Marieke J H Coenen

Radboud University Nijmegen, Nymegen, Gelderland, Netherlands

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Publications (111)853.77 Total impact

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    [Show abstract] [Hide abstract] ABSTRACT: Introduction: Adenosine exerts anti-inflammatory and tissue-protective effects during systemic inflammation. While the tissue-protective effects might limit organ damage, its anti-inflammatory properties may induce immunoparalysis and impede bacterial clearance. The common 34C<T loss-of-function variant of AMPD1 (rs17602729) is associated with increased adenosine formation, but effects on immune function and outcome in sepsis patients are unknown. Methods: The effects of the presence of the 34C<T variant on sepsis susceptibility, immune function, multi-organ dysfunction, and mortality in septic patients were studied. Patients suffering from community acquired pneumonia (CAP, initial cohort n=285; replication cohort n=212) and ventilator-associated pneumonia (VAP, n=117; n=33) and control patients without infection (n=101) were enrolled. Genetic distributions of the AMPD1 SNP were CC 76%, CT 22%, and TT 2% in the initial cohort and CC 80%, CT 18%, and TT 2% in the replication cohort. Results: The occurrence of septic CAP, but not septic VAP, was increased for the CT versus CC genotype (OR (95% CI) 2.0 (1.1-3.7); P=0.02) in the initial cohort. The increased risk for the CT versus CC genotype was also observed in the replication cohort but did not reach statistical significance there (P=0.38), resulting in an OR of the total group of 1.7 (95% CI 1.0-3.1), P=0.07. In septic patients carrying the CT genotype, the ex vivo production of TNF-a by LPS-stimulated monocytes was attenuated (P=0.005), indicative of a more pronounced immunoparalytic state in these patients. Conclusions: Presence of the AMPD1 34C<T variant is associated with higher infection susceptibility to CAP, but not to VAP. More pronounced immunoparalysis in these patients mediated by the anti-inflammatory effects of adenosine may account for this observation.
    Full-text · Article · Dec 2015 · Shock
  • No preview · Article · Nov 2015 · Pediatric Blood & Cancer
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    [Show abstract] [Hide abstract] ABSTRACT: Purpose: Overall survival in patients with osteosarcoma is only 60%. Poor response to chemotherapy is the dominant risk factor for poor survival. Pharmacogenetic research can offer possibilities to optimize treatment and improve outcome. We applied a pathway-based approach to evaluate the cumulative effect of genes involved in the metabolism of cisplatin and doxorubicin in relationship to clinical outcome. Experimental design: We included 126 patients with osteosarcoma. To comprehensively assess common genetic variation in the 54 genes selected, linkage disequilibrium (LD; r(2) = 0.8)-based tag-single nucleotide polymorphisms (SNP) strategy was used. A final set of 384 SNPs was typed using Illumina Beadarray platform. SNPs significantly associated with 5-year progression-free survival (PFS) were replicated in another 64 patients with osteosarcoma. Results: We identified five variants in FasL, MSH2, ABCC5, CASP3, and CYP3A4 that were associated with 5-year PFS. Risk stratification based on the combined effects of the risk alleles showed a significant improvement of 5-year PFS. Patients that carried no or only one risk allele had a 5-year PFS of 100% compared with a 5-year PFS of 84.4% for carriers of two or three risk alleles, 66.7% PFS if a patient carried four to five alleles, and a 5-year PFS of 41.8% for patients with >5 risk alleles (P < 0.001). Conclusions: We identified several genes that showed association with PFS in patients with osteosarcoma. These pharmacogenetic risk factors might be useful to predict treatment outcome and to stratify patients immediately after diagnosis and offer the possibility to improve treatment and outcome. Clin Cancer Res; 21(15); 3436-41. ©2015 AACR.
    Full-text · Article · Aug 2015 · Clinical Cancer Research
  • [Show abstract] [Hide abstract] ABSTRACT: During coronary artery bypass graft (CABG) surgery, ischaemia and reperfusion damage myocardial tissue, and increased postoperative plasma troponin concentration is associated with a worse outcome. We investigated whether metformin pretreatment limits cardiac injury, assessed by troponin concentrations, during CABG surgery in patients without diabetes. We did a placebo-controlled, double-blind, single-centre study in an academic hospital in Nijmegen (Netherlands) in adult patients without diabetes undergoing an elective on-pump CABG procedure. We randomly assigned patients (1:1) in blocks of ten via a computer-generated randomisation sequence to either metformin hydrochloride (500 mg three times per day) or placebo (three times per day) for 3 days before surgery. The last dose was given roughly 3 h before surgery. Patients, investigators, trial staff, and the statistician were all masked to treatment allocation. The primary endpoint was the plasma concentration of high-sensitive troponin I at 6, 12, and 24 h postreperfusion after surgery, analysed in the per-protocol population with a mixed-model analysis using all these timepoints. Secondary endpoints included the occurrence of clinically relevant arrhythmias within 24 hours after reperfusion, the need for inotropic support, time to detubation, duration of stay in the intensive-care unit, and postoperative use of insulin. This study is registered with, number NCT01438723. Between Nov 8, 2011, and Nov 22, 2013, we randomly assigned 111 patients to treatment (57 to metformin and 54 to placebo). Five patients dropped out from the metformin group, and six from the placebo group. 52 patients in the metformin group and 48 patients in the placebo group were included in the per-protocol analysis. Geometric mean high-sensitivity troponin I increased from 0 μg/L to 3·67 μg/L (95% CI 3·06-4·41) with metformin and to 3·32 μg/L (2·75-4·01) with placebo at 6 h after reperfusion; 2·84 μg/L (2·37-3·41) and 2·45 μg/L (2·02-2·96), respectively, at 12 h; and to 1·77 μg/L (1·47-2·12) and 1·60 μg/L (1·32-1·94) at 24 h. The concentrations did not differ significantly between the groups (difference 12·3% for all timepoints [95% CI -12·4 to 44·1] p=0·35). Occurrence of arrhythmias did not differ between groups (three [5·8%] of 52 patients who received metformin vs three [6·3%] of 48 patients who received placebo; p=1·00). There was no difference between groups in the need for inotropic support, time to detubation, duration of stay in the intensive-care unit, or postoperative use of insulin. No patients died within 30 days after surgery. Occurrence of gastrointestinal discomfort (mostly diarrhoea) was significantly higher with metformin than with placebo (11 [21·2%] of 52 vs two [4·2%] of 48 patients; p=0·01). Short-term metformin pretreatment, although safe, does not seem to be an effective strategy to reduce periprocedural myocardial injury in patients without diabetes undergoing CABG surgery. Netherlands Organisation for Health Research and Development and Netherlands Heart Foundation. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Jul 2015
  • [Show abstract] [Hide abstract] ABSTRACT: More than 20% of patients with inflammatory bowel disease (IBD) discontinue thiopurine therapy due to severe adverse drug reactions (ADRs); leucopenia is one of the most serious ADRs. Variants in the gene encoding thiopurine S-methyltransferase (TPMT) alter its enzymatic activity, resulting in higher levels of thiopurine metabolites, which can cause leucopenia. We performed a prospective study to determine whether genotype analysis of TPMT before thiopurine treatment, and dose selection based on the results, affects outcomes of patients with IBD. In a study performed at 30 Dutch hospitals, patients were randomly assigned to groups that received standard treatment (control) or pre-treatment screening (intervention) for 3 common variants of TPMT (TPMT*2, *3A, and *3C). Patients in the intervention group found to be heterozygous carriers of a variant received 50% of the standard dose of thiopurine (azathioprine or 6-mercaptopurine), and those homozygous for a variant received 0%-10% of the standard dose. We compared, in an intention-to-treat analysis, outcomes of the intervention (n=405) and control groups (n=378) after 20 weeks of treatment. Primary outcomes were occurrence of hematologic ADRs (leukocyte count <3.0*109/L or reduced platelet count <100*109/L) and disease activity (based on the Harvey-Bradshaw Index for Crohn's disease [n=356] or partial-Mayo score for ulcerative colitis [n=253]). Similar proportions of patients in the intervention and control groups developed a hematologic ADR (7.4% vs 7.9%; relative risk=0.93; 95% confidence interval, 0.57-1.52) in the 20 weeks of follow-up; the groups also had similar mean levels of disease activity (P=0.18 for Crohn's disease and P=0.14 for ulcerative colitis). However, a significantly smaller proportion of carriers of the TPMT variants in the intervention group (2.6%) developed hematologic ADRs compared with those in the control group (22.9%) (relative risk, 0.11; 95% confidence interval, 0.01-0.85). Screening for variants in TPMT did not reduce the proportions of patients with hematological ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. number: NCT00521950. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · Gastroenterology
  • No preview · Conference Paper · May 2015
  • No preview · Conference Paper · May 2015
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    [Show abstract] [Hide abstract] ABSTRACT: Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three pro-tein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3×10-21), A928V (rs35018800, OR = 0.53, P = 1.2×10-9), and I684S (rs12720356, OR = 0.86, P = 4.6×10-7). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6×10-18 ), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; Pomnibus = 0.005). Finally, in a phenomewide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases.
    Full-text · Article · Apr 2015 · PLoS ONE
  • No preview · Article · Apr 2015 · Gastroenterology
  • [Show abstract] [Hide abstract] ABSTRACT: Dipyridamole reduces reperfusion-injury in preclinical trials and may be beneficial in patients undergoing coronary angioplasty, but its effect in patients undergoing coronary artery bypass grafting (CABG) is unknown. We hypothesized that dipyridamole limits myocardial reperfusion-injury in patients undergoing CABG. Double-blind trial randomizing between pretreatment with dipyridamole or placebo. 94 patients undergoing elective on-pump CABG were recruited between February 2010 and June 2012. Primary endpoint: plasma high-sensitive (hs-) troponin-I at 6, 12 and 24 hours after reperfusion. Secondary endpoints: occurrence of bleeding, arrhythmias, need for inotropic support and intensive care unit length of stay. Finally, 79 patients (33 dipyridamole) were included in the per-protocol analysis. Dipyridamole did not significantly affect post-operative hs-troponin-I (change in plasma hs-troponin I -3% (95% CI from -23% to 36%); p >0.1). Secondary endpoints did not differ between groups. Dipyridamole prior to CABG does not significantly reduce post-operative hs-troponin release. This article is protected by copyright. All rights reserved. © 2015 American Society for Clinical Pharmacology and Therapeutics.
    No preview · Article · Mar 2015 · Clinical Pharmacology &#38 Therapeutics
  • M.M. Hagleitner · M.J.H. Coenen · D.M.W.M. Te Loo
    No preview · Article · Mar 2015
  • [Show abstract] [Hide abstract] ABSTRACT: The Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array covers 1936 markers in 231 genes involved in drug metabolism and transport. Blood- and saliva-derived DNA works well on the DMET array, but the utility of DNA from FFPE tissue has not been reported for this array. As the ability to use DNA from FFPE tissue on the array could open the potential for large retrospective sample collections, we examined the performance and reliability of FFPE-derived DNA on the DMET Plus array. Germline DNA isolated from archived normal FFPE tissue blocks stored for 3 to 19 years and matched blood or saliva from 16 patients with osteosarcoma were genotyped on the DMET Plus array. Concordance was assessed by calculating agreement and the κ-statistic. We observed high call rates for both the blood- or saliva-derived DNA samples (99.4%) and the FFPE-derived DNA samples (98.9%). Moreover, the concordance among the 16 blood- or saliva-derived DNA and FFPE DNA pairs was high (97.4%, κ = 0.915). This is the first study showing that DNA from normal FFPE tissue provides accurate and reliable genotypes on the DMET Plus array compared with blood- or saliva-derived DNA. This finding provides an opportunity for pharmacogenetic studies in diseases with high mortality rates and prevents a bias in studies where otherwise only alive patients can be included. Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Jan 2015 · Journal of Molecular Diagnostics
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    [Show abstract] [Hide abstract] ABSTRACT: Treatment with cisplatin-containing chemotherapy regimens causes hearing loss in 40-60% of cancer patients. It has been suggested that genetic variants in the genes encoding thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) can predict the development of cisplatin-induced ototoxicity and may explain interindividual variability in sensitivity to cisplatin-induced hearing loss. Two recently published studies however, sought to validate these findings and showed inconsistent results. The aim of this study was to evaluate the role of polymorphisms in the TPMT and COMT genes in cisplatin-induced ototoxicity. Therefore we investigated two independent cohorts of 110 Dutch and 38 Spanish patients with osteosarcoma and performed a meta-analysis including all previously published studies resulting in a total population of 664 patients with cancer. With this largest meta-analysis performed to date, we show that the influence of TPMT and COMT on the development of cisplatin-induced hearing loss may be less important than previously suggested.
    Full-text · Article · Dec 2014 · PLoS ONE
  • [Show abstract] [Hide abstract] ABSTRACT: Objectives Pharmacogenetic studies of tumour necrosis factor inhibitors (TNFi) response in patients with rheumatoid arthritis (RA) have largely relied on the changes in complex disease scores, such as disease activity score 28 (DAS28), as a measure of treatment response. It is expected that genetic architecture of such complex score is heterogeneous and not very suitable for pharmacogenetic studies. We aimed to select the most optimal phenotype for TNFi response using heritability estimates. Methods Using two linear mixed-modelling approaches (Bayz and GCTA), we estimated heritability, together with genomic and environmental correlations for the TNFi drug-response phenotype ΔDAS28 and its separate components: Δ swollen joint count (SJC), Δ tender joint count (TJC), Δ erythrocyte sedimentation rate (ESR) and Δ visual-analogue scale of general health (VAS-GH). For this, we used genome-wide single nucleotide polymorphism (SNP) data from 878 TNFi-treated Dutch patients with RA. Furthermore, a multivariate genome-wide association study (GWAS) approach was implemented, analysing separate DAS28 components simultaneously. Results The highest heritability estimates were found for ΔSJC (=0.76 and =0.87) and ΔTJC (=0.62 and =0.82); lower heritability was found for ΔDAS28 (=0.59 and =0.71) while estimates for ΔESR and ΔVASGH were near or equal to zero. The highest genomic correlations were observed for ΔSJC and ΔTJC (0.49), and the highest environmental correlation was seen between ΔTJC and ΔVASGH (0.62). The multivariate GWAS did not generate excess of low p values as compared with a univariate analysis of ΔDAS28. Conclusions Our results indicate that multiple SNPs together explain a substantial portion of the variation in change in joint counts in TNFi-treated patients with RA. In conclusion, of the outcomes studied, the joint counts are most suitable for TNFi pharmacogenetics in RA.
    No preview · Article · Aug 2014 · Annals of the Rheumatic Diseases
  • No preview · Article · Aug 2014 · Clinical Therapeutics
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    [Show abstract] [Hide abstract] ABSTRACT: Background Activating mutations in the Transient Receptor Potential channel C6 (TRPC6) cause autosomal dominant focal segmental glomerular sclerosis (FSGS). TRPC6 expression is upregulated in renal biopsies of patients with idiopathic membranous glomerulopathy (iMN) and animal models thereof. In iMN, disease progression is characterized by glomerulosclerosis. In addition, a context-dependent TRPC6 overexpression was recently suggested in complement-mediated podocyte injury in e.g. iMN. Hence, we hypothesized that genetic variants in TRPC6 might affect susceptibility to development or progression of iMN. Methods & Results Genomic DNA was isolated from blood samples of 101 iMN patients and 292 controls. By direct sequencing of the entire TRPC6 gene, 13 single nucleotide polymorphisms (SNPs) were identified in the iMN cohort, two of which were causing an amino acid substitution (rs3802829; Pro15Ser and rs36111323, Ala404Val). No statistically significant differences in genotypes or allele frequencies between patients and controls were observed. Clinical outcome in patients was determined (remission n = 26, renal failure n = 46, persistent proteinuria n = 29, follow-up median 80 months {range 51–166}). The 13 identified SNPs showed no association with remission or renal failure. There were no differences in genotypes or allele frequencies between patients in remission and progressors. Conclusions Our data suggest that TRPC6 polymorphisms do not affect susceptibility to iMN, or clinical outcome in iMN.
    Full-text · Article · Jul 2014 · PLoS ONE
  • [Show abstract] [Hide abstract] ABSTRACT: Background Pain is the dominant and prevailing symptom of rheumatoid arthritis (RA). Tumor necrosis factor inihibitors (TNFi) have proven very successful in pain reduction. Interestingly, improvement of pain, is notable rapidly after administration of TNFi agents, and well before anti-inflammatory effects of treatment can be observed. The vast majority of pharmacogenetic studies of response to TNFi utilized the clinical outcome measure, disease activity score 28 (DAS28). This measure is very useful for clinical practice, however it might be less heritable as compared to individual, potentially more homogeneous, disease measures. Usage of less complex phenotypes, such as pain (heritability 28-71%), might significantly aid the identification of genetic markers predicting differential response to TNFi. Objectives We aimed to identify and replicate genetic factors predicting pain reduction upon TNFi treatment in patients with RA using genome-wide association approach. Methods We included 508 TNFi treated RA patients. Association analysis of change of visual analogue scale of pain (VAS-pain) after 14 weeks of treatment was performed on imputed genome-wide genotyping data under additive genetic model with adjustment for baseline VAS-pain. We also conducted a meta-analysis including 1287 RA patients. Gene-based analysis was performed using VEGAS. Results No findings reached the threshold for genome-wide significance (P-value≤1x10–8) in the discovery cohort. Meta-analysis revealed 213 SNPs suggestively associated (P<10–4) with change in VAS-pain after fourteen weeks of TNFi treatment. The most significant SNP rs2295739 (p=2.21x10–6), located ∼50kb upstream from the KCNK10 gene, which belongs to a family of genes involved in sensory perception. The top hit in the gene-based analysis was RET, known to regulate ion channels and receptors participating in detection and transduction of sensory stimuli. Besides Ret-deficient mice show elevated pain responses. Conclusions We have identified several suggestive genomic regions, further studies are required to validate if these regions play a role in pain reduction upon TNFi treatment. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4094
    No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
  • [Show abstract] [Hide abstract] ABSTRACT: Background: X-linked sideroblastic anaemia (XLSA; OMIM#300751) is the most common inherited form of sideroblastic anaemia and is associated with several mutations in the erythroid specific 5-aminolevulinate synthase gene (ALAS₂). This gene encodes for aminolevulinic acid synthase 2 (ALAS₂), the catalytic enzyme involved in the first en rate-limiting step of haem biosynthesis.1-3 The disorder is characterised by mostly mild hypochromic microcytic anaemia with bone marrow ring sideroblasts. Even untransfused patients with mild or no anaemia are at risk for severe systemic iron overload due to ineffective erythropoiesis. To date, 61 different ALAS₂ mutations have been reported in 120 families with XLSA. Descriptions of molecularly confirmed case series from the Netherlands, however, are lacking. Methods: We reviewed age of presentation, clinical and biochemical features, ALAS₋₂ defects and treatment characteristics of 15 Dutch patients from 11 unrelated families diagnosed with XLSA. Results and conclusions: In one family a novel pathogenic c.1412G>A (p.Cys471Tyr) mutation was found. All other families shared the previously described c.1355G>A (p.Arg452His) mutation. Haplotype analysis in seven probands with the p.Arg452His mutation strongly suggests that six of them were ancestrally related. Nevertheless, their phenotype was very different. Our patients illustrate the phenotypical heterogeneity in the presentation of XLSA patients, the effectiveness of treatment regimens and the various pitfalls associated with the diagnosis, follow-up and treatment of the disease. A timely diagnosis avoids unnecessary investigations and allows adequate treatment that can prevent systemic iron load with subsequent severe life-threatening complications. Therefore, we suggest considering XLSA in both male and female patients with unexplained iron overload and÷or (mild) microcytic anaemia, also at older age.
    No preview · Article · May 2014 · The Netherlands Journal of Medicine
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    [Show abstract] [Hide abstract] ABSTRACT: Rheumatoid arthritis (RA) patients can be classified based on presence or absence of anticitrullinated peptide antibodies (ACPA) in their serum. This heterogeneity among patients may reflect important biological differences underlying the disease process. To date, the majority of genetic studies have focused on the ACPA-positive group. Therefore, our goal was to analyse the genetic risk factors that contribute to ACPA-negative RA. We performed a large-scale genome-wide association study (GWAS) in three Caucasian European cohorts comprising 1148 ACPA-negative RA patients and 6008 controls. All patients were screened using the Illumina Human Cyto-12 chip, and controls were genotyped using different genome-wide platforms. Population-independent analyses were carried out by means of logistic regression. Meta-analysis with previously published data was performed as follow-up for selected signals (reaching a total of 1922 ACPA-negative RA patients and 7087 controls). Imputation of classical HLA alleles, amino acid residues and single nucleotide polymorphisms was undertaken. The combined analysis of the studied cohorts resulted in identification of a peak of association in the HLA-region and several suggestive non-HLA associations. Meta-analysis with previous reports confirmed the association of the HLA region with this subset and an observed association in the CLYBL locus remained suggestive. The imputation and deep interrogation of the HLA region led to identification of a two amino acid model (HLA-B at position 9 and HLA-DRB1 at position 11) that accounted for the observed genome-wide associations in this region. Our study shed light on the influence of the HLA region in ACPA-negative RA and identified a suggestive risk locus for this condition.
    Full-text · Article · Feb 2014 · Annals of the rheumatic diseases
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    [Show abstract] [Hide abstract] ABSTRACT: Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10(-6)). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.
    Full-text · Article · Feb 2014 · PLoS ONE

Publication Stats

3k Citations
853.77 Total Impact Points


  • 1999-2015
    • Radboud University Nijmegen
      • Department of Pediatrics
      Nymegen, Gelderland, Netherlands
    • University Medical Center Utrecht
      • Department of Immunology
      Utrecht, Utrecht, Netherlands
  • 2002-2011
    • UMC St. Radboud Nijmegen
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 2010
    • University of Milan
      Milano, Lombardy, Italy