Clinical Pharmacology and Pharmacogenomics Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
Department of Neurology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt.
Front Immunol. 2023 Feb 17;14:1087595. doi: 10.3389/fimmu.2023.1087595. eCollection 2023.
Multiple sclerosis (MS) is characterized by a complex etiology that is reflected in the lack of consistently predictable treatment responses across patients of seemingly similar characteristics. Approaches to demystify the underlying predictors of aberrant treatment responses have made use of genome-wide association studies (GWAS), with imminent progress made in identifying single nucleotide polymorphisms (SNPs) associated with MS risk, disease progression, and treatment response. Ultimately, such pharmacogenomic studies aim to utilize the approach of personalized medicine to maximize patient benefit and minimize rate of disease progression.
Very limited research is available around the long intergenic non-coding RNA (linc)00513, recently being reported as a novel positive regulator of the type-1 interferon (IFN) pathway, following its overexpression in the presence of two polymorphisms: rs205764 and rs547311 in the promoter region of this gene. We attempt to provide data on the prevalence of genetic variations at rs205764 and rs547311 in Egyptian MS patients, and correlate these polymorphisms with the patients' responses to disease-modifying treatments.
Genomic DNA from 144 RRMS patients was isolated and analyzed for genotypes at the positions of interest on linc00513 using RT-qPCR. Genotype groups were compared with regards to their response to treatment; additional secondary clinical parameters including the estimated disability status score (EDSS), and onset of the disease were examined in relation to these polymorphisms.
Polymorphisms at rs205764 were associated with a significantly higher response to fingolimod and a significantly lower response to dimethylfumarate. Moreover, the average EDSS of patients carrying polymorphisms at rs547311 was significantly higher, whereas no correlation appeared to exist with the onset of MS.
Understanding the complex interplay of factors influencing treatment response is pivotal in MS. One of the factors contributing to a patient's response to treatment, as well as disease disability, may be polymorphisms on non-coding genetic material, such as rs205764 and rs547311 on linc00513. Through this work, we propose that genetic polymorphisms may partially drive disease disability and inconsistent responses to treatment in MS; we also aim to draw attention towards genetic approaches, such as screening for specific polymorphisms, to possibly direct treatment choices in such a complex disease.
多发性硬化症（MS）的病因复杂，这反映在不同特征相似的患者之间缺乏一致的可预测的治疗反应。为了解释异常治疗反应的潜在预测因素，人们采用了全基因组关联研究（GWAS），在确定与 MS 风险、疾病进展和治疗反应相关的单核苷酸多态性（SNP）方面取得了进展。最终，这种药物基因组学研究旨在利用个性化医疗的方法，使患者获益最大化，疾病进展率最小化。
关于长非编码 RNA（lnc）00513 的研究非常有限，最近有研究报道，该基因的启动子区域中的两个多态性 rs205764 和 rs547311 存在时，其过表达会成为 1 型干扰素（IFN）途径的新的正调节剂。我们试图提供埃及 MS 患者中 rs205764 和 rs547311 遗传变异的流行率数据，并将这些多态性与患者对疾病修饰治疗的反应相关联。
从 144 例 RRMS 患者中提取基因组 DNA，使用 RT-qPCR 分析 linc00513 位置的基因型。将基因型组与治疗反应进行比较；还检查了包括估计残疾状态评分（EDSS）在内的其他次要临床参数与这些多态性之间的关系。
rs205764 多态性与 fingolimod 治疗反应显著升高相关，与 dimethylfumarate 治疗反应显著降低相关。此外，携带 rs547311 多态性的患者的平均 EDSS 显著较高，而与 MS 发病无相关性。
了解影响治疗反应的复杂因素相互作用对于 MS 至关重要。影响患者对治疗反应以及疾病残疾的因素之一可能是非编码遗传物质上的多态性，如 linc00513 上的 rs205764 和 rs547311。通过这项工作，我们提出遗传多态性可能部分导致 MS 疾病残疾和对治疗的不一致反应；我们还旨在引起对遗传方法的关注，例如筛选特定的多态性，以可能指导此类复杂疾病的治疗选择。
