Buck Dorothea, Cepok Sabine, Hoffmann Steve, Grummel Verena, Jochim Angela, Berthele Achim, Hartung Hans-Peter, Wassmuth Ralf, Hemmer Bernhard
Department of Neurology, Technische Universität München, Munich, Germany.
Arch Neurol. 2011 Apr;68(4):480-7. doi: 10.1001/archneurol.2011.65.
To determine relevant HLA-DRB1 alleles associated with the susceptibility of anti-interferon beta antibody development in a large patient cohort.
In a case-control study, HLA-DRB1 genotyping was performed in a discovery cohort (n = 268) and a validation cohort (n = 825).
Patients were recruited in Germany by primary care physicians and neurologists and were mainly of Northern European heritage.
All patients had a diagnosis of multiple sclerosis and were receiving long-term interferon beta therapy.
The antibody status to interferon beta was determined in all patients by capture enzyme-linked immunosorbent assay and in vivo myxovirus protein A assay and correlated with the HLA-DRB1 genotype.
In the discovery and validation cohorts, HLA-DRB1*04:01, *04:08, 16:01 were identified as genetic markers that are associated with an increased risk of anti-interferon beta antibody development (P < .05). In addition, alleles with a protective potential were identified, including HLA-DRB103:01, *04:04, *11:04. However, after correction for multiple testing, protective alleles did not reach statistical significance.
The HLA alleles identified in this study seem to be the major genetic determinant of antibody development, allowing the prediction of the individual risk of patients before initiation of therapy.
在一个大型患者队列中确定与抗干扰素β抗体产生易感性相关的HLA - DRB1等位基因。
在一项病例对照研究中，对一个发现队列（n = 268）和一个验证队列（n = 825）进行HLA - DRB1基因分型。
患者由德国的初级保健医生和神经科医生招募，主要为北欧血统。
所有患者均被诊断为多发性硬化症且正在接受长期干扰素β治疗。
通过捕获酶联免疫吸附测定法和体内黏液病毒蛋白A测定法确定所有患者的干扰素β抗体状态，并将其与HLA - DRB1基因型相关联。
在发现队列和验证队列中，HLA - DRB1*04:01、*04:08、16:01被确定为与抗干扰素β抗体产生风险增加相关的遗传标记（P <.05）。此外，还确定了具有保护潜力的等位基因，包括HLA - DRB103:01、*04:04、*11:04。然而，在进行多重检验校正后，保护等位基因未达到统计学显著性。
本研究中鉴定的HLA等位基因似乎是抗体产生的主要遗传决定因素，可在治疗开始前预测患者的个体风险。
