scholarly journals Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts

2021 ◽  
Vol 12 ◽  
Author(s):  
Jose Manuel Sánchez-Maldonado ◽  
Rafael Cáliz ◽  
Miguel Ángel López-Nevot ◽  
Antonio José Cabrera-Serrano ◽  
Ana Moñiz-Díez ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Multiple Testing ◽  
Drug Response ◽  
Disease Activity Score ◽  
Meta Analysis ◽  
Routine Care ◽  
Multiple Testing Correction ◽  
Discovery Cohort ◽  
E Coli ◽  
Inflammatory Effect

We aimed to validate the association of 28 GWAS-identified genetic variants for response to TNF inhibitors (TNFi) in a discovery cohort of 1361 rheumatoid arthritis (RA) patients monitored in routine care and ascertained through the REPAIR consortium and DANBIO registry. We genotyped selected markers and evaluated their association with response to TNFi after 6 months of treatment according to the change in disease activity score 28 (ΔDAS28). Next, we confirmed the most interesting results through meta-analysis of our data with those from the DREAM cohort that included 706 RA patients treated with TNFi. The meta-analysis of the discovery cohort and DREAM registry including 2067 RA patients revealed an overall association of the LINC02549rs7767069 SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (per-allele ORMeta=0.83, PMeta=0.000077; PHet=0.61). In addition, we found that each copy of the LRRC55rs717117G allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele ORMeta=0.67, P=0.00058; PHet=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; PHet=0.45; PInteraction=0.00028). Interestingly, although the identified associations did not survive multiple testing correction, the meta-analysis also showed overall and RF-specific associations for the MAFBrs6071980 and CNTN5rs1813443 SNPs with decreased changes in DAS28 (per-allele ORMeta_rs6071980 = 0.85, P=0.0059; PHet=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; PHet=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; PHet=0.12; PInteraction=0.032). Mechanistically, we found that subjects carrying the LINC02549rs7767069T allele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of the LINC02549rs7767069T/T genotype showed significantly increased levels of soluble scavengers CD5 and CD6 in serum (P=0.00037 and P=0.00041). In addition, carriers of the LRRC55rs717117G allele showed decreased production of IL6 after stimulation of PBMCs with B burgdorferi and E coli bacteria (P=0.00046 and P=0.00044), which suggested a reduced IL6-mediated anti-inflammatory effect of this marker to worsen the response to TNFi. In conclusion, this study confirmed the influence of the LINC02549 and LRRC55 loci to determine the response to TNFi in RA patients and suggested a weak effect of the MAFB and CNTN5 loci that need to be further investigated.

scholarly journals OP0017 VALIDATION OF GWAS-IDENTIFIED VARIANTS FOR ANTI-TNF DRUG RESPONSE IN RHEUMATOID ARTHRITIS: A META-ANALYSIS OF THREE LARGE COHORTS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 9.2-10
Author(s):  
J. M. Sánchez-Maldonado ◽  
R. Cáliz Cáliz ◽  
M. Á. López-Nevot ◽  
A. Moñiz-Díez ◽  
A. J. Cabrera-Serrano ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Multiple Testing ◽  
Drug Response ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Meta Analysis ◽  
Linear Regression Analysis ◽  
Ethical Review ◽  
Serum Samples

Background:The interplay between genetics and drug response in rheumatoid arthritis (RA) has shown that response to biologics varies between individuals and that a large proportion of patients show no clinical improvement (Plenge and Bridges, 2011). Despite the disappointing scenario, to date, only a few genetic markers have been consistently identified and we are far from being able to optimize drug dosing or prioritize drug combinations based on genetic findings.Objectives:With this background, we sought to validate the association of GWAS-identified variants for response to TNF inhibitors (TNFi) in a two-stage case control association study and to shed some light into the functional role of the most interesting markers.Methods:The discovery population consisted of 1361 RA patients ascertained through the REPAIR consortium and the DANBIO registry. RA patients fulfilled the 1987 revised American College of Rheumatology (ACR) and the ACR/EULAR 2010 classification criteria. The validation cohort included 706 Dutch RA patients from the DREAM registry. The study followed the Declaration of Helsinki and study participants gave their written informed consent to participate in the study, which was approved by the ethical review committee of participant institutions. Twenty-seven single-nucleotide polymorphisms (SNPs) were selected through a literature search of relevant GWAS. Linear regression analysis adjusted for age, sex and country of origin was used to determine the association between GWAS-identified SNPs and changes in DAS28 (ΔDAS28) after 3 or 6 months of treatment. The meta-analysis of both populations was performed using a fixed effect model. Correction for multiple testing was performed using the Bonferroni method but also considering the number of inheritance models tested (P=0.0009). To assess the role of the most interesting markers in modulating immune responses, stimulation experiments in whole blood, peripheral mononuclear cells (PBMCs) and monocyte-derived macrophages using a large number of pathogens and microbiome bacteria were performed in 408 subjects from the Human Functional Genomic Project cohort. We also evaluated the correlation of these SNPs with plasmatic levels of 108 inflammatory proteins, 7 serum steroid hormones and counts of 91 blood-derived immune cell populations.Results:The meta-analysis of the discovery cohort and DREAM registry including 2067 RA patients treated with TNFi revealed an overall association of the LINC02549rs7767069 SNP with a decreased drop in DAS28 that remained significant after correction for multiple testing (per-allele ORMeta=0.83, PMeta=0.000077; PHet=0.61). In addition, the meta-analysis of these large cohorts showed that each copy of the LARRC55rs717117G allele significantly decreased the drop in DAS28 in RF-positive patients (per-allele ORMeta=0.67, P=0.00058; PHet=0.06) whereas an opposite but not significant effect was found in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; PInteraction=0.00028; PHet=0.45). Interestingly, the meta-analysis also showed potentially interesting but not statistically significant overall and RF-specific associations for the MAFBrs6071980 and CNTN5rs1813443 SNPs with ΔDAS28 (per-allele ORMeta_rs6071980=0.84, P=0.0059; PHet=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; PHet=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; PHet=0.12; PInteraction=0.032). Although analysis of functional data is ongoing, so far, we found that carriers of the LARRC55rs717117G allele showed decreased levels of IL6 after stimulation of PBMCs with Borrelia burgdorferi and Escherichia Coli bacteria (P=0.00046 and 0.00044), which suggested a reduced IL6-mediated anti-inflammatory effect of this marker to worsen the response to TNFi.Conclusion:This study confirmed the influence of the LINC02549 and LARRC55 loci to determine the response to TNFi in RA patients and a weak effect of the MAFB and CNTN5 loci that needs to be further investigated.References:[1]Plenge RM et al 2011. Arthritis Rheum 63, 590-3.ACKNOWLEDGEMENTS:We thank all participants who have agreed to participate in this study. Authors also thank María Dolores Casares, Ángeles Molina, Carmen Oloriz for the collection of Spanish samples and Hans Jurgen Hoffmann, Marianne Thomsen, Vibeke Østergaard Thomsen, Malene Rohr Andersen, Lise Lotte B. Laursen, Helle Jørgensen, Ram Benny Christian Dessau, Niels Steen Krogh, Ulla Vogel, Paal Skytt Andersen, Ivan Brandslund, Steffen Bank, Frederik Trier Møller, Nikolai Toft and Niels Møller Andersen for the participation in collection and purification of Danish samples. We also thank the Danish Departments of Rheumatology for their implication in the collection of clinical data from RA patients included in the DANBIO cohort and the Danish Rheumatologic Biobank. Likewise, we would like to thank Teun van Herwaarden for steroid hormone measurements in serum samples from subjects ascertained through the HFGP initiative.Disclosure of Interests:None declared

scholarly journals Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

2018 ◽  
Author(s):  
David M. Howard ◽  
Mark J. Adams ◽  
Toni-Kim Clarke ◽  
Jonathan D. Hafferty ◽  
Jude Gibson ◽  
...  
Keyword(s):  
Multiple Testing ◽  
Drug Repositioning ◽  
Association Studies ◽  
Meta Analysis ◽  
Enrichment Analysis ◽  
Brain Regions ◽  
Genome Wide Association Studies ◽  
Multiple Testing Correction ◽  
Synaptic Structure ◽  
Genome Wide

AbstractMajor depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.

scholarly journals P0360URINARY PEPTIDOMIC ANALYSIS IN PROLIFERATIVE VERSUS NON-PROLIFERATIVE LUPUS NEPHRITIS : RESULTS OF THE PEPTIDU-LUP STUDY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Maxence Tailliar ◽  
Joost Schanstra ◽  
Tim Dierckx ◽  
BREUIL Benjamin ◽  
Guillaume Hanouna ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Lupus Nephritis ◽  
Multiple Testing ◽  
Kidney Biopsy ◽  
Validation Cohort ◽  
Response To Therapy ◽  
Multiple Testing Correction ◽  
Discovery Cohort ◽  
Model Combining ◽  
Urinary Peptides

Abstract Background and Aims Lupus nephritis (LN) is a frequent manifestation of Systemic Lupus Erythematosus (SLE). The therapeutic strategy relies on the result of kidney biopsy, which differentiates proliferative LN (PLN) from non-proliferative LN (NPLN). The analysis of the urinary peptidome has led to the identification of prognostic biomarkers in chronic kidney disease (CKD, namely the CKD273 classifier), or, as a liquid biopsy, for the diagnosis of glomerulonephritides. We verified whether urinary peptidomics could predict the severity of renal pathological injury and damage in LN. Method Urine samples, collected before kidney biopsy, were analyzed by capillary-electrophoresis coupled to mass-spectrometry (CE-MS). Urinary peptide profiles were compared between PLN and NPLN. Predictive values for chronic pathological lesions (glomerulosclerosis and interstitial fibrosis/tubular atrophy (IF/TA)), response to therapy and development of CKD were also assessed. Clinical characteristics, routine laboratory parameters and immunological SLE markers were collected at inclusion and prospectively for at least 24 months. Results We collected 100 urinary samples from patients with LN, forming a discovery (n=67) and an independent validation (n=33) cohort. Overall there were 69 patients with PLN (class III or IV +/-V with active lesions) and 31 patients with NPLN (class II or V or chronic lesions). In the discovery cohort, the abundance of 36 urinary peptides differed between PLN and NPLN (Mann-Whitney test). However, these peptides did not resist multiple testing correction. Among them, 17 could be sequenced (fragments of collagen-I, -II, -III, apolipoprotein A-I, Fibrinogen alpha chain and Histone H2B). Of the 17 sequenced peptides, 7 were also part of the CKD273 classifier. A mathematical model combining the 36 peptides classified PLN and NPLN patients from the validation cohort with an AUC of 0.75 and sensitivity and specificity of 0.81 and 0.53, respectively. Positivity of anti-dsDNA antibodies had the best sensitivity (0.96) and sterile pyuria the best specificity (0.68) to differentiate PLN from NPLN, and including the CKD273 score did not improve the accuracy of the predictive models. No urinary peptidomics profile was identified to predict early response to therapy in patients with LN. Glomerulosclerosis was observed in 63/100 biopsies. In the discovery cohort, the abundance of 38 urinary peptides (including 22 sequenced) differed between patients with vs without glomerulosclerosis (Mann-Whitney test). Again, these peptides did not resist multiple testing correction. Of the 22 sequenced peptides, 7 (different from the peptides associated with PLN) belonged to the CKD273 classifier. A mathematical model combining the 38 peptides classified patients from the validation cohort with an AUC of 0.75 and sensitivity and specificity of 0.82 and 0.54, respectively, for the presence of glomerulosclerosis. Although the quantification of IF/TA was correlated to the pre-existing CKD273 classifier, including the CKD273 score did not improve the prediction of IF/TA when tested in combination with simple clinical parameters. Only 3 patients developed CKD after a mean follow-up of 4 years, therefore contribution of urinary peptidomics for the prediction of CKD in LN could not be evaluated. Conclusion Different urinary peptidomics signatures were identified among patients with LN, according to the presence of active proliferative lesions or chronic lesions. However, these panels did not resist multiple testing correction, and did not improve the diagnostic accuracy when combined with clinical or immunological markers. The contribution of urinary peptidomics to predict CKD in patients with LN, or as an early predictor of renal flares, could not be evaluated. Kidney biopsy remains central for the care of patients with LN.

DAS-driven therapy versus routine care in patients with recent-onset active rheumatoid arthritis

2009 ◽  
Vol 69 (01) ◽  
pp. 65-69 ◽  
Author(s):  
Y P M Goekoop-Ruiterman ◽  
J K de Vries-Bouwstra ◽  
P J S M Kerstens ◽  
M M J Nielen ◽  
K Vos ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Disease Activity Score ◽  
Controlled Trial ◽  
Joint Damage ◽  
Routine Care ◽  
Activity Score ◽  
Recent Onset ◽  
Group A ◽  
Group B

Objectives:To compare the efficacy of Disease Activity Score (DAS)-driven therapy and routine care in patients with recent-onset rheumatoid arthritis.Methods:Patients with recent-onset rheumatoid arthritis receiving traditional antirheumatic therapy from either the BeSt study, a randomised controlled trial comparing different treatment strategies (group A), or two Early Arthritis Clinics (group B) were included. In group A, systematic DAS-driven treatment adjustments aimed to achieve low disease activity (DAS ⩽2.4). In group B, treatment was left to the discretion of the treating doctor. Functional ability (Health Assessment Questionnaire (HAQ)), Disease Activity Score in 28 joints (DAS28) and Sharp/van der Heijde radiographic score (SHS) were evaluated.Results:At baseline, patients in group A (n = 234) and group B (n = 201) had comparable demographic characteristics and a mean HAQ of 1.4. Group A had a longer median disease duration than group B (0.5 vs 0.4 years, p = 0.016), a higher mean DAS28 (6.1 vs 5.7, p<0.001), more rheumatoid factor-positive patients (66% vs 42%, p<0.001) and more patients with erosions (71% vs 53%, p<0.001). After 1 year, the HAQ improvement was 0.7 vs 0.5 (p = 0.029), and the percentage in remission (DAS28 <2.6) 31% vs 18% (p<0.005) in groups A and B, respectively. In group A, the median SHS progression was 2.0 (expected progression 7.0), in group B, the SHS progression was 1.0 (expected progression 4.4).Conclusions:In patients with recent-onset rheumatoid arthritis receiving traditional treatment, systematic DAS-driven therapy results in significantly better clinical improvement and possibly improves the suppression of joint damage progression.

scholarly journals Capturing SNP Association across the NK Receptor and HLA Gene Regions in Multiple Sclerosis by Targeted Penalised Regression Models

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 87
Author(s):  
Sean M. Burnard ◽  
Rodney A. Lea ◽  
Miles Benton ◽  
David Eccles ◽  
Daniel W. Kennedy ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Complex Traits ◽  
Multiple Testing ◽  
Large Scale ◽  
Disease Risk ◽  
Association Studies ◽  
Meta Analysis ◽  
Elastic Net ◽  
Genome Wide Association Studies ◽  
Multiple Testing Correction

Conventional genome-wide association studies (GWASs) of complex traits, such as Multiple Sclerosis (MS), are reliant on per-SNP p-values and are therefore heavily burdened by multiple testing correction. Thus, in order to detect more subtle alterations, ever increasing sample sizes are required, while ignoring potentially valuable information that is readily available in existing datasets. To overcome this, we used penalised regression incorporating elastic net with a stability selection method by iterative subsampling to detect the potential interaction of loci with MS risk. Through re-analysis of the ANZgene dataset (1617 cases and 1988 controls) and an IMSGC dataset as a replication cohort (1313 cases and 1458 controls), we identified new association signals for MS predisposition, including SNPs above and below conventional significance thresholds while targeting two natural killer receptor loci and the well-established HLA loci. For example, rs2844482 (98.1% iterations), otherwise ignored by conventional statistics (p = 0.673) in the same dataset, was independently strongly associated with MS in another GWAS that required more than 40 times the number of cases (~45 K). Further comparison of our hits to those present in a large-scale meta-analysis, confirmed that the majority of SNPs identified by the elastic net model reached conventional statistical GWAS thresholds (p < 5 × 10−8) in this much larger dataset. Moreover, we found that gene variants involved in oxidative stress, in addition to innate immunity, were associated with MS. Overall, this study highlights the benefit of using more advanced statistical methods to (re-)analyse subtle genetic variation among loci that have a biological basis for their contribution to disease risk.

scholarly journals The genetic architecture of the human cerebral cortex

2018 ◽  
Author(s):  
Katrina L. Grasby ◽  
Neda Jahanshad ◽  
Jodie N. Painter ◽  
Lucía Colodro-Conde ◽  
Janita Bralten ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Surface Area ◽  
Multiple Testing ◽  
Meta Analysis ◽  
Brain Mri ◽  
Regulatory Elements ◽  
Total Surface Area ◽  
Multiple Testing Correction ◽  
Cortical Structure ◽  
A Genome

The cerebral cortex underlies our complex cognitive capabilities, yet we know little about the specific genetic loci influencing human cortical structure. To identify genetic variants, including structural variants, impacting cortical structure, we conducted a genome-wide association meta-analysis of brain MRI data from 51,662 individuals. We analysed the surface area and average thickness of the whole cortex and 34 regions with known functional specialisations. We identified 255 nominally significant loci (P≤ 5 × 10−8); 199 survived multiple testing correction (P≤ 8.3 × 10−10; 187 surface area; 12 thickness). We found significant enrichment for loci influencing total surface area within regulatory elements active during prenatal cortical development, supporting the radial unit hypothesis. Loci impacting regional surface area cluster near genes in Wnt signalling pathways, known to influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression and ADHD.One Sentence SummaryCommon genetic variation is associated with inter-individual variation in the structure of the human cortex, both globally and within specific regions, and is shared with genetic risk factors for some neuropsychiatric disorders.

Safety and Efficacy of Mavrilimumab For Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

2020 ◽  
Vol 16 ◽  
Author(s):  
Laila Salah Shamseldin ◽  
Mohamed Mohamed Shawqi ◽  
Noor Adel Al Hashem ◽  
Majd Aleslam Hussein Alhyari ◽  
Hossam Aldein Samir Abd Elazeem ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity Score ◽  
Meta Analysis ◽  
Human Monoclonal Antibody ◽  
C Reactive Protein ◽  
Safety And Efficacy ◽  
Reactive Protein ◽  
American College Of Rheumatology ◽  
Autoimmune Inflammatory Disease ◽  
Review Manager

Background: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by progressive swelling and stiffness in the joints. Mavrilimumab is a human monoclonal antibody that may block the autoimmune mechanism of the antibodies cause RA. Objective: We aim to assess the safety and efficacy of Mavrilimumab in treating rheumatoid arthritis. Methods: We conducted an online search using PubMed, Scopus, Web of Science, and Cochrane CENTRAL till June 2019, and updated the search in May 2020, using relevant keywords. We screened studies for eligibility. Data were extracted from eligible studies and pooled as Risk ratio (RR) with a 95% confidence interval (CI), using Review Manager software (ver.3.5). Results: Five studies (with 1145 patients) were eligible to our criteria. Pooled result from three trials showed a significant reduction in Disease Activity Score 28 based on C-reactive protein (DAS28−CRP) remission < 2.6 after 12 weeks (RR = 3.31, 95% CI [1.53, 7.18], P = 0.002), American College of Rheumatology (ACR) 20, after 12 weeks (RR = 2.38, 95% CI [1.80, 3.16], P < 0.00001), ACR 50, after 12 weeks (RR = 2.93, 95% CI [1.67, 5.15], P = 0.0002), ACR 70, after 12 weeks (RR = 4.90, 95% CI [1.60, 15.00], P = 0.005). Mavrilimumab not associated with a significant adverse event (RR = 1.22, 95% CI [0.89, 1.68], P = 0.22). Conclusion: We found that subcutaneous Mavrilimumab was effective and well-tolerating in treating RA patients, with no significant adverse events.

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