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Publications (10 of 97) Show all publications
Rasmussen, E. R., Buchwald, C. ,., Wadelius, M., Prasad, S. C., Kamaleswaran, S., Ajgeiy, K. K., . . . Bygum, A. (2018). Assessment of 105 patients with angiotensin converting enzyme-inhibitor induced angioedema eva. Paper presented at Congress of the European-Academy-of-Allergy-and-Clinical-Immunology (EAACI), MAY 26-30, 2018, Munich, GERMANY. Allergy. European Journal of Allergy and Clinical Immunology, 73(Suppl. 105), 415-415, Article ID 738.
Open this publication in new window or tab >>Assessment of 105 patients with angiotensin converting enzyme-inhibitor induced angioedema eva
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2018 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 73, no Suppl. 105, p. 415-415, article id 738Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
WILEY, 2018
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-364736 (URN)10.1111/all.13539 (DOI)000441690402159 ()
Conference
Congress of the European-Academy-of-Allergy-and-Clinical-Immunology (EAACI), MAY 26-30, 2018, Munich, GERMANY
Available from: 2018-11-01 Created: 2018-11-01 Last updated: 2018-11-01Bibliographically approved
Lindh, M., Hallberg, P., Yue, Q.-Y. & Wadelius, M. (2018). Clinical factors predicting drug-induced liver injury due to flucloxacillin. Drug, Healthcare and Patient Safety, 10, 95-101
Open this publication in new window or tab >>Clinical factors predicting drug-induced liver injury due to flucloxacillin
2018 (English)In: Drug, Healthcare and Patient Safety, ISSN 1179-1365, E-ISSN 1179-1365, Vol. 10, p. 95-101Article in journal (Refereed) Published
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.

Keywords
floxacillin, chemical and drug induced liver injury, drug-related side effects and adverse reactions, alanine transaminase, bilirubin
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-371131 (URN)10.2147/DHPS.S178394 (DOI)000451111200001 ()30538582 (PubMedID)
Funder
Swedish Research Council, 2017-00641Swedish Research Council, 521-2011-2440Swedish Research Council, 521-2014-3370Swedish Heart Lung Foundation, 20120557Swedish Heart Lung Foundation, 20140291Swedish Heart Lung Foundation, 20170711
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2018-12-19Bibliographically approved
Kowalec, K., Wright, G. E. B., Drogemoller, B. I., Aminkeng, F., Bhavsar, A. P., Kingwell, E., . . . Carleton, B. C. (2018). Common variation near IRF6 is associated with IFN-beta-induced liver injury in multiple sclerosis. Nature Genetics, 50(8), 1081-+
Open this publication in new window or tab >>Common variation near IRF6 is associated with IFN-beta-induced liver injury in multiple sclerosis
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2018 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 8, p. 1081-+Article in journal (Refereed) Published
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.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-364491 (URN)10.1038/s41588-018-0168-y (DOI)000440423400006 ()30013178 (PubMedID)
Funder
Wellcome trust, 076113; 085475; 090355NIH (National Institute of Health), U01-DK065176 U01-DK065201 U01-DK065184 U01-DK065211; U01DK065193; U01-DK065238; U01-DK083023; U01-DK083027 ;U01-DK082992; U01-DK083020; U01-DK100928NIH (National Institute of Health), ULTR000445
Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2018-10-29Bibliographically approved
Takeuchi, M., Kobayashi, T., Biss, T., Kamali, F., Vear, S., Ho, R., . . . Ito, S. (2018). Effect of CYP2C9, VKORC1, and CYP4F2 on warfarin maintenance dose in children aged less than 18 year of age: systematic review and meta-analysis. Paper presented at 119th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) - Breaking Down Barriers to Effective Patient Care, MAR 21-24, 2018, Orlando, FL. Clinical Pharmacology and Therapeutics, 103(S1), S52-S52
Open this publication in new window or tab >>Effect of CYP2C9, VKORC1, and CYP4F2 on warfarin maintenance dose in children aged less than 18 year of age: systematic review and meta-analysis
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2018 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 103, no S1, p. S52-S52Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2018
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-348313 (URN)10.1002/cpt.993 (DOI)000424997100183 ()
Conference
119th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) - Breaking Down Barriers to Effective Patient Care, MAR 21-24, 2018, Orlando, FL
Available from: 2018-04-25 Created: 2018-04-25 Last updated: 2018-04-25Bibliographically approved
Wadelius, M., Eriksson, N., Smedje, H., Yue, Q.-Y. -., Magnusson, P. K. & Hallberg, P. (2018). Genome‐Wide Association Study of Pandemrix‐Induced Narcolepsy in Sweden – A Possible Role for Glial Derived Neurotrophic Factor (GDNF). Paper presented at First Nordic Conference on Personalized Medicine (NORPM 2018), May 30th ‐ June 1st 2018, Nyborg, Denmark.. Basic & Clinical Pharmacology & Toxicology, 123(S1), 12-13
Open this publication in new window or tab >>Genome‐Wide Association Study of Pandemrix‐Induced Narcolepsy in Sweden – A Possible Role for Glial Derived Neurotrophic Factor (GDNF)
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2018 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no S1, p. 12-13Article in journal, Meeting abstract (Other academic) Published
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-362656 (URN)10.1111/bcpt.13020 (DOI)000434060000033 ()
Conference
First Nordic Conference on Personalized Medicine (NORPM 2018), May 30th ‐ June 1st 2018, Nyborg, Denmark.
Note

Meeting Abstract: NorPM-O5

Available from: 2018-10-16 Created: 2018-10-16 Last updated: 2018-10-16Bibliographically approved
Sundbaum, J. K., Ericsson, N., Hallberg, P., Lehto, N., Wadelius, M. & Baecklund, E. (2018). Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: a long-term follow-up of occurrence, predictors, surveillance, and outcome in clinical practice. Paper presented at Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS. Annals of the Rheumatic Diseases, 77, 977-977
Open this publication in new window or tab >>Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: a long-term follow-up of occurrence, predictors, surveillance, and outcome in clinical practice
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, p. 977-977Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-368665 (URN)10.1136/annrheumdis-2018-eular.2778 (DOI)000444351002595 ()
Conference
Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2018-12-10Bibliographically approved
Wadelius, M., Eriksson, N., Kreutz, R., Bondon-Guitton, E., Ibañez, L., Carvajal, A., . . . Hallberg, P. (2018). Sulfasalazine-Induced Agranulocytosis Is Associated With the Human Leukocyte Antigen Locus.. Clinical Pharmacology and Therapeutics, 103(5), 843-853
Open this publication in new window or tab >>Sulfasalazine-Induced Agranulocytosis Is Associated With the Human Leukocyte Antigen Locus.
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2018 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 103, no 5, p. 843-853Article in journal (Refereed) Published
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.

National Category
Clinical Laboratory Medicine
Research subject
Clinical Pharmacology
Identifiers
urn:nbn:se:uu:diva-342623 (URN)10.1002/cpt.805 (DOI)000430118300025 ()28762467 (PubMedID)
Projects
Farmakogenomik
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research Council, 521-2014-3370; 521-2011-2440Swedish Heart Lung Foundation, 20120557; 20140291
Available from: 2018-02-22 Created: 2018-02-22 Last updated: 2018-06-19Bibliographically approved
Siddiqui, M. K., Maroteau, C., Veluchamy, A., Tornio, A., Tavendale, R., Carr, F., . . . Palmer, C. N. A. (2017). A common missense variant of LILRB5 is associated with statin intolerance and myalgia. European Heart Journal, 38(48), 3569-U31
Open this publication in new window or tab >>A common missense variant of LILRB5 is associated with statin intolerance and myalgia
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2017 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 38, no 48, p. 3569-U31Article in journal (Refereed) Published
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.

Keywords
Statins, Pharmacogenetics, Immunogenetics, Precision medicine, Adverse drug reactions, Myalgia
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-339765 (URN)10.1093/eurheartj/ehx467 (DOI)000418697400011 ()29020356 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 602108Wellcome trust, 099177/Z/12/Z; 072960; 084726AstraZenecaSwedish Research Council, 521-2011-2440; 521-2014-3370Swedish Heart Lung Foundation, 20120557; 20140291
Available from: 2018-02-02 Created: 2018-02-02 Last updated: 2018-02-02Bibliographically approved
Rasmussen, E. R., von Buchwald, C., Wadelius, M., Prasad, S. C., Kamaleswaran, S., Ajgeiy, K. K., . . . Bygum, A. (2017). Assessment of 105 Patients with Angiotensin Converting Enzyme-Inhibitor Induced Angioedema. International Journal of Otolaryngology, 2017, Article ID 1476402.
Open this publication in new window or tab >>Assessment of 105 Patients with Angiotensin Converting Enzyme-Inhibitor Induced Angioedema
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2017 (English)In: International Journal of Otolaryngology, ISSN 1687-9201, E-ISSN 1687-921X, Vol. 2017, article id 1476402Article in journal (Refereed) Published
Abstract [en]

Objective. To asses a cohort of 105 consecutive patients with angiotensin converting enzyme-inhibitor induced angioedema withregard to demographics, risk factors, family history of angioedema, hospitalization, airway management, outcome, and use ofdiagnostic codes used for the condition.

Study Design. Cohort study.

Methods.This was a retrospective cohort study of 105 patientswith angiotensin converting enzyme-inhibitor induced angioedema in the period 1995–2014.

Results. The cohort consisted of 67females and 38 males (F :Mratio 1.8), with a mean age of 63 [range 26–86] years. Female gender was associated with a significantlyhigher risk of angiotensin converting enzyme-inhibitor induced angioedema. 6.7% had a positive family history of angioedema.Diabetes seemed to be a protective factor with regard to angioedema. 95% experienced angioedema of the head and neck. 4.7%needed intubation or tracheostomy. 74 admissions took place during the study period with a total of 143 days spent in the hospital.The diagnosis codes most often used for this condition were “DT783 Quincke’s oedema” and “DT78.4 Allergy unspecified”.Complement C1 inhibitor was normal in all tested patients.

Conclusion. Female gender predisposes to angiotensin convertingenzyme-inhibitor induced angioedema, whereas diabetes seems to be a protective factor.

National Category
Otorhinolaryngology
Research subject
Pharmacology
Identifiers
urn:nbn:se:uu:diva-342586 (URN)10.1155/2017/1476402 (DOI)28286522 (PubMedID)
Available from: 2018-02-22 Created: 2018-02-22 Last updated: 2018-03-15Bibliographically approved
Nicoletti, P., Aithal, G. P., Bjornsson, E. S., Andrade, R. J., Sawle, A., Arrese, M., . . . Daly, A. K. (2017). Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study. Gastroenterology, 152(5), 1078-1089
Open this publication in new window or tab >>Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study
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2017 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 152, no 5, p. 1078-1089Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
W B SAUNDERS CO-ELSEVIER INC, 2017
Keywords
Medication, Liver Damage, Side Effect, Anti-Fungal Agent
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-320025 (URN)10.1053/j.gastro.2016.12.016 (DOI)000397297700035 ()28043905 (PubMedID)
Funder
NIH (National Institute of Health), U01-DK065176 U01-DK065201 U01-DK065184 U01-DK065211 U01DK065193 U01-DK065238 U01-DK083023 U01-DK083027 U01-DK082992 U01-DK083020 U01-DK100928EU, European Research Council, QLRI-CT-2002-02757Swedish Society of Medicine, 2008-21619Swedish Research Council, 521-2011-2440Swedish Heart Lung Foundation, 20120557
Available from: 2017-04-13 Created: 2017-04-13 Last updated: 2017-11-29Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-6368-2622

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