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Kharazmi, M., Michaëlsson, K., Schilcher, J., Eriksson, N., Melhus, H., Wadelius, M. & Hallberg, P. (2019). A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture. Calcified Tissue International, 105(1), 51-67
Open this publication in new window or tab >>A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture
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2019 (English)In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 105, no 1, p. 51-67Article in journal (Refereed) Published
Abstract [en]

Atypical femoral fracture is a well-documented adverse reaction to bisphosphonates. It is strongly related to duration of bisphosphonate use, and the risk declines rapidly after drug withdrawal. The mechanism behind bisphosphonate-associated atypical femoral fracture is unclear, but a genetic predisposition has been suggested. With the aim to identify common genetic variants that could be used for preemptive genetic testing, we performed a genome-wide association study. Cases were recruited mainly through reports of adverse drug reactions sent to the Swedish Medical Products Agency on a nation-wide basis. We compared atypical femoral fracture cases (n=51) with population-based controls (n=4891), and to reduce the possibility of confounding by indication, we also compared with bisphosphonate-treated controls without a current diagnosis of cancer (n=324). The total number of single-nucleotide polymorphisms after imputation was 7,585,874. A genome-wide significance threshold of p<5x10(-8) was used to correct for multiple testing. In addition, we performed candidate gene analyses for a panel of 29 genes previously implicated in atypical femoral fractures (significance threshold of p<5.7x10(-6)). Compared with population controls, bisphosphonate-associated atypical femoral fracture was associated with four isolated, uncommon single-nucleotide polymorphisms. When cases were compared with bisphosphonate-treated controls, no statistically significant genome-wide association remained. We conclude that the detected associations were either false positives or related to the underlying disease, i.e., treatment indication. Furthermore, there was no significant association with single-nucleotide polymorphisms in the 29 candidate genes. In conclusion, this study found no evidence of a common genetic predisposition for bisphosphonate-associated atypical femoral fracture. Further studies of larger sample size to identify possible weakly associated genetic traits, as well as whole exome or whole-genome sequencing studies to identify possible rare genetic variation conferring a risk are warranted.

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
Genome-wide association study, Atypical fractures, Bisphosphonate, Drug-related side effects and adverse reactions, Pharmacogenetics
National Category
Orthopaedics Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-386428 (URN)10.1007/s00223-019-00546-9 (DOI)000469477400005 ()31006051 (PubMedID)
Funder
Swedish Research Council, 521-2011-2440; 521-2014-337; 2015-035270Swedish Heart Lung FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceErik, Karin och Gösta Selanders FoundationÖstergötland County Council
Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2019-06-25Bibliographically approved
Cirulli, E. T., Nicoletti, P., Abramson, K., Andrade, R. J., Bjornsson, E. S., Chalasani, N., . . . Wadelius, M. (2019). A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury. Gastroenterology, 156(6), 1707-1716
Open this publication in new window or tab >>A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury
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2019 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 156, no 6, p. 1707-1716Article in journal (Refereed) Published
Abstract [en]

BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility.

METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings.

RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 x 10(-9) and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 x 10(-6); allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 x 10(-6); allele frequency = 11.5%). Among amoxicillin-and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A* 02: 01 and DRB1* 15: 01.

CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.

Place, publisher, year, edition, pages
W B SAUNDERS CO-ELSEVIER INC, 2019
Keywords
Amino Acid Change, GWAS, Mutation, Inflammation
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-382821 (URN)10.1053/j.gastro.2019.01.034 (DOI)000464659200032 ()30664875 (PubMedID)
Funder
Swedish Research Council, 521-2011-2440Swedish Society of Medicine, 2008-21619Swedish Heart Lung Foundation, 20120557
Available from: 2019-05-06 Created: 2019-05-06 Last updated: 2019-05-06Bibliographically approved
Nicoletti, P., Aithal, G. P., Chamberlain, T. C., Coulthard, S., Alshabeeb, M., Grove, J. I., . . . Daly, A. K. (2019). Drug-Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles. Clinical Pharmacology and Therapeutics, 106(1), 245-253
Open this publication in new window or tab >>Drug-Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles
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2019 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 106, no 1, p. 245-253Article in journal (Refereed) Published
Abstract [en]

Some patients prescribed flucloxacillin (similar to 0.01%) develop drug-induced liver injury (DILI). HLA-B*57:01 is an established genetic risk factor for flucloxacillin DILI. To consolidate this finding, identify additional genetic factors, and assess relevance of risk factors for flucloxacillin DILI in relation to DILI due to other penicillins, we performed a genomewide association study involving 197 flucloxacillin DILI cases and 6,835 controls. We imputed single-nucleotide polymorphism and human leukocyte antigen (HLA) genotypes. HLA-B*57:01 was the major risk factor (allelic odds ratio (OR) = 36.62; P = 2.67 x 10(-97)). HLA-B*57:03 also showed an association (OR = 79.21; P = 1.2 x 10(-6)). Within the HLA-B protein sequence, imputation showed valine(97), common to HLA-B*57:01 and HLA-B*57:03, had the largest effect (OR = 38.1; P = 9.7 x 10(-97)). We found no HLA-B*57 association with DILI due to other isoxazolyl penicillins (n = 6) or amoxicillin (n = 15) and no significant non-HLA signals for any penicillin-related DILI.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-390905 (URN)10.1002/cpt.1375 (DOI)000474029300041 ()30661239 (PubMedID)
Funder
Swedish Research Council, Medicine 521-2011-2440Swedish Research Council, 521-2014-3370Swedish Research Council, 2017-00641Swedish Heart Lung Foundation, 20120557Swedish Society of Medicine, 2008-21619GlaxoSmithKline (GSK)Wellcome trustAstraZenecaEU, European Research Council, QLRI-CT-2002-02757
Available from: 2019-08-19 Created: 2019-08-19 Last updated: 2019-08-19Bibliographically approved
Hallberg, P., Smedje, H., Eriksson, N., Kohnke, H., Daniilidou, M., Öhman, I., . . . Wadelius, M. (2019). Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival. EBioMedicine, 40, 595-604
Open this publication in new window or tab >>Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 40, p. 595-604Article in journal (Refereed) Published
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.

Keywords
(MeSH), Autoimmune diseases, Drug-related side effects and adverse reactions, Genetic variation, Genome-wide association study, Glial cell line-derived neurotrophic factor, H1N1 subtype, Influenza A virus, Influenza vaccines, Narcolepsy, Pharmacogenetics, RNA, long noncoding
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-377169 (URN)10.1016/j.ebiom.2019.01.041 (DOI)000460696900067 ()30711515 (PubMedID)
Funder
Swedish Research Council, 521-2011-2440Swedish Research Council, 521-2014-3370Swedish Research Council, 2018-03307Swedish Heart Lung Foundation, 20120557Swedish Heart Lung Foundation, 20140291Swedish Heart Lung Foundation, 20170711Erik, Karin och Gösta Selanders FoundationThuréus stiftelse för främjande av geriatrisk forskningSwedish Research Council, 2017-00641
Available from: 2019-02-15 Created: 2019-02-15 Last updated: 2019-05-13Bibliographically 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
Kharazmi, M. & Hallberg, P. (2018). Early removal of sequestrum in patients affected by medication-related osteonecrosis of the jaw [Letter to the editor]. British Journal of Oral & Maxillofacial Surgery, 56(3), 237-238
Open this publication in new window or tab >>Early removal of sequestrum in patients affected by medication-related osteonecrosis of the jaw
2018 (English)In: British Journal of Oral & Maxillofacial Surgery, ISSN 0266-4356, E-ISSN 1532-1940, Vol. 56, no 3, p. 237-238Article in journal, Letter (Other academic) Published
National Category
Dentistry
Identifiers
urn:nbn:se:uu:diva-357034 (URN)10.1016/j.bjoms.2018.01.012 (DOI)000428810300020 ()29422306 (PubMedID)
Available from: 2018-08-10 Created: 2018-08-10 Last updated: 2018-08-10Bibliographically approved
Rönnqvist, J., Hallberg, P., Yue, Q.-Y. & Wadelius, M. (2018). Fusidic Acid: A Neglected Risk Factor for Statin-Associated Myopathy. Clinical Medicine Insights: Cardiology, 12
Open this publication in new window or tab >>Fusidic Acid: A Neglected Risk Factor for Statin-Associated Myopathy
2018 (English)In: Clinical Medicine Insights: Cardiology, ISSN 1179-5468, E-ISSN 1179-5468, Vol. 12Article in journal (Refereed) Published
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).

Keywords
adverse drug reactions, cardiovascular drugs, drug-induced disorders, drug safety, dyslipidemia, hypercholesterolemia, hyperlipidemia, myopathy and statins
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-375852 (URN)10.1177/1179546818815162 (DOI)000455898100001 ()30618488 (PubMedID)
Funder
Swedish Research Council, 521-2011-2440Swedish Research Council, 521-2014-3370Swedish Heart Lung Foundation
Available from: 2019-02-01 Created: 2019-02-01 Last updated: 2019-02-01Bibliographically 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
Watkins, P. B., Nicoletti, P., Cirulli, E., Abramson, K., Andrade, R. J., Bjornsson, E., . . . Aithal, G. P. (2018). Identification of a PTPN22 Missense Variant As a General Genetic Risk Factor for Drug-Induced Liver Injury. Paper presented at Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) / Liver Meeting, NOV 09-13, 2018, San Francisco, CA. Hepatology, 68, 25A-25A
Open this publication in new window or tab >>Identification of a PTPN22 Missense Variant As a General Genetic Risk Factor for Drug-Induced Liver Injury
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2018 (English)In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 68, p. 25A-25AArticle in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2018
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-368373 (URN)000446020500039 ()
Conference
Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) / Liver Meeting, NOV 09-13, 2018, San Francisco, CA
Available from: 2018-12-06 Created: 2018-12-06 Last updated: 2018-12-06Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-3465-3280

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