Whole genome case-control study of central nervous system toxicity due to antimicrobial drugs.

A genetic predisposition to central nervous system (CNS) toxicity induced by antimicrobial drugs (antibiotics, antivirals, antifungals, and antiparasitic drugs) has been suspected. Whole genome sequencing of 66 cases and 833 controls was performed to investigate whether antimicrobial drug-induced CNS toxicity was associated with genetic variation. The primary objective was to test whether antimicrobial-induced CNS toxicity was associated with seventeen efflux transporters at the blood-brain barrier. In this study, variants or structural elements in efflux transporters were not significantly associated with CNS toxicity. Secondary objectives were to test whether antimicrobial-induced CNS toxicity was associated with genes over the whole genome, with HLA, or with structural genetic variation. Uncommon variants in and close to three genes were significantly associated with CNS toxicity according to a sequence kernel association test combined with an optimal unified test (SKAT-O). These genes were LCP1 (q = 0.013), RETSAT (q = 0.013) and SFMBT2 (q = 0.035). Two variants were driving the LCP1 association: rs6561297 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51-8.46]) and the regulatory variant rs10492451 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51-8.46]). No common genetic variant, HLA-type or structural variation was associated with CNS toxicity. In conclusion, CNS toxicity due to antimicrobial drugs was associated with uncommon variants in LCP1, RETSAT and SFMBT2.

Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.

BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

No link between type I interferon autoantibody positivity and adverse reactions to COVID-19 vaccines.

Type I interferons act as gatekeepers against viral infection, and autoantibodies that neutralize these signaling molecules have been associated with COVID-19 severity and adverse reactions to the live-attenuated yellow fever vaccine. On this background, we sought to examine whether autoantibodies against type I interferons were associated with adverse events following COVID-19 vaccination. Our nationwide analysis suggests that type I interferon autoantibodies were not associated with adverse events after mRNA or viral-vector COVID-19 vaccines.

Identification of risk factors for adverse drug reactions in a pharmacovigilance database.

INTRODUCTION: In addition to identifying new safety signals, pharmacovigilance databases could be used to identify potential risk factors for adverse drug reactions (ADRs). OBJECTIVE: To evaluate whether data mining in a pharmacovigilance database can be used to identify known and possible novel risk factors for ADRs, for use in pharmacovigilance practice. METHOD: Exploratory data mining was performed within the Swedish national database of spontaneously reported ADRs. Bleeding associated with direct oral anticoagulants (DOACs)-rivaroxaban, apixaban, edoxaban, and dabigatran-was used as a test model. We compared demographics, drug treatment, and clinical features between cases with bleeding (N = 965) and controls who had experienced other serious ADRs to DOACs (N = 511). Statistical analysis was performed by unadjusted and age adjusted logistic regression models, and the random forest based machine-learning method Boruta. RESULTS: In the logistic regression, 13 factors were significantly more common among cases of bleeding compared with controls. Eleven were labelled or previously proposed risk factors. Cardiac arrhythmia (e.g., atrial fibrillation), hypertension, mental impairment disorders (e.g., dementia), renal and urinary tract procedures, gastrointestinal ulceration and perforation, and interacting drugs remained significant after adjustment for age. In the Boruta analysis, high age, arrhythmia, hypertension, cardiac failure, thromboembolism, and pharmacodynamically interacting drugs had a larger than random association with the outcome. High age, cardiac arrhythmia, hypertension, cardiac failure, and pharmacodynamically interacting drugs had odds ratios for bleeding above one, while thromboembolism had an odds ratio below one. CONCLUSIONS: We demonstrated that data mining within a pharmacovigilance database identifies known risk factors for DOAC bleeding, and potential risk factors such as dementia and atrial fibrillation. We propose that the method could be used in pharmacovigilance for identification of potential ADR risk factors that merit further evaluation.

Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events.

Apixaban is a direct oral anticoagulant, a factor Xa inhibitor, used for the prevention of ischemic stroke in patients with atrial fibrillation. Despite using recommended dosing a few patients might still experience bleeding or lack of efficacy that might be related to inappropriate drug exposure. We conducted a genome-wide association study using data from 1,325 participants in the pivotal phase three trial of apixaban with the aim to identify genetic factors affecting the pharmacokinetics of apixaban. A candidate gene analysis was also performed for pre-specified variants in ABCB1, ABCG2, CYP3A4, CYP3A5, and SULT1A1, with a subsequent analysis of all available polymorphisms within the candidate genes. Significant findings were further evaluated to assess a potential association with clinical outcome such as bleeding or thromboembolic events. No variant was consistently associated with an altered apixaban exposure on a genome-wide level. The candidate gene analyses showed a statistically significant association with a well-known variant in the drug transporter gene ABCG2 (c.421G > T, rs2231142). Patients carrying this variant had a higher exposure to apixaban [area under the curve (AUC), beta = 151 (95% CI 59-243), p = 0.001]. On average, heterozygotes displayed a 5% increase of AUC and homozygotes a 17% increase of AUC, compared with homozygotes for the wild-type allele. Bleeding or thromboembolic events were not significantly associated with ABCG2 rs2231142. This large genome-wide study demonstrates that genetic variation in the drug transporter gene ABCG2 is associated with the pharmacokinetics of apixaban. However, the influence of this finding on drug exposure was small, and further studies are needed to better understand whether it is of relevance for ischemic and bleeding events.

Genome-wide association study of liver enzyme elevation in an extended cohort of rheumatoid arthritis patients starting low-dose methotrexate.

Aim: A follow-up genome-wide association study (GWAS) in an extended cohort of rheumatoid arthritis (RA) patients starting low-dose methotrexate (MTX) treatment was performed to identify further genetic variants associated with alanine aminotransferase (ALT) elevation. Patients & methods: A GWAS was performed on 346 RA patients. Two outcomes within the first 6 months of MTX treatment were assessed: ALT >1.5-times the upper level of normal (ULN) and maximum level of ALT. Results: SPATA9 (rs72783407) was significantly associated with maximum level of ALT (p = 2.58 × 10-8) and PLCG2 (rs60427389) was tentatively associated with ALT >1.5 × ULN. Conclusion: Associations with SNPs in genes related to male fertility (SPATA9) and inflammatory processes (PLCG2) were identified.

Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes.

Angioedema is a relatively rare but potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). As with hereditary forms of angioedema (HAE), this adverse reaction is mediated by bradykinin. Research suggests that ACEi/ARB-induced angioedema has a multifactorial etiology. In addition, recent case reports suggest that some ACEi/ARB-induced angioedema patients may carry pathogenic HAE variants. The aim of the present study was to investigate the possible association between ACEi/ARB-induced angioedema and HAE genes via systematic molecular genetic screening in a large cohort of ACEi/ARB-induced angioedema cases. Targeted re-sequencing of five HAE-associated genes (SERPING1, F12, PLG, ANGPT1, and KNG1) was performed in 212 ACEi/ARB-induced angioedema patients recruited in Germany/Austria, Sweden, and Denmark, and in 352 controls from a German cohort. Among patients, none of the identified variants represented a known pathogenic variant for HAE. Moreover, no significant association with ACEi/ARB-induced angioedema was found for any of the identified common [minor allele frequency (MAF) >5%] or rare (MAF < 5%) variants. However, several non-significant trends suggestive of possible protective effects were observed. The lowest p-value for an individual variant was found in PLG (rs4252129, p.R523W, p = 0.057, p.adjust > 0.999, Fisher's exact test). Variant p.R523W was found exclusively in controls and has previously been associated with decreased levels of plasminogen, a precursor of plasmin which is part of a pathway directly involved in bradykinin production. In addition, rare, potentially functional variants (MAF < 5%, Phred-scaled combined annotation dependent depletion score >10) showed a nominally significant enrichment in controls both: 1) across all five genes; and 2) in the F12 gene alone. However, these results did not withstand correction for multiple testing. In conclusion, our results suggest that HAE-associated mutations are, at best, a rare cause of ACEi/ARB-induced angioedema. Furthermore, we were unable to identify a significant association between ACEi/ARB-induced angioedema and other variants in the investigated genes. Further studies with larger sample sizes are warranted to draw more definite conclusions concerning variants with limited effect sizes, including protective variants.

HLA variants associated with azathioprine-induced pancreatitis in patients with Crohn's disease.

The immunosuppressant drug azathioprine is associated with a 4% risk of acute pancreatitis in patients with inflammatory bowel disease (IBD). Studies have demonstrated an increased risk in carriers of HLA-DQA1*02:01 and HLA-DRB1*07:01. We investigated whether these human leukocyte antigen (HLA) types were associated with azathioprine-induced pancreatitis also in Swedish patients with IBD, and whether the type of disease affected the association. Nineteen individuals with IBD who developed acute pancreatitis after initiation of azathioprine were genotyped and compared with a population control cohort (n = 4891) and a control group matched for disease (n = 81). HLA-DQA1*02:01 and HLA-DRB1*07:01 were in full linkage disequilibrium, and were significantly associated with acute pancreatitis both when cases were compared with population controls (OR 3.97 [95% CI 1.57-9.97], p = 0.0035) and matched controls (OR 3.55 [95% CI 1.23-10.98], p = 0.0275). In a disease-specific analysis, the correlation was positive in patients with Crohn's disease versus matched controls (OR 9.27 [95% CI 1.86-46.19], p = 0.0066), but not in those with ulcerative colitis versus matched controls (OR 0.69 [95% CI 0.07-6.74], p = 0.749). In patients with Crohn's disease, we estimated the conditional risk of carriers of HLA-DQA1*02:01-HLA-DRB1*07:01 to 7.3%, and the conditional risk of a non-carrier to 2.2%. We conclude that HLA-DQA1*02:01-HLA-DRB1*07:01 is a marker for increased risk of acute pancreatitis in individuals of Swedish genetic origin, treated with azathioprine for Crohn's disease.

Genome-wide association study of liver enzyme elevation in rheumatoid arthritis patients starting methotrexate.

Aim: To identify novel genetic variants predisposing to elevation of Alanine aminotransferase (ALT) in rheumatoid arthritis (RA) patients after initiation of methotrexate (MTX) treatment. Patients & methods: We performed genome-wide association studies in 198 RA patients starting MTX. Outcomes were maximum level of ALT and ALT >1.5-times the upper level of normal within the first 6 months of treatment. Results:RAVER2 (rs72675408) was significantly associated with maximum level of ALT (p = 4.36 × 10-8). This variant is in linkage disequilibrium with rs72675451, which is associated with differential expression of JAK1 and RAVER2. Conclusion: We found an association between ALT elevation and genetic variants that may regulate the expression of JAK1 and RAVER2. JAK1 encodes a janus kinase involved in the pathogenesis of RA.

Association of Variants Near the Bradykinin Receptor B2 Gene With Angioedema in Patients Taking ACE Inhibitors.

BACKGROUND: Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. OBJECTIVES: The aim of this study was to identify genetic factors associated with ACE inhibitor-associated angioedema. METHODS: A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors ≤180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model. RESULTS: The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor-treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor-treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 × 10-8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 × 10-9). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 × 10-3). We found that carriers of the risk allele had significantly lower systolic (-0.46 mm Hg per T allele; 95% CI: -0.83 to -0.10; P = 0.013) and diastolic (-0.26 mm Hg per T allele; 95% CI: -0.46 to -0.05; P = 0.013) blood pressure. CONCLUSIONS: In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with increased risk for ACE inhibitor-related angioedema.

Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations.

Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p < 1 × 10-7) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41-6.68, p = 1.01 × 10-7) and rs4427239 (OR = 5.47, 95%CI: 2.81-10.65, p = 5.75 × 10-7), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.

High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis.

Background and Objective: Agranulocytosis is a rare and potentially life-threatening complication of metamizole (dipyrone) intake that is characterized by a loss of circulating neutrophil granulocytes. While the mechanism underlying this adverse drug reaction is not well understood, involvement of the immune system has been suggested. In addition, associations between genetic variants in the Human Leukocyte Antigen (HLA) region and agranulocytosis induced by other drugs have been reported. The aim of the present study was to assess whether genetic variants in classical HLA genes are associated with the susceptibility to metamizole-induced agranulocytosis (MIA) in a European population by targeted resequencing of eight HLA genes. Design: A case-control cohort of Swiss patients with a history of neutropenia or agranulocytosis associated with metamizole exposure (n = 53), metamizole-tolerant (n = 39) and unexposed controls (n = 161) was recruited for this study. A high-throughput resequencing (HTS) and high-resolution typing method was used to sequence and analyze eight HLA loci in a discovery subset of this cohort (n = 31 cases, n = 38 controls). Identified candidate alleles were investigated in the full Swiss cohort as well as in two independent cohorts from Germany and Spain using HLA imputation from genome-wide SNP array data. In addition, variant calling based on HTS data was performed in the discovery subset for the class I genes HLA-A, -B, and -C using the HLA-specific mapper hla-mapper. Results: Eight candidate alleles (p < 0.05) were identified in the discovery subset, of which HLA-C∗04:01 was associated with MIA in the full Swiss cohort (p < 0.01) restricted to agranulocytosis (ANC < 0.5 × 109/L) cases. However, no candidate allele showed a consistent association in the Swiss, German and Spanish cohorts. Analysis of individual sequence variants in class I genes produced consistent results with HLA typing but did not reveal additional small nucleotide variants associated with MIA. Conclusion: Our results do not support an HLA-restricted T cell-mediated immune mechanism for MIA. However, we established an efficient high-resolution (three-field) eight-locus HTS HLA resequencing method to interrogate the HLA region and demonstrated the feasibility of its application to pharmacogenetic studies.

Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker-Induced Angioedema.

Angioedema occurring in the head and neck region is a rare and sometimes life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI-induced angioedema (ACEI-AE) or ARB-induced angioedema (ARB-AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI-AE, ARB-AE, and 658 controls) was performed using exome-enriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI-AE and ARB-AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89-4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEI-AE or ARB-AE, P = 2.09 × 10-3 . A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49-3.27, P = 6.30 × 10-9 ) times the odds of having ACEI-AE or ARB-AE. The increased risk due to the common Leiden allele was confirmed in a genome-wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect-causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI-AE or ARB-AE.

Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.

Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10-5). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10-8). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05-2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema.

MTHFR, TYMS and SLCO1B1 polymorphisms and adverse liver effects of methotrexate in rheumatoid arthritis.

Aims: To investigate whether variants of MTHFR, TYMS and SLCO1B1 are associated with ALT elevation in rheumatoid arthritis patients starting methotrexate (MTX). Patients & methods: Clinical and laboratory data were collected from the start of MTX treatment. Genotyping of MTHFR, TYMS and SLCO1B1 was performed. Univariate and multiple logistic regression were used for statistical analysis. Results: 34 out of 369 patients experienced ALT >1.5 × ULN less than 6 months from start. MTHFR A1298C (rs1801131) was nominally associated with an ALT >1.5 × ULN within 6 months after the start of MTX (OR = 1.7 [95% CI: 1.04-2.9]; p = 0.03), but did not pass correction for multiple testing. A multiple model containing MTHFR 1298C and clinical factors predicted the outcome (C-statistic 0.735). TYMS and SLCO1B1 were not associated with the outcome. Conclusions: A model containing MTHFR 1298C and clinical factors might predict risk of early ALT elevation.

SWEDEGENE-a Swedish nation-wide DNA sample collection for pharmacogenomic studies of serious adverse drug reactions.

SWEDEGENE is a Swedish nation-wide sample collection established to facilitate studies of clinical and genetic risk factors for adverse drug reactions (ADRs). Most cases are recruited among patients reported to the ADR registry at the Swedish Medical Products Agency by health-care professionals. Clinical data are collected both from medical and laboratory records and through interviews using standardized questionnaires. Genome-wide scans and whole-genome sequencing are done, and association studies are conducted using mainly controls from the Swedish TwinGene biobank with data on diagnoses and prescribed drugs. SWEDEGENE was established in 2008 and currently contains DNA and information from about 2550 adults who have experienced specific ADRs, and from 580 drug exposed controls. Results from genome-wide association studies have now been published, and data from whole-genome sequencing are being analyzed. SWEDEGENE has the potential to offer a new means of developing individualized and safe drug therapy through patient pre-treatment screening.

[Bisphosphonate-associated atypical fractures of the femur: an update of the current evidence]. / Atypisk femurfraktur en allvarlig komplikation till bisfosfonater - En uppdatering av evidensläget.

Atypical fracture of the femur is a well-documented adverse reaction to antiresorptive treatment with bisphosphonates. Although there has been significant gain of knowledge during the past decade, the pathogenesis of this type of fracture is still poorly understood. We present an update on the evidence in regard to epidemiology, pathophysiology, and management of atypical fractures.

Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing.

AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM. METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance. CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions.

Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10-9 ) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10-9 ) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.

Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long-term follow-up of predictors, surveillance, and outcome in clinical practice.

AIM: To assess predictors of alanine aminotransferase (ALT) elevation in methotrexate (MTX) treated rheumatoid arthritis (RA) patients, and to describe the monitoring of liver enzymes, including handling and outcome of elevated ALT. METHODS: All RA patients starting MTX in January, 2005 to April, 2013 at a rheumatology clinic, (Uppsala University Hospital, Sweden) were identified from electronic medical records. Clinical and laboratory data were obtained from medical records, supplemented by telephone interviews. Predictors for ALT >1.5× over the upper limit of normal (ULN) were identified by multiple regression analysis. RESULTS: The study comprised 213 RA patients starting MTX. During a mean follow-up of 4.3 years, 6288 ALT tests were performed; 7% of tests with ALT were >ULN. ALT >1.5× ULN was observed in 44 (21%) patients and the strongest predictor was a pre-treatment elevation of ALT (adjusted odds ratio = 6.8, 95% CI 2.2-20.5). Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions, for example MTX dose reduction (67% vs 73%, P = 0.43). Seven patients (3%) permanently stopped MTX due to ALT elevation, and two were eventually diagnosed with non-alcoholic fatty liver disease. No patient developed hepatic failure. CONCLUSION: Only a small number of ALT tests performed during MTX therapy in RA capture an elevation. A pre-treatment elevation of ALT was the strongest predictor for early and recurrent ALT elevations during therapy. This study supports a more individualized approach to monitoring and handling of ALT elevations during MTX therapy in RA than recommended in current guidelines.