scholarly journals HLA-DRB1*08:02 Is Associated with Bucillamine-Induced Proteinuria in Japanese Rheumatoid Arthritis Patients

2014 ◽  
Vol 9 ◽  
pp. BMI.S13654 ◽  
Author(s):  
Hiroshi Furukawa ◽  
Shomi Oka ◽  
Kota Shimada ◽  
Shoji Sugii ◽  
Atsushi Hashimoto ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Adverse Reactions ◽  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Drug Induced ◽  
Leukocyte Antigen ◽  
Increased Risk ◽  
Gold Salts ◽  
Drug Hypersensitivity Reaction ◽  
Preliminary Study

Background Drug-induced proteinuria can occur in rheumatoid arthritis (RA) patients treated with d-penicillamine, gold salts, or bucillamine (Buc), and represents a drug hypersensitivity reaction. Striking associations of human leukocyte antigen (HLA) alleles with adverse reactions have recently been reported for many drugs. Methods We investigated the association of HLA class II with Buc-induced proteinuria (BI-Pro) in 485 Japanese RA patients treated with Buc, of whom 25 had developed BI-Pro. Results and Conclusion This preliminary study showed a highly significant association of DRB1*08:02 with BI-Pro ( P = 1.09 × 10−6, corrected P [ Pc] = 1.96 × 10−5, odds ratio [OR] 25.17, 95% confidence interval [CI] 7.98-79.38). DQB1*04:02 was also significantly associated with increased risk of BI-Pro ( P = 2.44 × 10−5, Pc = 2.69 × 10−4, OR 10.35, 95%CI 3.99–26.83). These findings provide useful information for promoting personalized medicine for RA.

A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population

2008 ◽  
Vol 68 (3) ◽  
pp. 377-383 ◽  
Author(s):  
K Shimane ◽  
Y Kochi ◽  
R Yamada ◽  
Y Okada ◽  
A Suzuki ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Human Leukocyte ◽  
Promoter Polymorphism ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Leukocyte Antigen ◽  
Asian Populations ◽  
Increased Risk ◽  
Stratified Analysis ◽  
Japanese Subjects

Objectives:Interferon regulatory factor 5 (IRF5) is a member of the IRF family of transcription factors, which regulate the production of proinflammatory cytokines. Polymorphisms in the IRF5 gene have been associated with susceptibility to systemic lupus erythaematosus (SLE) in Caucasian and Asian populations, but their involvement in other autoimmune diseases is still uncertain. Here, we assessed the genetic role of IRF5 in susceptibility to rheumatoid arthritis (RA) in Japanese subjects.Methods:We selected 13 single nucleotide polymorphisms (SNPs) and a CGGGG insertion–deletion polymorphism in the IRF5 gene. We performed 2 sets of case–control comparisons using Japanese subjects (first set: 830 patients with RA and 658 controls; second set: 1112 patients with RA and 940 controls), and then performed a stratified analysis using human leukocyte antigen (HLA)-DRB1 shared epitope (SE) status. We genotyped the SNPs using TaqMan assays.Results:A significant association of the rs729302 A allele with RA susceptibility was found in both sets (odds ratio (OR) 1.22, 95% CI 1.09 to 1.35, p<0.001 in the combined analysis). When the patients were stratified by the SE, the rs729302 A allele was found to confer increased risk to RA in patients that were SE negative (OR 1.50, 95% CI 1.17 to 1.92, p = 0.001) as compared with patients carrying the SE (OR 1.11, 95% CI 0.93 to 1.33, p = 0.24). In both sets, no genotyped polymorphisms were significantly associated with RA susceptibility, but rs729302 was significantly associated.Conclusions:These findings indicate that the promoter polymorphism of IRF5 is a genetic factor conferring predisposition to RA, and that it contributes considerably to disease pathogenesis in patients that were SE negative.

scholarly journals Novel Concepts for Drug Hypersensitivity Based on the Use of Long-Time Scale Molecular Dynamic Simulation

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Takahiro Murai ◽  
Norihito Kawashita ◽  
Yu-Shi Tian ◽  
Tatsuya Takagi
Keyword(s):  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Md Simulations ◽  
Hypersensitivity Reactions ◽  
Drug Induced ◽  
Leukocyte Antigen ◽  
Cell Clones ◽  
Drug Hypersensitivity Reactions ◽  
Long Time ◽  
Underlying Mechanisms

The discovery that several drug hypersensitivity reactions (DHRs) are associated with specific human leukocyte antigen (HLA) alleles has attracted increasing research interest. However, the underlying mechanisms of these HLA-induced DHRs remain unclear, especially for drug-induced immediate activation of T-cell clones (TCCs). Recently, a novel hypothesis involving partial detachment between self-peptide(s) and the HLA molecule (altered peptide-HLA (pHLA) model) has been proposed to explain these phenomena. In order to clarify this hypothesis, we performed long-timescale molecular dynamics (MD) simulations. We focused on HLA-B⁎57:01-restricted abacavir hypersensitivity reactions (AHRs), one of the most famous DHRs. One of the simulation results showed that this altered-pHLA model might be driven by an increase in the distance not only between HLA and self-peptides but also between the α1 and α2 helices of HLA. Our findings provide novel insights into abacavir-induced immediate activation of TCCs and these findings might also be applied to other DHRs, such as HLA-B⁎58:01-restricted allopurinol hypersensitivity reactions.

scholarly journals Toxic epidermal necrolysis

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 951 ◽  
Author(s):  
Wolfram Hoetzenecker ◽  
Tarun Mehra ◽  
Ieva Saulite ◽  
Martin Glatz ◽  
Peter Schmid-Grendelmeier ◽  
...  
Keyword(s):  
Cell Death ◽  
Mortality Rate ◽  
Toxic Epidermal Necrolysis ◽  
Human Leukocyte ◽  
Best Supportive Care ◽  
Drug Induced ◽  
Leukocyte Antigen ◽  
Mucosal Involvement ◽  
Keratinocyte Cell ◽  
Life Threatening

Toxic epidermal necrolysis (TEN) is a rare, life-threatening drug-induced skin disease with a mortality rate of approximately 30%. The clinical hallmark of TEN is a marked skin detachment caused by extensive keratinocyte cell death associated with mucosal involvement. The exact pathogenic mechanism of TEN is still uncertain. Recent advances in this field have led to the identification of several factors that might contribute to the induction of excessive apoptosis of keratinocytes. In addition, specific human leukocyte antigen types seem to be associated with certain drugs and the development of TEN. As well-controlled studies are lacking, patients are treated with various immunomodulators (e.g. intravenous immunoglobulin) in addition to the best supportive care.

scholarly journals Non-inherited maternal human leukocyte antigen alleles in susceptibility to familial rheumatoid arthritis

2008 ◽  
Vol 68 (1) ◽  
pp. 107-109 ◽  
Author(s):  
K A Guthrie ◽  
N R Tishkevich ◽  
J L Nelson
Keyword(s):  
Rheumatoid Arthritis ◽  
Human Leukocyte Antigen ◽  
Age Of Onset ◽  
Human Leukocyte ◽  
Paternal Allele ◽  
Hla Alleles ◽  
Leukocyte Antigen ◽  
The North ◽  
Significant Difference ◽  
Hla Genotype

Objectives:Some patients with rheumatoid arthritis (RA) lack RA-associated human leukocyte antigen (HLA) alleles. Prior studies investigated non-inherited maternal HLA alleles (NIMA) in RA risk with conflicting results.Methods:We examined NIMA in a large cohort of families from the North American Rheumatoid Arthritis Consortium (NARAC).Results:Among 620 patients with 1 or both parents having a HLA genotype, patients with RA informative for analysis included 176 without HLA-DRB1*04 and 86 without the HLA shared epitope (SE). The frequency of NIMA encoding HLA-DR4 or the SE was compared to the non-inherited paternal allele (NIPA). DR4-encoding NIMA vs NIPA revealed no significant difference (27% vs 20%). However, parity is known to modulate RA risk and analyses stratified by sex and age of onset showed significant variation among women. Interestingly, among women with onset <45 years DR4-encoding NIMA was increased compared to NIPA; among women ⩾45 years at onset the reverse was observed (31% vs 16% compared to 10% vs 60%, p = 0.008). DR4 encoding NIMA vs NIPA did not differ in men. The SE did not differ in men or women.Conclusions:Risk of RA was associated with HLA-DR4 encoding NIMA in younger-onset women but not in older-onset women or men. These observations could help explain conflicting prior results of NIMA in RA.

scholarly journals Roles of Genes in the Susceptibility to and Severity of Rheumatoid Arthritis - A Review

1970 ◽  
Vol 13 (1) ◽  
pp. 51-54
Author(s):  
Abul Khair Ahmedullah ◽  
Shamim Ahmed ◽  
MD Ariful Islam
Keyword(s):  
Rheumatoid Arthritis ◽  
Genetic Factors ◽  
Human Leukocyte ◽  
Drug Efficacy ◽  
Autoimmune Disorder ◽  
Individual Variability ◽  
Unknown Etiology ◽  
Entire Genome ◽  
Gene Effects ◽  
Leukocyte Antigen

Rheumatoid arthritis (RA) is a chronic heterogeneous autoimmune disorder of unknown etiology. Genetic factors play an important role in susceptibility to RA as the heritability of RA is between 50% and 60%, with the human leukocyte antigen (HLA) locus accounting for at least 30% of overall genetic risk. It is conceivable that there is more than one susceptible gene(s) operative in RA, and an interaction of the relevant genes may predispose the offspring to develop the disease under certain conditions .Outside the major histocompatibility complex (MHC) region, some additional risk loci have been identified and validated including PTPN22, STAT4, PADI4, CTLA4 and others Genetic factors are also important in RA pharmacotherapy due to the gene-dependent activity of enzymes involved in the pharmacokinetics and/or pharmacodynamics of RA medications. Indeed, there is great variability in drug efficacy as well as adverse events associated with any anti-rheumatic therapy and genetics is thought to contribute significantly to this inter-individual variability in response. The ability to screen the entire genome for association to complex diseases has great potential for identifying gene effects. DOI: http://dx.doi.org/10.3329/jom.v13i1.10048 JOM 2012; 13(1): 51-54

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