scholarly journals HLA-DQA1*05 is associated with the development of antibodies to anti-TNF therapy

2018 ◽  
Author(s):  
Aleksejs Sazonovs ◽  
Nick Kennedy ◽  
Loukas Moutsianas ◽  
Graham A. Heap ◽  
Daniel L. Rice ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Genome Wide Association Study ◽  
Human Leukocyte ◽  
Human Leukocyte Antigen Allele ◽  
A Genome ◽  
Antibody Titres ◽  
Clinical Benefits ◽  
Pre Treatment ◽  
Hla Dqa1

SummaryBackgroundAnti-tumour necrosis factor (anti-TNF) therapies are the most widely used biologic therapies for treating immune-mediated diseases. Their efficacy is significantly reduced by the development of anti-drug antibodies which can lead to treatment failure and adverse reactions. The biological mechanisms underlying antibody development are unknown but the ability to identify subjects at higher risk would have significant clinical benefits.MethodsThe PANTS cohort consists of Crohn’s disease patients recruited prior to first administration of anti-TNF, with serial measurements of anti-drug antibody titres. We performed a genome-wide association study across 1240 individuals from this cohort to identify genetic variants associated with anti-drug antibody development.FindingsThe Human Leukocyte Antigen allele, HLA-DQA1*05, carried by approximately 40% of Europeans, significantly increased the rate of anti-drug antibody development (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60 to 2.25; P=5.88×10-13). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32 to 2.70) and infliximab (HR, 1.92; 95% CI, 1.57 to 2.33), and for patients treated with mono-(HR, 1.75; 95% CI, 1.37 to 2.22) or combination therapy with immunomodulators (HR, 2.0; 95% CI, 1.57 to 2.58).InterpretationHLA-DQA1*05 is significantly associated with an increased rate of anti-drug antibody formation in patients with Crohn’s disease treated with infliximab and adalimumab. Pre-treatment HLA-DQA1*05 genetic testing may help personalise the choice of anti-TNF therapy and allow the targeted use of immunomodulator therapy to minimise risk and maximise response.

Identification of Risk Loci for Crohn’s Disease Phenotypes Using a Genome-Wide Association Study

2015 ◽  
Vol 148 (4) ◽  
pp. 794-805 ◽  
Author(s):  
Arnald Alonso ◽  
Eugeni Domènech ◽  
Antonio Julià ◽  
Julián Panés ◽  
Valle García-Sánchez ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Disease Phenotypes ◽  
Genome Wide ◽  
A Genome

Pathway Analysis of a Genome-Wide Association Study of Ileal Crohn's Disease

2012 ◽  
Vol 31 (10) ◽  
pp. 1549-1554 ◽  
Author(s):  
Young Ho Lee ◽  
Gwan Gyu Song
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Association Study ◽  
Pathway Analysis ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

A Genome-Wide Association Study Identifies 2 Susceptibility Loci for Crohn's Disease in a Japanese Population

2013 ◽  
Vol 144 (4) ◽  
pp. 781-788 ◽  
Author(s):  
Keiko Yamazaki ◽  
Junji Umeno ◽  
Atsushi Takahashi ◽  
Atsushi Hirano ◽  
Todd Andrew Johnson ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Association Study ◽  
Japanese Population ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Susceptibility Loci ◽  
Genome Wide ◽  
A Genome

scholarly journals Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yong-Fei Wang ◽  
Yan Zhang ◽  
Zhiming Lin ◽  
Huoru Zhang ◽  
Ting-You Wang ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Genome Wide Association Study ◽  
Age Of Onset ◽  
Treatment Options ◽  
Human Leukocyte ◽  
Risk Scores ◽  
Systemic Lupus ◽  
Disease Manifestation ◽  
A Genome

AbstractSystemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.

scholarly journals A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn’s Disease in Japanese Individuals

2018 ◽  
Vol 13 (5) ◽  
pp. 648-658 ◽  
Author(s):  
Yoichi Kakuta ◽  
Yosuke Kawai ◽  
Takeo Naito ◽  
Atsushi Hirano ◽  
Junji Umeno ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Mononuclear Cells ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Genome Wide Association ◽  
Effector Memory ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

Abstract Background and Aims Genome-wide association studies [GWASs] of European populations have identified numerous susceptibility loci for Crohn’s disease [CD]. Susceptibility genes differ by ethnicity, however, so GWASs specific for Asian populations are required. This study aimed to clarify the Japanese-specific genetic background for CD by a GWAS using the Japonica array [JPA] and subsequent imputation with the 1KJPN reference panel. Methods Two independent Japanese case/control sets (Tohoku region [379 CD patients, 1621 controls] and Kyushu region [334 CD patients, 462 controls]) were included. GWASs were performed separately for each population, followed by a meta-analysis. Two additional replication sets [254 + 516 CD patients and 287 + 565 controls] were analysed for top hit single nucleotide polymorphisms [SNPs] from novel genomic regions. Results Genotype data of 4 335 144 SNPs from 713 Japanese CD patients and 2083 controls were analysed. SNPs located in TNFSF15 (rs78898421, Pmeta = 2.59 × 10−26, odds ratio [OR] = 2.10), HLA-DQB1 [rs184950714, pmeta = 3.56 × 10−19, OR = 2.05], ZNF365, and 4p14 loci were significantly associated with CD in Japanese individuals. Replication analyses were performed for four novel candidate loci [p <1 × 10−6], and rs488200 located upstream of RAP1A was significantly associated with CD [pcombined = 4.36 × 10−8, OR = 1.31]. Transcriptome analysis of CD4+ effector memory T cells from lamina propria mononuclear cells of CD patients revealed a significant association of rs488200 with RAP1A expression. Conclusions RAP1A is a novel susceptibility locus for CD in the Japanese population.

935 PRE-TREATMENT MUCOSAL INFLAMMATORY AND WOUND HEALING GENE PROGRAMS REVEAL MECHANISMS ASSOCIATED WITH FUTURE STRICTURING BEHAVIOR DURING FIVE YEAR FOLLOW-UP IN PEDIATRIC CROHN'S DISEASE

2020 ◽  
Vol 158 (6) ◽  
pp. S-187-S-188
Author(s):  
Yael Haberman ◽  
Phillip P. Minar ◽  
Rebekah Karns ◽  
Phillip J. Dexheimer ◽  
Sudhir Ghandikota ◽  
...  
Keyword(s):  
Wound Healing ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Pre Treatment

P095 AMISELIMOD SAFETY PROFILE FOR CROHN’S DISEASE, STRATIFIED BY PREVIOUS TREATMENT WITH ANTI-TNF AGENTS

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S1-S1
Author(s):  
Geert R A M D’Haens ◽  
Neal Slatkin ◽  
Robert Israel ◽  
Zeev Heimanson
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Safety Data ◽  
Previous Treatment ◽  
Treatment Phase ◽  
Prior Treatment ◽  
Open Label ◽  
Double Blind ◽  
Clinical Benefits ◽  
Previously Treated

Abstract Background Anti-TNF agents are an established treatment modality for ulcerative colitis (UC); however, as many as 30% of patients do not respond to anti-TNF agents, and almost 50% of responders lose clinical benefits after a year of treatment. Furthermore, numerous safety concerns are associated with long-term use of anti-TNF agents. An alternative treatment in development for autoimmune-mediated diseases, including Crohn’s disease (CD) and UC, are sphingosine 1-phosphate receptor modulators such as amiselimod (AMS). Methods The safety and efficacy of oral AMS 0.4 mg/d in adults with moderate to severe active CD over 14 wks were evaluated in a multicenter, randomized, double-blind, parallel-group, placebo (PBO)-controlled (DBPC), phase 2a clinical trial, followed by an open-label extension (OLE) study with AMS for up to 36 wks. Patients had previously used anti-TNF-α agents, immunosuppressants, or corticosteroids. Safety data (adverse events [AEs]) were stratified by patients with and without prior anti-TNF treatment. Results Of the 78 patients randomized 1:1 to receive AMS (n=40) or PBO (n=38), 78% (n=61) completed the DBPC treatment phase. Of those patients continuing into the OLE, 26 patients (AMS/AMS [n=14]; PBO/AMS [n=12]) completed it. Oral AMS 0.4 mg for 12 wks did not have a significant effect on clinical disease activity in CD. Patients previously treated with anti-TNF agents had more serious AEs (SAEs) (27% AMS [n=22]; 4% PBO [n=25]) than did patients without prior anti-TNF treatment (0 AMS and 0 PBO patients). Relative numbers of treatment-emergent AEs (TEAEs) were similar between groups receiving prior anti-TNF agents (68% AMS [n=22]; 68% PBO [n=25]) and no prior treatment (65% AMS [n=17]; 31% PBO [n=13]). There was a trend toward more mild TEAEs and less severe AEs in patients not previously treated with anti-TNF agents compared to those previously treated. Conversely, in the OLE, patients not previously treated with anti-TNF agents had more AEs (100% AMS/AMS [n=11]; 67% PBO/AMS [n=9]) than those with prior treatment (60% AMS/AMS [n=10]; 87% PBO/AMS [n=16]). All of these TEAEs were mild or moderate. In the OLE, only 1 patient receiving AMS/AMS with no prior anti-TNF treatment had an SAE versus no patients with prior treatment. Conclusions Previous treatment with anti-TNF agents did not significantly affect the TEAEs associated with AMS. While SAEs appeared to be more common in previously treated patients in the DBPC, patients had fewer AEs during the OLE. This analysis suggests that previous treatment with anti-TNF agents should be considered when assessing the AE profile of AMS in future trials.

scholarly journals Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease

2017 ◽  
Vol 49 (2) ◽  
pp. 262-268 ◽  
Author(s):  
James C Lee ◽  
◽  
Daniele Biasci ◽  
Rebecca Roberts ◽  
Richard B Gearry ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
Genetic Contributions

644 Early Mucosal Healing Status Predicts Long-Term Clinical Benefits for Adalimumab-Treated Patients With Moderate to Severe Crohn's Disease

2010 ◽  
Vol 138 (5) ◽  
pp. S-85 ◽  
Author(s):  
Paul J. Rutgeerts ◽  
Walter Reinisch ◽  
Roopal Thakkar ◽  
Eric Q. Wu ◽  
Anna Kaltenboeck ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Mucosal Healing ◽  
Clinical Benefits
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