Pharmacogenomics of multiple sclerosis: Association of immune response gene polymorphisms with copaxone treatment efficacy

Tsareva, Ekaterina; Кулакова, О. Г.; Makarycheva, O. Yu.; Boyko, A. N.; Shchur, S G; Lashch, N. Yu.; Popova, N. F.; Гусев, Е. И.; Bashinskaya, Vitalina; Lvov, D. V.; Favorov, Alexander V.; Ochs, Michael F.; Фаворова, О. О.

doi:10.1134/s0026893311060185

Cited by 14 publications

(4 citation statements)

References 22 publications

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“…Prior pharmacogenetic studies of Copaxone response have utilized candidate-gene approaches in cohorts largely drawn from observational and hospital-based patient populations [ 16 – 19 , 21 ]. This has resulted in limited reproducibility, potentially due to variable response criteria and small sample sizes.…”

Section: Discussionmentioning

confidence: 99%

“…To date, pharmacogenetic studies of Copaxone, ranging in size from tens to a few hundreds of patients (Additional file 1 ), have been based on candidate-genes presumed to be associated with its MoA, e.g., production and activation of Copaxone-specific anti-inflammatory and regulatory T-cells [ 16 – 19 , 21 ]. The presence of variants in the HLA class II genes has been observed to be positively associated with Copaxone response.…”

Section: Introductionmentioning

confidence: 99%

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A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis

Ross

Towfic²,

Shankar³

et al. 2017

Genome Med

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BackgroundCopaxone is an efficacious and safe therapy that has demonstrated clinical benefit for over two decades in patients with relapsing forms of multiple sclerosis (MS). On an individual level, patients show variability in their response to Copaxone, with some achieving significantly higher response levels. The involvement of genes (e.g., HLA-DRB1*1501) with high inter-individual variability in Copaxone’s mechanism of action (MoA) suggests the potential contribution of genetics to treatment response. This study aimed to identify genetic variants associated with Copaxone response in patient cohorts from late-phase clinical trials.MethodsSingle nucleotide polymorphisms (SNPs) associated with high and low levels of response to Copaxone were identified using genome-wide SNP data in a discovery cohort of 580 patients from two phase III clinical trials of Copaxone. Multivariable Bayesian modeling on the resulting SNPs in an expanded discovery cohort with 1171 patients identified a multi-SNP signature of Copaxone response. This signature was examined in 941 Copaxone-treated MS patients from seven independent late-phase trials of Copaxone and assessed for specificity to Copaxone in 310 Avonex-treated and 311 placebo-treated patients, also from late-phase trials.ResultsA four-SNP signature consisting of rs80191572 (in UVRAG), rs28724893 (in HLA-DQB2), rs1789084 (in MBP), and rs139890339 (in ZAK(CDCA7)) was identified as significantly associated with Copaxone response. Copaxone-treated signature-positive patients had a greater reduction in annualized relapse rate (ARR) compared to signature-negative patients in both discovery and independent cohorts, an effect not observed in Avonex-treated patients. Additionally, signature-positive placebo-treated cohorts did not show a reduction in ARR, demonstrating the predictive as opposed to prognostic nature of the signature. A 10% subset of patients, delineated by the signature, showed marked improvements across multiple clinical parameters, including ARR, MRI measures, and higher proportion with no evidence of disease activity (NEDA).ConclusionsThis study is the largest pharmacogenetic study in MS reported to date. Gene regions underlying the four-SNP signature have been linked with pathways associated with either Copaxone’s MoA or the pathophysiology of MS. The pronounced association of the four-SNP signature with clinical improvements in a ~10% subset of the MS patient population demonstrates the complex interplay of immune mechanisms and the individualized nature of response to Copaxone.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0436-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis

Ross

Towfic²,

Shankar³

et al. 2017

Genome Med

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“…The Yakut population is of particular interest in terms of ethnogenomics, since the founder effect and a certain geographic and cultural isolation are observed in it [ 76 ]. APSampler was also used in pharmacogenetic studies of MS for the investigation of the relationship between the genetic status in patients and the efficacy of treatment with immunomodulatory drugs, interferon beta (in Irish patients, [ 67 ]) and glatiramer acetate (in Russian patients, [ 29 , 77 ]).…”

Section: Studies Performed Using Apsamplermentioning

confidence: 99%

A Polygenic Approach to the Study of Polygenic Diseases

2012

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Polygenic diseases are caused by the joint contribution of a number of independently acting or interacting polymorphic genes; the individual contribution of each gene may be small or even unnoticeable. The carriage of certain combinations of genes can determine the occurrence of clinically heterogeneous forms of the disease and treatment efficacy. This review describes the approaches used in a polygenic analysis of data in medical genomics, in particular, pharmacogenomics, aimed at identifying the cumulative effect of genes. This effect may result from the summation of gains of different genes or be caused by the epistatic interaction between the genes. Both cases are undoubtedly of great interest in investigating the nature of polygenic diseases. The means that allow one to discriminate between these two possibilities are discussed. The methods for searching for combinations of alleles of different genes associated with the polygenic phenotypic traits of the disease, as well as the methods for presenting and validating the results, are described and compared. An attempt is made to evaluate the applicability of the existing methods to an epistasis analysis. The results obtained by the authors using the APSampler software are described and summarized.

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“…A significant genetic determinism of individual response to treatment with many drugs may be evidence of genetic predisposition. For example, the pharmacogenomic studies of MS have revealed a significant role for a number of polymorphic variants of genes ( CCR5, DRB1, IFNG, TGFB1, IFNAR1, IL7RA, and possibly , TNF and CTLA4 ) in response to the administration of Copaxone [16]. Epidemiological studies, in turn, have identified several risk factors for MS, including bacterial and viral infections, climatic conditions, and smoking.…”

Section: Introductionmentioning

confidence: 99%

Polyreactive Monoclonal Autoantibodies in Multiple Sclerosis: Functional Selection from Phage Display Library and Characterization by Deep Sequencing Analysis

Lomakin¹,

Захарова²,

Belogurov³

et al. 2013

Acta Naturae

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Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that primarily affects young and middle-aged people. It is widely accepted that B lymphocyte activation is required for MS progression. Despite the fact that the exact triggering mechanisms of MS remain enigmatic, one may suggest that MS can be induced by viral or bacterial infection in combination with specific genetic and environmental factors. Using deep sequencing and functional selection methodologies we characterized clones of poly- and cross-reactive antibodies that are capable of simultaneous recognition of viral proteins and autoantigens. The latter, in turn, possibly may trigger MS progression through molecular mimicry. It was identified that two cross-reactive antigens are probably recognized by light or heavy chains individually. According to the high structural homology between selected autoantibodies and a number of various antiviral IgGs, we suggest that a wide range of pathogens, instead of a single virus, be regarded as possible triggers of MS.

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Pharmacogenomics of multiple sclerosis: Association of immune response gene polymorphisms with copaxone treatment efficacy

Cited by 14 publications

References 22 publications

A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis

A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis

A Polygenic Approach to the Study of Polygenic Diseases

Polyreactive Monoclonal Autoantibodies in Multiple Sclerosis: Functional Selection from Phage Display Library and Characterization by Deep Sequencing Analysis

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