Publications by authors named "Niclas Eriksson"

56 Publications

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

Pharmacogenomics 2021 Sep 15. Epub 2021 Sep 15.

Department of Medical Sciences, Clinical Pharmacogenomics & Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden.

To identify novel genetic variants predisposing to elevation of Alanine aminotransferase (ALT) in rheumatoid arthritis (RA) patients after initiation of methotrexate (MTX) treatment. 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. (rs72675408) was significantly associated with maximum level of ALT (p = 4.36 × 10). This variant is in linkage disequilibrium with rs72675451, which is associated with differential expression of and . We found an association between ALT elevation and genetic variants that may regulate the expression of and . encodes a janus kinase involved in the pathogenesis of RA.
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http://dx.doi.org/10.2217/pgs-2021-0064DOI Listing
September 2021

Factor V Leiden and the Risk of Bleeding in Patients With Acute Coronary Syndromes Treated With Antiplatelet Therapy: Pooled Analysis of 3 Randomized Clinical Trials.

J Am Heart Assoc 2021 Sep 28;10(17):e021115. Epub 2021 Aug 28.

Department of Cardiology St. Antonius Hospital Nieuwegein the Netherlands.

Background Whether factor V Leiden is associated with lower bleeding risk in patients with acute coronary syndromes using (dual) antiplatelet therapy has yet to be investigated. Methods and Results We pooled data from 3 randomized clinical trials, conducted in patients with acute coronary syndromes, with adjudicated bleeding outcomes. Cox regression models were used to obtain overall and cause-specific hazard ratios (HRs) to account for competing risk of atherothrombotic outcomes (ie, composite of ischemic stroke, myocardial infarction, and cardiovascular death) in each study. Estimates from the individual studies were pooled using fixed effect meta-analysis. The 3 studies combined included 17 623 patients of whom 969 (5.5%) were either heterozygous or homozygous (n=23) carriers of factor V Leiden. During 1 year of follow-up, a total of 1289 (7.3%) patients developed major (n=559) or minor bleeding. Factor V Leiden was associated with a lower risk of combined major and minor bleeding (adjusted cause-specific HR, 0.75; 95% CI, 0.56-1.00; =0.046; I=0%) but a comparable risk of major bleeding (adjusted cause-specific HR, 0.93; 95% CI, 0.62-1.39; =0.73; I=0%). Adjusted pooled cause-specific HRs for the association of factor V Leiden with atherothrombotic events alone and in combination with bleeding events were 0.75 (95% CI, 0.55-1.02; =0.06; I=0%) and 0.75 (95% CI, 0.61-0.92; =0.007; I=0%), respectively. Conclusions Given that the lower risk of bleeding conferred by factor V Leiden was not counterbalanced by a higher risk of atherothrombotic events, these findings warrant future assessment for personalized medicine such as selecting patients for extended or intensive antiplatelet therapy.
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http://dx.doi.org/10.1161/JAHA.120.021115DOI Listing
September 2021

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

J Am Coll Cardiol 2021 Aug;78(7):696-709

Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

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. 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). 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). 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 B gene were associated with increased risk for ACE inhibitor-related angioedema.
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http://dx.doi.org/10.1016/j.jacc.2021.05.054DOI Listing
August 2021

Osteoprotegerin predicts cardiovascular events in patients treated with hemodialysis.

Nephrol Dial Transplant 2021 Jun 4. Epub 2021 Jun 4.

Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Background: Disturbances in bone mineral metabolism are associated with increased mortality and cardiovascular events (CVEs). However, the association between bone-associated protein biomarkers, mortality, and CVEs independent of cytokine activation remains unknown. This study aimed to investigate bone-associated protein biomarkers, and the association with inflammatory cytokines, and cardiovascular outcomes.

Methods: This prospective study enrolled hemodialysis (HD) patients in Denmark between December 2010 and March 2011. Using a proximity extension proteomics assay, nine bone-associated proteins were examined: cathepsin D (CTSD), cathepsin L1 (CTSL1), dickkopf-related protein 1 (Dkk-1), fibroblast growth factor 23 (FGF-23), leptin, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-Β ligand (RANKL), TNF-related apoptosis-inducing ligand (TRAIL), and TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2). The importance of the bone-associated protein markers was evaluated by a random forest algorithm (RF). The association between bone-associated proteins with all-cause death, cardiovascular death, and CVEs was analyzed in multivariable Cox models adjusted for age, gender, comorbidities, laboratory data, and dialysis duration.

Results: We enrolled 331 patients (63.7% men; mean [SD] age, 65 [14.6] years) in a prospective cohort study with five years follow-up. When adjusting for confounders, CTSL1 remained associated with all-cause death, and four biomarkers were associated with CVE. However, the association between bone markers and the outcomes was attenuated after adjusting for inflammatory proteins, and just OPG remained associated with CVE in the adjusted model. Evaluating the importance of bone markers by RF, OPG was the most important marker related to CVEs. OPG also improved the prediction of CVE when added clinical information alone in integrated discrimination improvement and net reclassification improvement analyses.

Discussion: OPG, a well-known bone biomarker, was associated with CVEs independent of cytokine activity. In contrast, the association between CVEs and the remaining three bone-associated proteins (TRAIL-R2, CTSD, and CTSL1) was affected by cytokine inflammation activity.
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http://dx.doi.org/10.1093/ndt/gfab192DOI Listing
June 2021

Factor V Leiden Does Not Modify the Phenotype of Acute Coronary Syndrome or the Extent of Myocardial Necrosis.

J Am Heart Assoc 2021 Jun 17;10(11):e020025. Epub 2021 May 17.

Department of Cardiology St. Antonius Hospital Nieuwegein the Netherlands.

Background The prothrombotic defect factor V Leiden (FVL) may confer higher risk of ST-segment-elevation myocardial infarction (STEMI), compared with non-ST-segment-elevation acute coronary syndrome, and may be associated with more myocardial necrosis caused by higher thrombotic burden. Methods and Results Patients without history of cardiovascular disease were selected from 2 clinical trials conducted in patients with acute coronary syndrome. FVL was defined as G-to-A substitution at nucleotide 1691 in the factor V (factor V R506Q) gene. Odds ratios were calculated for the association of FVL with STEMI adjusted for age and sex in the overall population and in the subgroups including sex, age (≥70 versus <70 years), and traditional cardiovascular risk factors. The peak biomarker levels (ie, creatine kinase-myocardial band and high-sensitivity troponin I or T) after STEMI were contrasted between FVL carriers and noncarriers. Because of differences in troponin assays, peak high-sensitivity troponin levels were converted to a ratio scale. The prevalence of FVL mutation was comparable in patients with STEMI (6.0%) and non-ST-segment-elevation acute coronary syndrome (5.8%). The corresponding sex- and age-adjusted odds ratio was 1.06 (95% CI, 0.86-1.30; =0.59) for the association of FVL with STEMI. Subgroup analysis did not show any differences. In patients with STEMI, neither the median peak creatine kinase-myocardial band nor the peak high-sensitivity troponin ratio showed any differences between wild-type and FVL carriers ( for difference: creatine kinase-myocardial band=0.33; high sensitivity troponin ratio=0.54). Conclusions In a general population with acute coronary syndrome, FVL did not discriminate between a STEMI or non-ST-segment-elevation acute coronary syndrome presentation and was unrelated to peak cardiac necrosis markers in patients with STEMI. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00391872 and NCT01761786.
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http://dx.doi.org/10.1161/JAHA.120.020025DOI Listing
June 2021

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.

medRxiv 2021 Apr 7. Epub 2021 Apr 7.

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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http://dx.doi.org/10.1101/2021.04.01.21254789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043484PMC
April 2021

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

Eur Heart J 2021 05;42(18):1742-1756

Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, 1462 Clifton Road NE, Atlanta, GA 30322, USA.

Aims: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.

Methods And Results: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality.

Conclusion: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.
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http://dx.doi.org/10.1093/eurheartj/ehab107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244638PMC
May 2021

Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study.

PLoS Med 2021 01 13;18(1):e1003513. Epub 2021 Jan 13.

Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden.

Background: Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD.

Methods And Findings: The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events.

Conclusions: Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD.

Trial Registration: ClinicalTrials.gov NCT00799903.
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http://dx.doi.org/10.1371/journal.pmed.1003513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817029PMC
January 2021

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

Genes (Basel) 2020 10 29;11(11). Epub 2020 Oct 29.

Department of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland.

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 ( < 1 × 10) 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, = 1.01 × 10) and rs4427239 (OR = 5.47, 95%CI: 2.81-10.65, = 5.75 × 10), of which the latter is located in the 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.
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http://dx.doi.org/10.3390/genes11111275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716224PMC
October 2020

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.

Nat Metab 2020 10 16;2(10):1135-1148. Epub 2020 Oct 16.

SCALLOP consortium.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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http://dx.doi.org/10.1038/s42255-020-00287-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611474PMC
October 2020

Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation.

Eur Heart J 2020 11;41(41):4037-4046

Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.

Aims: The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability.

Methods And Results: Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level.

Conclusions: Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.
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http://dx.doi.org/10.1093/eurheartj/ehaa697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543499PMC
November 2020

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data.

Circulation 2020 08 13;142(6):546-555. Epub 2020 Jul 13.

Department of Cardiology, Division Heart and Lungs (V.T., A.F.S., J.v.S., A.O.K., F.W.A.), UMC Utrecht, Utrecht University, the Netherlands.

Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD.

Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality.

Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; =28%; -heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity.

Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.045526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493828PMC
August 2020

Next-Generation Sequencing of CYP2C19 in Stent Thrombosis: Implications for Clopidogrel Pharmacogenomics.

Cardiovasc Drugs Ther 2021 06;35(3):549-559

Department of Cardiovascular Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.

Purpose: Describe CYP2C19 sequencing results in the largest series of clopidogrel-treated cases with stent thrombosis (ST), the closest clinical phenotype to clopidogrel resistance. Evaluate the impact of CYP2C19 genetic variation detected by next-generation sequencing (NGS) with comprehensive annotation and functional studies.

Methods: Seventy ST cases on clopidogrel identified from the PLATO trial (n = 58) and Mayo Clinic biorepository (n = 12) were matched 1:1 with controls for age, race, sex, diabetes mellitus, presentation, and stent type. NGS was performed to cover the entire CYP2C19 gene. Assessment of exonic variants involved measuring in vitro protein expression levels. Intronic variants were evaluated for potential splicing motif variations.

Results: Poor metabolizers (n = 4) and rare CYP2C19*8, CYP2C19*15, and CYP2C19*11 alleles were identified only in ST cases. CYP2C19*17 heterozygote carriers were observed more frequently in cases (n = 29) than controls (n = 18). Functional studies of CYP2C19 exonic variants (n = 11) revealed 3 cases and only 1 control carrying a deleterious variant as determined by in vitro protein expression studies. Greater intronic variation unique to ST cases (n = 169) compared with controls (n = 84) was observed with predictions revealing 13 allele candidates that may lead to a potential disruption of splicing and a loss-of-function effect of CYP2C19 in ST cases.

Conclusion: NGS detected CYP2C19 poor metabolizers and paradoxically greater number of so-called rapid metabolizers in ST cases. Rare deleterious exonic variation occurs in 4%, and potentially disruptive intronic alleles occur in 16% of ST cases. Additional studies are required to evaluate the role of these variants in platelet aggregation and clopidogrel metabolism.
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http://dx.doi.org/10.1007/s10557-020-06988-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779664PMC
June 2021

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

Clin Pharmacol Ther 2020 12 18;108(6):1195-1202. Epub 2020 Jul 18.

Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.

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 . 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 ) 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.
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http://dx.doi.org/10.1002/cpt.1927DOI Listing
December 2020

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

Pharmacogenomics J 2020 12 21;20(6):770-783. Epub 2020 Feb 21.

Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

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). 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). 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.
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http://dx.doi.org/10.1038/s41397-020-0165-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674154PMC
December 2020

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

Pharmacogenomics 2020 04 6;21(5):337-346. Epub 2020 Feb 6.

Department of Medical Sciences, Clinical Pharmacology & Science for Life Laboratory, Uppsala University, Sweden.

To investigate whether variants of , and are associated with ALT elevation in rheumatoid arthritis patients starting methotrexate (MTX). Clinical and laboratory data were collected from the start of MTX treatment. Genotyping of , and was performed. Univariate and multiple logistic regression were used for statistical analysis. 34 out of 369 patients experienced ALT >1.5 × ULN less than 6 months from start. 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 1298C and clinical factors predicted the outcome (C-statistic 0.735). and were not associated with the outcome. A model containing 1298C and clinical factors might predict risk of early ALT elevation.
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http://dx.doi.org/10.2217/pgs-2019-0186DOI Listing
April 2020

No generally increased risk of cancer after total hip arthroplasty performed due to osteoarthritis.

Int J Cancer 2020 07 5;147(1):76-83. Epub 2019 Nov 5.

Section of Orthopaedics, Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden.

Previous studies on the risk of cancer after total hip arthroplasty (THA) contradict each other, and many are hampered by small cohort sizes, residual confounding, short observation times or a mix of indications underlying the THA procedure. We evaluated the risk of cancer after total hip arthroplasty due to osteoarthritis in a nationwide cohort by comparing cancer incidences in individuals exposed to total hip arthroplasty due to osteoarthritis and in unexposed, sex-, age- and residence matched individuals. To address some previous studies' shortcomings, information on comorbidity and socioeconomic background were obtained and adjusted for. We included 126,276 patients exposed to a cemented THA between 1992 and 2012, and 555,757 unexposed individuals. Follow-up started on the day of surgery for exposed individuals and respective date for matched, unexposed individuals, and ended on the day of death, emigration, censuring or December 31st, 2012, whichever came first. The Swedish Hip Arthroplasty Registry (SHAR), the Swedish Cancer Registry, the Swedish National Patient Registry and Statistics Sweden were accessed to obtain information on procedural details of the THA, cancer diagnoses, comorbidities, and socioeconomic background. The primary outcome measure was the occurrence of any cancer after the index date. Exposed individuals had a slightly lower adjusted risk of developing any cancer than unexposed individuals (hazard ratio [HR] 0.97; CI 0.95-0.99). The only cancer with a statistically significant risk increase in exposed individuals was skin melanoma (HR 1.15; CI 1.05-1.24). We attained similar risk estimates in analyses stratified by sex, in individuals with minimum 5 years of follow-up, in an analysis including individuals with a history of previous cancer, and in patients with cementless THA. In this study on a large and well-defined population with long follow-up, we found no increased overall risk of cancer after THA. These reassuring findings could be included in the guidelines on preoperative information given to THA patients.
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http://dx.doi.org/10.1002/ijc.32711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317978PMC
July 2020

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

Int J Rheum Dis 2019 Jul 22;22(7):1226-1232. Epub 2019 Apr 22.

Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden.

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.
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http://dx.doi.org/10.1111/1756-185X.13576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767545PMC
July 2019

A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture.

Calcif Tissue Int 2019 07 20;105(1):51-67. Epub 2019 Apr 20.

Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

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 < 5 × 10 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 < 5.7 × 10). 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.
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http://dx.doi.org/10.1007/s00223-019-00546-9DOI Listing
July 2019

Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events.

Circ Genom Precis Med 2019 04 21;12(4):e002471. Epub 2019 Mar 21.

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital (M.H.).

Background: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.

Methods: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.

Results: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).

Conclusions: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
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http://dx.doi.org/10.1161/CIRCGEN.119.002471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625876PMC
April 2019

Subsequent Event Risk in Individuals With Established Coronary Heart Disease.

Circ Genom Precis Med 2019 04 21;12(4):e002470. Epub 2019 Mar 21.

Department of Pharmacotherapy and Translational Research, Centre for Pharmacogenomics (Y.G., R.M.C.-D., J.A.J.), University of Florida, Gainesville.

Background: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.

Methods: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.

Results: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.

Conclusions: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
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http://dx.doi.org/10.1161/CIRCGEN.119.002470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629546PMC
April 2019

Association of the coronary artery disease risk gene GUCY1A3 with ischaemic events after coronary intervention.

Cardiovasc Res 2019 08;115(10):1512-1518

Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.

Aim: A common genetic variant at the GUCY1A3 coronary artery disease locus has been shown to influence platelet aggregation. The risk of ischaemic events including stent thrombosis varies with the efficacy of aspirin to inhibit platelet reactivity. This study sought to investigate whether homozygous GUCY1A3 (rs7692387) risk allele carriers display higher on-aspirin platelet reactivity and risk of ischaemic events early after coronary intervention.

Methods And Results: The association of GUCY1A3 genotype and on-aspirin platelet reactivity was analysed in the genetics substudy of the ISAR-ASPI registry (n = 1678) using impedance aggregometry. The clinical outcome cardiovascular death or stent thrombosis within 30 days after stenting was investigated in a meta-analysis of substudies of the ISAR-ASPI registry, the PLATO trial (n = 3236), and the Utrecht Coronary Biobank (n = 1003) comprising a total 5917 patients. Homozygous GUCY1A3 risk allele carriers (GG) displayed increased on-aspirin platelet reactivity compared with non-risk allele (AA/AG) carriers [150 (interquartile range 91-209) vs. 134 (85-194) AU⋅min, P < 0.01]. More homozygous risk allele carriers, compared with non-risk allele carriers, were assigned to the high-risk group for ischaemic events (>203 AU⋅min; 29.5 vs. 24.2%, P = 0.02). Homozygous risk allele carriers were also at higher risk for cardiovascular death or stent thrombosis (hazard ratio 1.70, 95% confidence interval 1.08-2.68; P = 0.02). Bleeding risk was not altered.

Conclusion: We conclude that homozygous GUCY1A3 risk allele carriers are at increased risk of cardiovascular death or stent thrombosis within 30 days after coronary stenting, likely due to higher on-aspirin platelet reactivity. Whether GUCY1A3 genotype helps to tailor antiplatelet treatment remains to be investigated.
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http://dx.doi.org/10.1093/cvr/cvz015DOI Listing
August 2019

Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival.

EBioMedicine 2019 Feb 30;40:595-604. Epub 2019 Jan 30.

Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

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, 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. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10, 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.
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http://dx.doi.org/10.1016/j.ebiom.2019.01.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413474PMC
February 2019

Equilibrative nucleoside transporter 1 gene polymorphisms and clinical outcomes following acute coronary syndromes: findings from the PLATelet inhibition and patient Outcomes (PLATO) study.

Platelets 2019 31;30(5):579-588. Epub 2018 May 31.

a Department of Infection, Immunity and Cardiovascular Disease , University of Sheffield , Sheffield , United Kingdom.

In the PLATelet inhibition and patient Outcomes (PLATO) study, the P2Y inhibitors ticagrelor and clopidogrel were compared in the treatment of acute coronary syndromes (ACS). Ticagrelor was shown to reduce occurrence of the primary end point - a composite of death from vascular causes, myocardial infarction, or stroke - compared to clopidogrel. Ticagrelor's pleiotropic effects on reuptake of adenosine via inhibition of equilibrative nucleoside transporter 1 (ENT1) have been hypothesized to contribute to this. Several polymorphisms of ENT1 are known to exist. We explored the interaction between ENT1 polymorphisms and clinical outcomes in ACS patients participating in the PLATO genetic substudy. Using genotyping data obtained in a genome-wide association study, the gene region encoding ENT1 was assessed and 94 polymorphisms were identified. After quality control filtering, data from 9943 participants were included. Subjects were divided into discovery (phase 1, n = 3970) and replication (phase 2, n = 5973) cohorts. Cox-regression analysis of the relationship between variants and seven efficacy and safety outcomes was performed in discovery, replication, and combined cohorts. Treatment-marker interactions were also determined. Although 35 variants were found with associations to the investigated outcomes reaching p < 0.05 in the discovery cohort, only one of these was replicated in phase 2 of the analysis and also reached the predetermined level of statistical significance in the combined data, taking into account the number of tests performed: the rare polymorphism rs141034817, with a frequency of 0.2%, was significantly associated with bleeding. Thirty-three treatment-marker interactions were found with a significance level of p < 0.05 in phase 1, but none was replicated in phase 2. We found no significant interaction between ENT1 genotype and clinical outcomes in ACS patients treated with ticagrelor or clopidogrel, apart from the association between a rare polymorphism and bleeding that requires further study. If ticagrelor's pleiotropic effects on adenosine uptake are clinically relevant, these do not appear to be significantly affected by variation in the ENT1 gene.
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http://dx.doi.org/10.1080/09537104.2018.1478404DOI Listing
November 2019

Sulfasalazine-Induced Agranulocytosis Is Associated With the Human Leukocyte Antigen Locus.

Clin Pharmacol Ther 2018 05 28;103(5):843-853. Epub 2017 Sep 28.

Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

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 ). 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.
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http://dx.doi.org/10.1002/cpt.805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947520PMC
May 2018

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.

Lancet Diabetes Endocrinol 2017 07 26;5(7):534-543. Epub 2017 May 26.

Heart and Lung Centre, Helsinki University Hospital, Helsinki, Finland.

Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.

Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.

Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies.

Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.

Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.
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http://dx.doi.org/10.1016/S2213-8587(17)30096-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651679PMC
July 2017

Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough: a genome-wide association study in a Swedish population.

Pharmacogenomics 2017 Feb 13;18(3):201-213. Epub 2017 Jan 13.

Department of Medical Sciences, Clinical Pharmacology & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Aim: We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes identified 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 × 10.

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 × 10). 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.
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http://dx.doi.org/10.2217/pgs-2016-0184DOI Listing
February 2017

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals.

Nat Genet 2016 10 12;48(10):1171-1184. Epub 2016 Sep 12.

Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.
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http://dx.doi.org/10.1038/ng.3667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042863PMC
October 2016

Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range: a RE-LY genomics substudy.

Pharmacogenomics 2016 08 4;17(13):1425-39. Epub 2016 Aug 4.

Department Medical Sciences & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Aims: We investigated associations between genetic variation in candidate genes and on a genome-wide scale with warfarin maintenance dose, time in therapeutic range (TTR), and risk of major bleeding.

Materials & Methods: In total, 982 warfarin-treated patients from the RE-LY trial were studied.

Results: After adjusting for SNPs in VKORC1 and CYP2C9, SNPs in DDHD1 (rs17126068) and NEDD4 (rs2288344) were associated with dose. Adding these SNPs and CYP4F2 (rs2108622) to a base model increased R(2) by 2.9%. An SNP in ASPH (rs4379440) was associated with TTR (-6.8% per minor allele). VKORC1 was associated with time less than INR 2.0. VKORC1 and CYP2C9 were associated with time more than INR 3.0, but not with major bleeding.

Conclusions: We identified two novel genes associated with warfarin maintenance dose and one gene associated with TTR. These genes need to be replicated in an independent cohort.
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http://dx.doi.org/10.2217/pgs-2016-0061DOI Listing
August 2016

Genetic variants associated with antithyroid drug-induced agranulocytosis: a genome-wide association study in a European population.

Lancet Diabetes Endocrinol 2016 06 3;4(6):507-16. Epub 2016 May 3.

Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. Electronic address:

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 × 10(9)/L [≤500/μL]) 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 × 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 × 10(-11)) for HLA-B*27:05 and 3·57 (2·61-4·90, p=2·32 × 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 × 10(-9)) and 16·91 (3·44-83·17) when compared with a small group of hyperthyroid controls (p=5·04 × 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 × 10(-11)) and rs199564443 (17·42, 7·38-41·12, p=7·04 × 10(-11)), which were independent of HLA-B*27:05, and rs1071816 (5·27, 3·06-9·10, p=2·35 × 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.

Funding: Swedish Research Council, Swedish Heart and Lung Foundation, Clinical Research Support at Uppsala University, German Federal Institute for Drugs and Medical Devices, Carlos III Spanish Health Institute, European Regional Development Fund, UK National Institute for Health Research, The Selander's Foundation, Thuréus Foundation, European Commission, and Science for Life Laboratory.
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http://dx.doi.org/10.1016/S2213-8587(16)00113-3DOI Listing
June 2016
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