 polymorphism of the B2BKR was shown to be strongly associated with LV growth response among normotensive males undergoing physical training. We aimed to clarify whether the processes found in exercise-induced LV growth in normotensive people also occur in pathological LV hypertrophy. DESIGN AND METHODS: We determined the B2BKR genotype of 90 patients with essential hypertension and echocardiographically diagnosed LV hypertrophy, included in a double-blind study to receive treatment for 48 weeks with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan or the beta1-adrenoceptor antagonist atenolol. RESULTS: B2BKR +9/+9 genotypes responded poorly in LV mass regression, independent of blood pressure reduction or treatment, as compared to the other genotypes (adjusted mean change in LV mass index = -10.0 +/- 4.6 versus -21.6 +/- 2.2 g/m2, P = 0.03). CONCLUSIONS: Our results suggest an impact of the B2BKR polymorphism on LV mass regression during antihypertensive treatment.

  • 12.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kurland, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kahan, Thomas
    Malmqvist, Karin
    Öhman, Karl Peter
    Nyström, Fredrik
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Adipocyte-derived leucine aminopeptidase genotype and response to antihypertensive therapy2003In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 18, no 3, p. 11-Article in journal (Refereed)
    Abstract [en]

    Background

    Adipocyte-derived leucine aminopeptidase (ALAP) is a recently identified member of the M1 family of zinc-metallopeptidases and is thought to play a role in blood pressure control through inactivation of angiotensin II and/or generation of bradykinin. The enzyme seems to be particularly abundant in the heart. Recently, the Arg528-encoding allele of the ALAP gene was shown to be associated with essential hypertension.

    Methods

    We evaluated the influence of this polymorphism on the change in left ventricular mass index in 90 patients with essential hypertension and echocardiographically diagnosed left ventricular hypertrophy, randomised in a double-blind study to receive treatment with either the angiotensin II type I receptor antagonist irbesartan or the beta1-adrenoceptor blocker atenolol for 48 weeks. Genyotyping was performed using minisequencing.

    Results

    After adjustment for potential covariates (blood pressure and left ventricular mass index at baseline, blood pressure change, age, sex, dose and added antihypertensive treatment), there was a marked difference between the Arg/Arg and Lys/Arg genotypes in patients treated with irbesartan; those with the Arg/Arg genotype responded on average with an almost two-fold greater regression of left ventricular mass index than patients with the Lys/Arg genotype (-30.1 g/m2 [3.6] vs -16.7 [4.5], p = 0.03).

    Conclusions

    The ALAP genotype seems to determine the degree of regression of left ventricular hypertrophy during antihypertensive treatment with the angiotensin II type I receptor antagonist irbesartan in patients with essential hypertension and left ventricular hypertrophy. This is the first report of a role for ALAP/aminopeptidases in left ventricular mass regulation, and suggests a new potential target for antihypertensive drugs.

  • 13.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindbäck, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Stenestrand, Ulf
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Digoxin and mortality in atrial fibrillation: a prospective cohort study2007In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 63, no 10, p. 959-971Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study showed that rhythm-control treatment of patients with atrial fibrillation (AF) offered no survival advantage over a rate-control strategy. In a subgroup analysis of that study, it was found that digoxin increased the death rate [relative risk (RR) = 1.42), but it was suggested that this may have been attributable to prescription of digoxin for patients at greater risk of death, such as those with congestive heart failure (CHF). No study has investigated a priori the effect of digoxin on mortality in patients with AF. This study aimed to address this question. METHODS: Using data from the Registry of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA), we studied the 1-year mortality among patients admitted to coronary care units with AF, CHF, or AF+CHF with or without digoxin (n = 60,764) during 1995-2003. Adjustment for differences in background characteristics and other medications and treatments was made by propensity scoring. RESULTS: Twenty percent of patients with AF without CHF in this cohort were discharged with digoxin. This group had a higher mortality rate than the corresponding group not given digoxin [adjusted RR 1.42 (95% CI 1.29-1.56)], whereas no such difference was seen among patients with CHF with or without AF, although these patients had a nearly three-times higher mortality. CONCLUSION: The results suggest that long-term therapy with digoxin is an independent risk factor for death in patients with AF without CHF.

  • 14.
    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)
  • 15.
    Hallberg, Pär
    et al.
    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.
    Candidate genes in the pharmacogenomics of antihypertensive treatment:  a review and future aspects2004In: Current Pharmacogenomics, ISSN 1570-1603, Vol. 2, no 1, p. 83-112Article, review/survey (Other academic)
    Abstract [en]

    Diversity in response to antihypertensive therapy is well-documented. Among many variables in the biological system, reasons include the genetic make-up of individuals. Although individual human genomes are 99.9% identical, the 0.1% difference predicts as many as three million polymorphisms. Some will affect protein expression or function, resulting in phenotypes affected for disease or with altered drug response. Pharmacogenomics focuses on the link between polymorphism in genes and variable response to drugs. The genetic approach to the study of the mechanisms underlying hypertension has led to the identification of some quantitative trait loci or genes that influence blood pressure regulation. An ultimate goal of pharmacogenomic knowledge is to advance beyond the current approach to antihypertensive drug therapy to more individualized approaches. Drugs that are more specific for the molecular characteristics of individual patients should contribute to greater efficacy and reduced toxicity.

     

    In this article, we review the pathophysiology of essential hypertension, the principles of its drug treatment, and those pharmacogenomic studies of antihypertensive treatment which, to our knowledge, have been published so far and which deals primarily with two aspects: the blood pressure lowering effect and the regression of left ventricular hypertrophy. Also, a selection of functional polymorphisms in potential candidate genes which have not yet appeared in pharmacogenomic studies of antihypertensive treatment but in various ways have been linked to hypertension and / or its related diseases / organ damages are discussed.

  • 16.
    Hallberg, Pär
    et al.
    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.
    Digitalis intoxication induced by paroxetine co-administration2006In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 368, no 9551, p. 1963-Article in journal (Refereed)
  • 17.
    Hallberg, Pär
    et al.
    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.
    Hansson, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cystatin C vs creatinine as markers of renal function in patients on digoxin treatment2004In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 109, no 3, p. 247-253Article in journal (Other academic)
    Abstract [en]

    BACKGROUND: The kidney function is a major determinant of the serum concentration of digoxin as this drug is mainly eliminated unchanged through the kidneys. Since digoxin is widely prescribed among the elderly, and the glomerular filtration rate (GFR) declines with age, it is important that the clinician takes the patient's GFR into account when prescribing digoxin. Serum cystatin C has been suggested to be superior to creatinine for estimation of GFR, which may have relevance for the optimization of treatment with digoxin. METHODS: To evaluate which of the two GFR markers serum creatinine and serum cystatin C that best correlates with serum digoxin, we compared the serum levels of digoxin with the serum levels of creatinine and cystatin C in 149 patients on therapeutic drug monitoring of digoxin at our hospital. RESULTS: Overall, there was a stronger correlation between serum digoxin concentrations and cystatin C (p=0.00001) as compared to creatinine (p= 0.00003). Interestingly, of the patients with a serum digoxin concentration > or = 1.5 nmol/L, 29% had a serum creatinine level within normal limits, as compared to 20% with normal cystatin C levels. CONCLUSIONS: In this study, serum cystatin C correlated better to serum digoxin than did serum creatinine. With improved GFR monitoring, digoxin concentrations should be better controlled.

  • 18.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    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.
    Digoxin for the treatment of heart failure2003In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 348, no 7, p. 661-662Article in journal (Refereed)
  • 19.
    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.
    Islander, Gunilla
    Norling, Pia
    Johansson, Hans-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kämpe, Mary
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Hugosson, Svante
    Yue, Qun-Ying
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Comparison of Clinical Factors Between Patients With Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema and Cough2017In: The Annals of Pharmacotherapy, ISSN 1060-0280, E-ISSN 1542-6270, Vol. 51, no 4, p. 293-300Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Angioedema is a rare and serious adverse drug reaction (ADR) to angiotensin-converting enzyme (ACE) inhibitor treatment. Dry cough is a common side effect of ACE inhibitors and has been identified as a possible risk factor for angioedema.

    OBJECTIVE: We compared characteristics between patients with ACE inhibitor-induced angioedema and cough with the aim of identifying risk factors that differ between these adverse events.

    METHODS: Data on patients with angioedema or cough induced by ACE inhibitors were collected from the Swedish database of spontaneously reported ADRs or from collaborating clinicians. Wilcoxon rank sum test, Fisher's exact test, and odds ratios (ORs) with 95% CIs were used to test for between-group differences. The significance threshold was set to P <0.00128 to correct for multiple comparisons.

    RESULTS: Clinical characteristics were compared between 168 patients with angioedema and 121 with cough only. Smoking and concomitant selective calcium channel blocker treatment were more frequent among patients with angioedema than cough: OR = 4.3, 95% CI = 2.1-8.9, P = 2.2 × 10(-5), and OR = 3.7, 95% CI = 2.0-7.0, P = 1.7 × 10(-5). Angioedema cases were seen more often in male patients (OR = 2.2, 95% CI = 1.4-3.6, P = 1.3 × 10(-4)) and had longer time to onset and higher doses than those with cough ( P = 3.2 × 10(-10) and P = 2.6 × 10(-4)). A multiple model containing the variables smoking, concurrent calcium channel blocker treatment, male sex, and time to onset accounted for 26% of the variance between the groups.

    CONCLUSION: Smoking, comedication with selective calcium channel blockers, male sex, and longer treatment time were associated with ACE inhibitor-induced angioedema rather than cough.

  • 20.
    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.
    Persson, Matilda
    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.
    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.
    Cavalli, Marco
    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.
    Norling, Pia
    Sickla Hlth Ctr, Nacka, Sweden..
    Johansson, Hans-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Yue, Qun-Ying
    Med Prod Agcy, Uppsala, Sweden..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Swedish Twin Registry, Stockholm, Sweden..
    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.
    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.
    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 angiotensin-converting enzyme inhibitor-induced cough: a genome-wide association study in a Swedish population2017In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 18, no 3, p. 201-213Article in journal (Refereed)
    Abstract [en]

    Aim: We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes iden-tified in previous studies. Patients & methods: A total of 124 patients and 1345 treated controls were genotyped using Illumina arrays. The genome-wide significance level was set to p < 5 x 10(-8). Results: We identified nearly genome-wide significant associations in CLASP1, PDE11A, KCNMB2, TGFA, SLC38A6 and MMP16. The strongest association was with rs62151109 in CLASP1 (odds ratio: 3.97; p = 9.44 x 10(-8)). All top hits except two were located in intronic or noncoding DNA regions. None of the candidate genes were significantly associated in our study. Conclusion: Angiotensin-converting enzyme inhibitor-induced cough is potentially associated with genes that are independent of bradykinin pathways.

  • 21.
    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.
    Smedje, Hans
    Division of Child and Adolescent Psychiatry, Karolinska Institutet, Stockholm, Sweden.
    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.
    Kohnke, Hugo
    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.
    Daniilidou, Makrina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Öhman, Inger
    Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden.
    Yue, Qun-Ying
    Medical Products Agency, Uppsala, Sweden.
    Cavalli, Marco
    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, 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.
    Magnusson, Patrik K. E.
    Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    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.
    Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival2019In: EBioMedicine, E-ISSN 2352-3964, Vol. 40, p. 595-604Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The incidence of narcolepsy rose sharply after the swine influenza A (H1N1) vaccination campaign with Pandemrix. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. The most frequent form is strongly associated with HLA-DQB1*06:02, but only a minority of carriers develop narcolepsy. We aimed to identify genetic markers that predispose to Pandemrix-induced narcolepsy.

    METHODS: We tested for genome-wide and candidate gene associations in 42 narcolepsy cases and 4981 controls. Genotyping was performed on Illumina arrays, HLA alleles were imputed using SNP2HLA, and single nucleotide polymorphisms were imputed using the haplotype reference consortium panel. The genome-wide significance threshold was p < 5 × 10-8, and the nominal threshold was p < 0.05. Results were replicated in 32 cases and 7125 controls. Chromatin data was used for functional annotation.

    FINDINGS: Carrying HLA-DQB1*06:02 was significantly associated with narcolepsy, odds ratio (OR) 39.4 [95% confidence interval (CI) 11.3, 137], p = 7.9 × 10-9. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10-9, and this was replicated, OR = 3.4 [95% CI 1.2-9.6], p = 0.022. Functional analysis revealed variants in high LD with rs62360233 that might explain the detected association. The candidate immune-gene locus TRAJ (rs1154155) was nominally associated in both the discovery and replication cohorts, meta-analysis OR = 2.0 [95% CI 1.4, 2.8], p = 0.0002.

    INTERPRETATION: We found a novel association between Pandemrix-induced narcolepsy and the non-coding RNA gene GDNF-AS1, which has been shown to regulate expression of the essential neurotrophic factor GDNF. Changes in regulation of GDNF have been associated with neurodegenerative diseases. This finding may increase the understanding of disease mechanisms underlying narcolepsy. Associations between Pandemrix-induced narcolepsy and immune-related genes were replicated.

  • 22.
    Holmström, Benny
    et al.
    Gävle sjukhus, Kirurgkliniken, Urologsektionen .
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Antibiotikabehandling vid kronisk prostatit saknar i princip evidens2006In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, no 48, p. 3822-3828Article, review/survey (Refereed)
    Abstract [sv]

    Sammanfattat

    Prostatit förekommer hos 50 procent av alla män någon gång i livet.

    I stort sett saknas evidens för antibiotikabehandling vid alla typer av prostatit undantaget akut prostatit (kategori I).

    Behovet av randomiserade, kontrollerade prövningar är stort.

    Forskning kring prostatit av kategori II–IV är angelägen.

  • 23.
    Karlsson, Julia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    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.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Kurland, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kahan, T.
    Malmqvist, K.
    Ohman, K. P.
    Nyström, F.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Beta1-adrenergic receptor gene polymorphisms and response to beta1-adrenergic receptor blockade in patients with essential hypertension2004In: Clinical Cardiology, ISSN 0160-9289, E-ISSN 1932-8737, Vol. 27, no 6, p. 347-350Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Studies suggest that the Ser49Gly and Arg389Gly polymorphisms in the beta1-adrenergic receptor might be of functional importance for the cardiovascular system. Both have been associated with altered receptor activity in vitro, and with hypertension and cardiac failure in vivo. HYPOTHESIS: The aim of this study was to test whether these polymorphisms were associated with the change in heart rate or blood pressure in patients with essential hypertension and left ventricular (LV) hypertrophy treated with the beta1-adrenergic receptor blocker atenolol. METHODS: Blood pressure and heart rate were measured in 101 hypertensive patients with echocardiographically verified LV hypertrophy, randomized in a double-blind study to treatment with either the beta1-adrenergic receptor blocker atenolol or the angiotensin II type I receptor antagonist irbesartan. Changes in blood pressure and heart rate were evaluated after 12 weeks. Beta1-adrenergic receptor genotyping was performed using polymerase chain reaction and restriction fragment length polymorphism. RESULTS: We found no significant associations between the changes in the measured variables and either of the two polymorphisms. However, carriers of the 49Gly allele showed a tendency toward a greater reduction in heart rate compared with patients with the Ser/Ser49 genotype (p = 0.06). CONCLUSIONS: The Ser49Gly and Arg389Gly beta1-adrenergic receptor polymorphisms do not seem to exert a major effect on the changes in heart rate and blood pressure during 12 weeks of treatment with atenolol in patients with essential hypertension and LV hypertrophy.

  • 24.
    Kharazmi, M.
    et al.
    Cent Hosp Västerås, Dept Oral & Maxillofacial Surg, Västerås, Sweden.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Early removal of sequestrum in patients affected by medication-related osteonecrosis of the jaw2018In: British Journal of Oral & Maxillofacial Surgery, ISSN 0266-4356, E-ISSN 1532-1940, Vol. 56, no 3, p. 237-238Article in journal (Other academic)
  • 25.
    Kharazmi, M.
    et al.
    Cent Hosp Västerås, Dept Oral & Maxillofacial Surg, Västerås, Sweden.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Secondary sinus lift: viable technique for when a membrane is raised without a graft, and fails2018In: British Journal of Oral & Maxillofacial Surgery, ISSN 0266-4356, E-ISSN 1532-1940, Vol. 56, no 3, p. 234-235Article in journal (Other academic)
  • 26.
    Kharazmi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bjornstad, Lillemor
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Wanbro, Jonas
    Carlsson, Anders-Petter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Habib, Samandar
    Uppsala University.
    Warfvinge, Gunnar
    Mandibular bone exposure and osteonecrosis as a complication of general anaesthesia2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 3, p. 215-216Article in journal (Refereed)
  • 27.
    Kharazmi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Carlsson, Anders-Petter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Mandibular Bone Exposure and Osteonecrosis in a Patient With an Uncomplicated Medical History2015In: The Journal of craniofacial surgery (Print), ISSN 1049-2275, E-ISSN 1536-3732, Vol. 26, no 5, p. 1719-1720Article in journal (Refereed)
  • 28.
    Kharazmi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Carlsson, Anders-Petter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Oral surgery: Prominent bone shelves2014In: British Dental Journal, ISSN 0007-0610, E-ISSN 1476-5373, Vol. 216, no 10, p. 544-545Article in journal (Refereed)
  • 29.
    Kharazmi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Carlsson, Anders-Petter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Modig, Maria
    Bjornstad, Lillemor
    Hirsch, Jan-Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Surgical approach to snus-induced injury of the oral mucosa2014In: Journal of Oral Science, ISSN 1343-4934, E-ISSN 1880-4926, Vol. 56, no 1, p. 91-94Article in journal (Refereed)
    Abstract [en]

    Snus (Swedish moist snuff) causes lesions in the oral mucosa at the location where pinches are regularly placed. In addition, some patients develop irreversible local gingival recession and sometimes ulcers with perforations to the roots. Such injuries lead to denuded roots that are at risk for caries and periodontal disease, with subsequent esthetic consequences. Therapy for irreversible local gingival recession is currently lacking. In the present report, we describe two cases of successful surgical treatment for irreversible lesions caused by snus.

  • 30.
    Kharazmi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Bisphosphonate-associated atypical femoral fractures and one-year mortality2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 4, p. 357-358Article in journal (Refereed)
  • 31.
    Kharazmi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hallberg, Pär
    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.
    Gender related difference in the risk of bisphosphonate associated atypical femoral fracture and osteonecrosis of the jaw2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no 8, p. 1594-1594Article in journal (Refereed)
  • 32.
    Kharazmi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Persson, Ulf
    Warfvinge, Gunnar
    Bisphosphonate-associated osteonecrosis of the auditory canal2013In: British Journal of Oral & Maxillofacial Surgery, ISSN 0266-4356, E-ISSN 1532-1940, Vol. 51, no 8, p. E285-E287Article in journal (Refereed)
    Abstract [en]

    Only rare cases of osteonecrosis of the auditory canal associated with bisphosphonates, have been published. Our results confirm that similar reports can also be encountered in databases of adverse drug reactions.

  • 33.
    Kharazmi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Schilcher, Jörg
    Linkoping Univ, Fac Hlth Sci, Sect Orthoped, Dept Clin & Expt Med, Linkoping, Sweden.
    Aspenberg, Per
    Linkoping Univ, Fac Hlth Sci, Sect Orthoped, Dept Clin & Expt Med, Linkoping, Sweden.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Mortality After Atypical Femoral Fractures: A Cohort Study2016In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 31, no 3, p. 491-497Article in journal (Refereed)
    Abstract [en]

    Although osteoporotic fracture rates can be reduced by bisphosphonates, prolonged therapy is associated with higher risk of atypical femoral fractures. Ordinary fragility fractures are linked to high mortality rates. We aimed to determine whether atypical femoral fractures also confer excess mortality. Radiographs were reviewed for all patients ≥55 years of age who had experienced a subtrochanteric or femoral shaft fracture in Sweden in 2008-2010. The fractures were classified as either atypical or ordinary. Data on medication use, coexisting conditions, and date of death were obtained from national registers. We estimated multivariable-adjusted relative risks of death after atypical femoral fractures compared with ordinary subtrochanteric or femoral shaft fractures and calculated age- and sex-standardized mortality ratios (SMRs) for atypical and ordinary fractures compared with the population average. During a mean of 4 years of follow-up, 39 of 172 (23%) patients with an atypical fracture had died compared with 588 of 952 (62%) with an ordinary fracture, corresponding to a relative risk of 0.51 (95% CI 0.38-0.68). The lower risk was evident in both users and non-users of bisphosphonates. No patient with atypical fracture died in the first year after fracture. Individuals with an ordinary fracture had a higher mortality risk than the general population (SMR 1.82; 95% CI 1.69-1.99) but no excess risk was found in patients with atypical fracture (SMR 0.92; 95% CI 0.65-1.26). We conclude that in contrast to ordinary subtrochanteric and femoral shaft fractures, atypical femoral fractures are not associated with excess mortality.

  • 34. Kharazmi, Mohammad
    et al.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Warfvinge, Gunnar
    Bisphosphonate-Associated Osteonecrosis of the External Auditory Canal2013In: The Journal of craniofacial surgery (Print), ISSN 1049-2275, E-ISSN 1536-3732, Vol. 24, no 6, p. 2218-2220Article in journal (Refereed)
  • 35.
    Kharazmi, Mohammad
    et al.
    Department of Oral and Maxillofacial Surgery, Central Hospital, Västerås, Sweden.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Warfvinge, Gunnar
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Risk of atypical femoral fractures and osteonecrosis of the jaw associated with alendronate use compared with other oral bisphosphonates2014In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 53, no 10, p. 1911-1913Article in journal (Refereed)
  • 36.
    Kharazmi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Prodromal Symptoms in Patients with Bisphosphonate-Associated Atypical Fractures of the Femur2015In: Journal of Bone and Mineral Metabolism, ISSN 0914-8779, E-ISSN 1435-5604, Vol. 33, no 5, p. 516-522Article in journal (Refereed)
    Abstract [en]

    Symptoms have been reported to precede bisphosphonate-associated atypical fractures (AFs) of the femoral shaft. We aimed to determine the frequency and clinical characteristics of such prodromal symptoms. We searched the Swedish national database of spontaneously reported adverse drug reactions for all cases of AF associated with bisphosphonates from January 2006 to March 2013. To confirm diagnostic accuracy and to characterize and determine the frequency of any prodromal symptoms we retrieved copies of medical journals and radiographs for patients who consented to participate in the study. The frequency of prodromal symptoms was compared with that of patients where information was based only on narratives from the adverse drug reaction case reports. A total of 45 reports of AF were identified. We were able to obtain medical records and x-rays for 21 cases and diagnostic accuracy was confirmed for all. Medical records revealed prodromal symptoms in 86 % (n = 18), most commonly pain in the ipsilateral thigh (14 out of 18 patients) preceding the fracture for weeks or longer. Awareness of such symptoms may facilitate early diagnosis and possible prevention of the AF.

  • 37.
    Kharazmi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Vastmanland Hosp Vasteras, Dept Oral & Maxillofacial Surg, SE-72189 Vasteras, Sweden..
    Scheer, Hakan
    Vastmanland Hosp Vasteras, Dept Anaesthesiol & Intens Care, SE-73130 Vasteras, Sweden..
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Reduced obstacles, maximized vision (ROMV): a new technique to facilitate laryngoscopy for endotracheal intubation2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, p. 68-69Article in journal (Refereed)
  • 38.
    Kowalec, K.
    et al.
    Univ British Columbia, Vancouver, BC, Canada..
    Wright, G. E. B.
    Univ British Columbia, Vancouver, BC, Canada..
    Drogemoller, B. I.
    Univ British Columbia, Vancouver, BC, Canada..
    Aminkeng, F.
    Univ British Columbia, Vancouver, BC, Canada..
    Bhavsar, A. P.
    Univ British Columbia, Vancouver, BC, Canada..
    Kingwell, E.
    Univ British Columbia, Vancouver, BC, Canada..
    Yoshida, E. M.
    Univ British Columbia, Vancouver, BC, Canada..
    Traboulsee, A.
    Univ British Columbia, Vancouver, BC, Canada..
    Marrie, R. A.
    Univ Manitoba, Winnipeg, MB, Canada..
    Kremenchutzky, M.
    Western Univ, London, ON, Canada..
    Campbell, T.
    Dalhousie Multiple Sclerosis Res Unit, Halifax, NS, Canada..
    Duquette, P.
    Ctr Hosp Univ Montreal, Montreal, PQ, Canada..
    Chalasani, N.
    Indiana Univ, Indianapolis, IN 46204 USA..
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Xia, Z.
    Univ Pittsburgh, Sch Med, Pittsburgh, PA USA..
    De Jager, P.
    Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA..
    Ross, C. J. D.
    Univ British Columbia, Vancouver, BC, Canada..
    Tremlett, H.
    Univ British Columbia, Vancouver, BC, Canada..
    Carleton, B.
    Univ British Columbia, Vancouver, BC, Canada..
    Genome-wide scan identifies association between an interferon regulatory factor-related variant and interferon-beta induced liver injury in multiple sclerosis patients2016In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, no 3, p. 834-836Article in journal (Refereed)
  • 39.
    Kowalec, Kaarina
    et al.
    Univ British Columbia, Div Neurol, Fac Med, Vancouver, BC, Canada;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden;Univ British Columbia, Div Translat Therapeut, Dept Pediat, Vancouver, BC, Canada.
    Wright, Galen E. B.
    Univ British Columbia, Div Translat Therapeut, Dept Pediat, Vancouver, BC, Canada;British Columbia Childrens Hosp Res Inst, Vancouver, BC, Canada;Univ British Columbia, Dept Med Genet, Fac Med, Vancouver, BC, Canada.
    Drogemoller, Britt I.
    Univ British Columbia, Div Translat Therapeut, Dept Pediat, Vancouver, BC, Canada;British Columbia Childrens Hosp Res Inst, Vancouver, BC, Canada;Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada.
    Aminkeng, Folefac
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore, Singapore;Agcy Sci Res & Technol, Translat Lab Genet Med, Singapore, Singapore.
    Bhavsar, Amit P.
    British Columbia Childrens Hosp Res Inst, Vancouver, BC, Canada;Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada;Univ Alberta, Fac Med & Dent, Dept Med Microbiol & Immunol, Edmonton, AB, Canada.
    Kingwell, Elaine
    Univ British Columbia, Div Neurol, Fac Med, Vancouver, BC, Canada.
    Yoshida, Eric M.
    Univ British Columbia, Div Gastroenterol, Fac Med, Vancouver, BC, Canada.
    Traboulsee, Anthony
    Univ British Columbia, Div Neurol, Fac Med, Vancouver, BC, Canada.
    Marrie, Ruth Ann
    Univ Manitoba, Rady Fac Hlth Sci, Max Rady Coll Med, Dept Internal Med, Winnipeg, MB, Canada;Univ Manitoba, Rady Fac Hlth Sci, Max Rady Coll Med, Dept Community Hlth Sci, Winnipeg, MB, Canada.
    Kremenchutzky, Marcelo
    Western Univ, Fac Med, London Hlth Sci Ctr, London, ON, Canada;Western Univ, Fac Med, Dept Clin Neurol Sci, London, ON, Canada.
    Campbell, Trudy L.
    Dalhousie Univ, Dalhousie Multiple Sclerosis Res Uni, Halifax, NS, Canada;Dalhousie Univ, Sch Nursing, Halifax, NS, Canada.
    Duquette, Pierre
    Univ Montreal, Dept Neurosci, Montreal, PQ, Canada.
    Chalasani, Naga
    Indiana Univ Sch Med, Div Gastroenterol Hepatol, Indianapolis, IN 46202 USA.
    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.
    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.
    Xia, Zongqi
    Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA.
    De Jager, Philip L.
    Columbia Univ, Med Ctr, Dept Neurol, Ctr Translat & Computat Neuroimmunol, New York, NY USA.;Columbia Univ, Med Ctr, Dept Neurol, Multiple Sclerosis Ctr, New York, NY USA.;Broad Inst, Cambridge, MA USA.
    Denny, Joshua C.
    Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA.;Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Davis, Mary F.
    Brigham Young Univ, Dept Microbiol & Mol Biol, Provo, UT 84602 USA.
    Ross, Colin J. D.
    British Columbia Childrens Hosp Res Inst, Vancouver, BC, Canada.;Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada.
    Tremlett, Helen
    Univ British Columbia, Div Neurol, Fac Med, Vancouver, BC, Canada.
    Carleton, Bruce C.
    Univ British Columbia, Div Translat Therapeut, Dept Pediat, Vancouver, BC, Canada.;British Columbia Childrens Hosp Res Inst, Vancouver, BC, Canada.
    Common variation near IRF6 is associated with IFN-beta-induced liver injury in multiple sclerosis2018In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 8, p. 1081-+Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-β (IFN-β). Up to 60% of IFN-β-exposed MS patients develop abnormal biochemical liver test results1,2, and 1 in 50 experiences drug-induced liver injury3. Since genomic variation contributes to other forms of drug-induced liver injury4,5, we aimed to identify biomarkers of IFN-β-induced liver injury using a two-stage genome-wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P= 2.3 × 10–8, odds ratio = 8.3, 95% confidence interval = 3.6–19.2). Analysis of an independent cohort of IFN-β-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P= 7.6 × 10–5) and alkaline phosphatase (P= 4.9 × 10-4). We show that these findings may be applicable to predicting IFN-β-induced liver injury, offering insight into its safer use.

  • 40.
    Lindh, Mikaela
    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.
    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.
    Yue, Qun-Ying
    Swedish Med Prod Agcy, Uppsala, 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.
    Clinical factors predicting drug-induced liver injury due to flucloxacillin2018In: Drug, Healthcare and Patient Safety, ISSN 1179-1365, E-ISSN 1179-1365, Vol. 10, p. 95-101Article in journal (Refereed)
    Abstract [en]

    Objectives: Drug-induced liver injury (DILI) is a serious adverse reaction due to flucloxacillin. The pathogenesis is not fully understood. Female sex, age over 60 years, and a longer treatment duration have been suggested to be predisposing factors. Carriers of HLA-B*57:01 have an 80-fold increased risk, but due to the rarity of the reaction, testing of all patients is not cost-effective. We aimed to validate and detect clinical risk factors for flucloxacillin DILI.

    Methods: Clinical characteristics of flucloxacillin-treated patients with (n=50) and without DILI (n=2,330) were compared in a retrospective case control study. Cases were recruited from the Swedish database of spontaneously reported adverse drug reactions. Treated controls were selected from the Swedish Twin Registry. Statistical comparisons were made using chi-squared test and logistic regression. The significance threshold was set to P<0.00357 to correct for multiple comparisons. Reliable variables were tested in a multiple regression model.

    Results: DILI was associated with female sex, OR 2.79,95% CI 1.50-5.17, P=0.0011, and with a history of kidney stones, OR 5.51, 95% CI 2.21-13.72, P=0.0003. Cases were younger than controls, OR per increase in years 0.91,95% CI 0.88-0.94, P<0.0001, probably due to selection bias. No difference in treatment duration was detected, OR 1.03,95% CI 0.98-1.08, P=0.1790.

    Conclusion: We established female sex as a risk factor for flucloxacillin-induced DILI, and a history of kidney stones was identified as a potential risk factor. Clinical risk factors for flucloxacillin-induced DILI could be used to indicate whom to test for HLA-B*57:01 before treatment.

  • 41. Lund, Lars H.
    et al.
    Svennblad, Bodil
    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.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Dahlstrom, Ulf
    Edner, Magnus
    Association of Spironolactone Use With All-Cause Mortality in Heart Failure A Propensity Scored Cohort Study2013In: Circulation Heart Failure, ISSN 1941-3289, E-ISSN 1941-3297, Vol. 6, no 2, p. 174-183Article in journal (Refereed)
    Abstract [en]

    Background-In 3 randomized controlled trials in heart failure (HF), mineralocorticoid receptor antagonists reduced mortality. The net benefit from randomized controlled trials may not be generalizable, and eplerenone was, but spironolactone was not, studied in mild HF. We tested the hypothesis that spironolactone is associated with reduced mortality also in a broad unselected contemporary population with HF and reduced ejection fraction, in particular New York Heart Association (NYHA) I-II. Methods and Results-We prospectively studied 18 852 patients (age 71+/-12 years; 28% women) with NYHA I-IV and ejection fraction <40% who were registered in the Swedish Heart Failure Registry between 2000 and 2012 and who were (n=6551) or were not (n=12 301) treated with spironolactone. We derived propensity scores for spironolactone treatment based on 41 covariates. We assessed survival by Cox regression with adjustment for propensity scores and with matching based on propensity score. We performed sensitivity and residual confounding analyses and analyzed the NYHA I-II and III-IV subgroups separately. One-year survival was 83% versus 84% in treated versus untreated patients (log rank P<0.001). After adjustment for propensity scores, the hazard ratio for spironolactone was 1.05 (95% confidence interval, 1.00-1.11; P=0.054). Spironolactone interacted with NYHA (P<0.001). In the NYHA I-II subgroup, after adjustment for propensity scores, the hazard ratio for spironolactone was 1.11 (95% confidence interval, 1.02-1.21; P=0.019). Conclusions-In an unselected contemporary population of HF with reduced ejection fraction, spironolactone was not associated with reduced mortality. The net benefits of spironolactone may be lower outside the clinical trial setting and in milder HF.

  • 42.
    Nicoletti, Paola
    et al.
    Columbia Univ, Dept Syst Biol, New York, NY USA..
    Aithal, Guruprasad P.
    Natl Hlth Serv Trust, Univ Nottingham Hosp, Natl Inst Hlth Res, Nottingham Digest Dis Biomed Res Unit, Nottingham, England.;Univ Nottingham, Nottingham, England..
    Bjornsson, Einar S.
    Landspitali Univ Hosp, Dept Internal Med, Reykjavik, Iceland..
    Andrade, Raul J.
    Univ Malaga, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Hosp Univ Virgen Victoria, Unidad Gest Clin Digest,Inst Invest Biomed Malaga, Malaga, Spain..
    Sawle, Ashley
    Columbia Univ, Dept Syst Biol, New York, NY USA..
    Arrese, Marco
    Pontificia Univ Catolica Chile, Dept Gastroenterol, Escuela Med, Santiago, Chile..
    Barnhart, Huiman X.
    Duke Univ, Durham, NC USA..
    Bondon-Guitton, Emmanuelle
    Univ Toulouse, Toulouse, France..
    Hayashi, Paul H.
    Univ North Carolina Chapel Hill, Dept Internal Med, Chapel Hill, NC USA..
    Bessone, Fernando
    Univ Nacl Rosario, Serv Gastroenterol & Hepatol, Rosario, Santa Fe, Argentina..
    Carvajal, Alfonso
    Univ Valladolid, Valladolid, Spain..
    Cascorbi, Ingolf
    Univ Hosp Schleswig Holstein, Inst Expt & Clin Pharmacol, Kiel, Germany..
    Cirulli, Elizabeth T.
    Duke Univ, Durham, NC USA..
    Chalasani, Naga
    Indiana Univ Sch Med, Div Gastroenterol & Hepatol, Indianapolis, IN 46202 USA..
    Conforti, Anita
    Univ Hosp, Verona, Italy..
    Coulthard, Sally A.
    Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England..
    Daly, Mark J.
    Broad Inst Harvard & Massachusetts Inst Technol, Boston, MA USA..
    Day, Christopher P.
    Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England..
    Dillon, John F.
    Univ Dundee, Res Inst, Ninewells Hosp, Dundee, Scotland..
    Fontana, Robert J.
    Univ Michigan, Ann Arbor, MI 48109 USA..
    Grove, Jane I.
    Natl Hlth Serv Trust, Univ Nottingham Hosp, Natl Inst Hlth Res, Nottingham Digest Dis Biomed Res Unit, Nottingham, England.;Univ Nottingham, Nottingham, England..
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hernandez, Nelia
    Univ Republica, Fac Med, Montevideo, Uruguay..
    Ibanez, Luisa
    Univ Autonoma Barcelona, Fundacio Inst Catala Farmacol, Hosp Univ Vall dHebron, Barcelona, Spain..
    Kullak-Ublick, Gerd A.
    Univ Hosp, Dept Clin Pharmacol & Toxicol, Zurich, Switzerland.;Univ Zurich, Zurich, Switzerland..
    Laitinen, Tarja
    Univ Helsinki, Cent Hosp, Clin Res Unit Pulm Dis, Helsinki, Finland..
    Larrey, Dominique
    St Eloi Hosp, Liver Unit, Ctr Hosp Univ, Montpellier, France..
    Lucena, M. Isabel
    Univ Malaga, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Hosp Univ Virgen Victoria, Unidad Gest Clin Digest,Inst Invest Biomed Malaga, Malaga, Spain..
    Maitland-van der Zee, Anke H.
    Univ Utrecht, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands..
    Martin, Jennifer H.
    Univ Newcastle, Sch Med & Publ Hlth, Callaghan, NSW 2308, Australia..
    Molokhia, Mariam
    Kings Coll London, Dept Primary Care & Publ Hlth Sci, London, England..
    Pirmohamed, Munir
    Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England..
    Powell, Elizabeth E.
    Univ Queensland, Sch Med, Ctr Liver Dis Res, Brisbane, Qld, Australia..
    Qin, Shengying
    Shanghai Jiao Tong Univ, BioX Inst, Key Lab Genet Dev & Neuropsychiat Disorders, Shanghai, Peoples R China..
    Serrano, Jose
    Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA. Univ Southern Calif, Los Angeles, CA USA..
    Stephens, Camilla
    Univ Malaga, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Hosp Univ Virgen Victoria, Unidad Gest Clin Digest,Inst Invest Biomed Malaga, Malaga, Spain..
    Stolz, Andrew
    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.
    Watkins, Paul B.
    Univ N Carolina, Inst Drug Safety Sci, Eshelman Sch Pharm, Chapel Hill, NC USA..
    Floratos, Aris
    Columbia Univ, Dept Syst Biol, New York, NY USA..
    Shen, Yufeng
    Columbia Univ, Dept Syst Biol, New York, NY USA..
    Nelson, Matthew R.
    GlaxoSmithKlein, Target Sci, King Of Prussia, PA USA..
    Urban, Thomas J.
    Univ N Carolina, UNC Eshelman Sch Pharm, Chapel Hill, NC USA..
    Daly, Ann K.
    Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England..
    Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study2017In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 152, no 5, p. 1078-1089Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for druginduced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A* 33: 01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9 - 3.8; P = 2.4 x 10(-8)) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6 - 2.5; P = 9.7 x 10(-9)). The association with A* 33: 01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A* 33: 01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6 - 2.7; P = 4.8 x 10(-9)). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0 - 9.5; P = 7.1 x 10(-9)). We validated the association between A* 33: 01 terbinafine-and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A* 33: 01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.

  • 43.
    Rönnqvist, Josefine
    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.
    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. Uppsala Univ, Uppsala Univ Hosp, Uppsala, Sweden;Uppsala Univ, Dept Med Sci, Clin Pharmacol & Sci Life Lab, Uppsala, Sweden.
    Yue, Qun-Ying
    Swedish Med Prod Agcy, Uppsala, 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.
    Fusidic Acid: A Neglected Risk Factor for Statin-Associated Myopathy2018In: Clinical Medicine Insights: Cardiology, ISSN 1179-5468, E-ISSN 1179-5468, Vol. 12Article in journal (Refereed)
    Abstract [en]

    Background: Statins are widely used lipid-lowering drugs used for the prevention of cardiovascular disease. Statins are known to cause myopathy, an adverse drug reaction with various clinical features rhabdomyolysis.

    Objective: To describe clinical characteristics of statin-treated individuals who experienced myopathy and identify risk factors of statin-associated myopathy.

    Methods: A retrospective study was conducted on cases of statin-associated myopathy reported to the Swedish Medical Products Agency. Clinical factors were compared between cases and statin-treated controls not diagnosed with myopathy. Statistical methods were univariate and multivariate logistic regression and results were presented as odds ratio (OR) with 95% confidence interval (CI). To correct for multiple comparisons, the cutoff for statistical significance was set to P < .0017.

    Results: In total, 47 cases of statin-associated myopathy were compared with 3871 treated controls. Rhabdomyolysis was diagnosed in 51% of the cases. Markers for cardiovascular disease were more common in cases than controls. Statistical analysis revealed the following independent risk factors for myopathy: high statin dose (OR = 1.54, calculated using the standard deviation 19.82, 95% CI = 1.32-1.80, P < .0001), and concomitant treatment with fusidic acid (OR = 1002, 95% CI = 54.55-18 410, P < .0001), cyclosporine (OR = 34.10, 95% CI = 4.43-262.45, P = .0007), and gemfibrozil (OR = 12.35, 95% CI = 2.38-64.10, P = .0028).

  • 44.
    Siddiqui, Moneeza K.
    et al.
    University of Dundee, Ninewells Hospital and Medical School, Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine.
    Maroteau, Cyrielle
    University of Dundee, Ninewells Hospital and Medical School, Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine.
    Veluchamy, Abirami
    University of Dundee, Ninewells Hospital and Medical School, Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine.
    Tornio, Aleksi
    University of Dundee, Ninewells Hospital and Medical School, Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine.
    Tavendale, Roger
    University of Dundee, Ninewells Hospital and Medical School, Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine.
    Carr, Fiona
    University of Dundee, Ninewells Hospital and Medical School, Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine.
    Abelega, Ngu-Uma
    University of Dundee, Ninewells Hospital and Medical School, Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine.
    Carr, Dan
    University of Liverpool, Institute of Translation Medicine.
    Bloch, Katyrzyna
    University of Liverpool, Institute of Translation Medicine.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Yue, Qun-Ying
    Medical Products Agency, Uppsala.
    Pearson, Ewan R.
    University of Dundee, Ninewells Hospital and Medical School, Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine.
    Colhoun, Helen M.
    University of Dundee, Ninewells Hospital and Medical School, Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine; University of Edinburgh, Institute of Genetics & Molecular.
    Morris, Andrew D.
    University of Dundee, Ninewells Hospital and Medical School, Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine; University of Edinburgh, Usher Institute of Population Health Sciences and Informatics.
    Dow, Eleanor
    Ninewells Hospital and Medical School.
    George, Jacob
    Ninewells Hospital and Medical School.
    Pirmohamed, Munir
    University of Liverpool, Institute of Translation Medicine.
    Ridker, Paul M.
    Harvard Medical School, Brigham and Women’s Hospital, Department of Medicine, Preventive Medicine.
    Doney, Alex S. F.
    Ninewells Hospital and Medical School.
    Alfirevic, Ana
    University of Liverpool, Institute of Translation Medicine.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Maitland-van der Zee, Anke-Hilse
    Utrecht University, Utrecht Institute of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology; University of Amsterdam, Academic Medical Center, Department of Respiratory Medicine.
    Chasman, Daniel I.
    Harvard Medical School, Brigham and Women’s Hospital, Department of Medicine, Preventive Medicine.
    Palmer, Colin N. A.
    University of Dundee, Ninewells Hospital and Medical School, Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine.
    A common missense variant of LILRB5 is associated with statin intolerance and myalgia2017In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 38, no 48, p. 3569-U31Article in journal (Refereed)
    Abstract [en]

    Aims: A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366: T > C: Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study.

    Methods and results: In the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy [odds ratio (OR) 1.81; 95% confidence interval (CI): 1.34–2.45] and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36; 95% CI: 1.07–1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48; 95% CI: 1.05–2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35, 95% CI: 1.10–1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34; 95% CI: 1.16–1.54).

    Conclusion: This study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins.

  • 45.
    Sundbaum, J. K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Lulea Univ Technol, Dept Hlth Sci, Lulea, Sweden.
    Ericsson, N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Lehto, N.
    Lulea Univ Technol, Dept Hlth Sci, Lulea, Sweden.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: a long-term follow-up of occurrence, predictors, surveillance, and outcome in clinical practice2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, p. 977-977Article in journal (Other academic)
  • 46.
    Wadelius, Mia
    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, 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.
    Kreutz, Reinhold
    Universitätsmedizin Berlin, Institut für Klinische Pharmakologie und Toxikologie, Berlin, Germany.
    Bondon-Guitton, Emmanuelle
    Service de Pharmacologie Médicale et Clinique, Centre Hospitalier Universitaire, Faculté de Médecine de l'Université de Toulouse, Toulouse, France.
    Ibañez, Luisa
    Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Fundació Institut Català de Farmacologia, Barcelona, Spain.
    Carvajal, Alfonso
    Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain.
    Lucena, M Isabel
    S Farmacologia Clinica, Instituto de Investigación Biomedica de Málaga (IBIMA), H Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, Madrid, Spain.
    Sancho Ponce, Esther
    Servei d'Hematologia i Banc de Sang, Hospital General de Catalunya, Sant Cugat del Vallès, Spain.
    Molokhia, Mariam
    NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London Department of Primary Care and Public Health Sciences, London, U.
    Martin, Javier
    Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
    Axelsson, Tomas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Yue, Qun-Ying
    Medical Products Agency, Uppsala, Sweden.
    Magnusson, Patrik K E
    Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bengtsson, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    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.
    Sulfasalazine-Induced Agranulocytosis Is Associated With the Human Leukocyte Antigen Locus.2018In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 103, no 5, p. 843-853Article in journal (Refereed)
    Abstract [en]

    Agranulocytosis is a serious, although rare, adverse reaction to sulfasalazine, which is used to treat inflammatory joint and bowel disease. We performed a genome‐wide association study comprising 9,380,034 polymorphisms and 180 HLA alleles in 36 cases of sulfasalazine‐induced agranulocytosis and 5,170 population controls. Sulfasalazine‐induced agranulocytosis was significantly associated with the HLA region on chromosome 6. The top hit (rs9266634) was located close to HLA‐B, odds ratio (OR) 5.36 (95% confidence interval (CI) (2.97, 9.69) P = 2.55 × 10−8). We HLA‐sequenced a second cohort consisting of 40 cases and 142 treated controls, and confirmed significant associations with HLA‐B*08:01, OR = 2.25 (95% CI (1.02, 4.97) P = 0.0439), in particular the HLA‐B*08:01 haplotype HLA‐DQB1*02:01‐DRB1*03:01‐B*08:01‐C*07:01, OR = 3.79 (95% CI (1.63, 8.80) P = 0.0019), and with HLA‐A*31:01, OR = 4.81 (95% CI (1.52, 15.26) P = 0.0077). The number needed to test for HLA‐B*08:01 and HLA‐A*31:01 to avoid one case was estimated to be 1,500. We suggest that intensified monitoring or alternative treatment should be considered for known carriers of HLA‐B*08:01 or HLA‐A*31:01.

  • 47.
    Wadelius, Mia
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Smedje, H.
    Karolinska Inst, Div Child & Adolescent Psychiat, Stockholm, Sweden.
    Yue, Q. -Y
    Med Prod Agcy, Uppsala, Sweden.
    Magnusson, P. K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    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.
    Genome‐Wide Association Study of Pandemrix‐Induced Narcolepsy in Sweden – A Possible Role for Glial Derived Neurotrophic Factor (GDNF)2018In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no S1, p. 12-13Article in journal (Other academic)
  • 48.
    Wadelius, Mia
    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.
    Marshall, S. E.
    Islander, G.
    Nordang, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Karawajczyk, Malgorzata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Yue, Q-Y
    Terreehorst, I.
    Baranova, E. V.
    Hugosson, S.
    Skoldefors, K.
    Pirmohamed, M.
    Maitland-van der Zee, A-H
    Alfirevic, A.
    Hallberg, Pär
    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.
    Palmer, C. N. A.
    Phenotype Standardization of Angioedema in the Head and Neck Region Caused by Agents Acting on the Angiotensin System2014In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 96, no 4, p. 477-481Article, review/survey (Refereed)
    Abstract [en]

    Angioedema is a potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. To study the genetic etiology of this rare adverse event, international consortia and multicenter recruitment of patients are needed. To reduce patient heterogeneity, we have standardized the phenotype. In brief, it comprises swelling in the head and neck region that first occurs during treatment. It should not coincide with urticaria or have another likely cause such as hereditary angioedema.

  • 49.
    Watkins, Paul B.
    et al.
    Univ N Carolina, Chapel Hill, NC 27515 USA.
    Nicoletti, Paola
    Mt Sinai, Genet, Sinai, Egypt.
    Cirulli, Elizabeth
    Duke, Genet, Durham, NC USA.
    Abramson, Karen
    Duke, Genet, Durham, NC USA.
    Andrade, Raul J.
    Univ Malaga, Ugc Aparato Digest, Inst Invest Biomed Malaga IBIMA, Hosp Univ Virgen De La Victoria, Malaga, Spain;Univ Malaga, Serv Farmacol Clin, Inst Invest Biomed Malaga IBIMA, Hosp Univ Virgen De La Victoria, Malaga, Spain.
    Bjornsson, Einar
    Univ Iceland, Fac Med, Sch Hlth Sci, Reykjavik, Iceland.
    Chalasani, Naga P.
    Indiana Univ Sch Med, Div Gastroenterol & Hepatol, Indianapolis, IN 46202 USA.
    Fontana, Robert J.
    Univ Michigan, Div Gastroenterol & Hepatol, Ann Arbor, MI 48109 USA.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Li, Yi-Ju
    Duke, Genet, Durham, NC USA.
    Lucena, Maribel
    Univ Malaga, Ugc Aparato Digest, Inst Invest Biomed Malaga IBIMA, Hosp Univ Virgen De La Victoria, Malaga, Spain;Univ Malaga, Serv Farmacol Clin, Inst Invest Biomed Malaga IBIMA, Hosp Univ Virgen De La Victoria, Malaga, Spain.
    Long, Nanye
    Duke, Genet, Durham, NC USA.
    Molokhia, Miriam
    Kings Coll London, Primary Care, London, England.
    Nelson, Mathew
    Glaxosmithkline, Genet, Brentford, England.
    Odin, Joseph
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA.
    Pirmohamed, Munir
    Univ Liverpool, Clin Pharmacol, Liverpool, Merseyside, England.
    Rafnar, Thorunn
    Decode, Genet, Bergen, Norway.
    Serrano, Jose
    NIH, Liver Pancreas & GI Neuroendocrine, Bldg 10, Bethesda, MD 20892 USA.
    Stefansson, Karen
    Decode, Genet, Bergen, Norway.
    Stolz, Andrew
    Univ Southern Calif, Los Angeles, CA USA.
    Daly, Ann
    Newcastle Univ, Newcastle Upon Tyne, Tyne & Wear, England.
    Aithal, Guruprasad P.
    Queens Med Ctr, Honolulu, HI USA.
    Identification of a PTPN22 Missense Variant As a General Genetic Risk Factor for Drug-Induced Liver Injury2018In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 68, p. 25A-25AArticle in journal (Other academic)
1 - 49 of 49
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