Gianni Panagiota, Loules Gedeon, Zamanakou Maria, Kompoti Maria, Csuka Dorottya, Psarros Fotis, Magerl Markus, Moldovan Dimitru, Maurer Marcus, Speletas Matthaios G, Farkas Henriette, Germenis Anastasios E
Department of Immunology and Histocompatibility, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
Int Arch Allergy Immunol. 2017;174(3-4):200-204. doi: 10.1159/000481987. Epub 2017 Nov 9.
In view of the large heterogeneity in the clinical presentation of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE), great efforts are being made towards detecting measurable biological determinants of disease severity that can help to improve the management of the disease. Considering the central role that plasma kallikrein plays in bradykinin production, we investigated the contribution of the functional polymorphism KLKB1-428G/A to the disease phenotype.
We studied 249 C1-INH-HAE patients from 114 European families, and we explored possible associations of C1-INH-HAE clinical features with carriage of KLKB1-428G/A, combined or not with that of the functional F12-46C/T polymorphism.
Carriers of the G allele of the KLKB1-428G/A polymorphism exhibited a significantly delayed disease onset (i.e., by 4.1 years [p < 0.001], depending on the zygocity status), while carriers of both the KLKB1-428G/A and the F12-46C/T polymorphism displayed an 8.8-year delay in disease onset (p < 0.001) and a 64% lower probability of needing long-term prophylactic treatment (p = 0.019).
These findings support our initial hypothesis that functional alterations in genes of proteins involved in bradykinin metabolism and function affect the clinical phenotype and possibly contribute to the pathogenesis of C1-INH-HAE. Given that an earlier onset of symptoms is inversely correlated with the subsequent course of the disease and, eventually, the need for long-term prophylaxis, these polymorphisms may be helpful prognostic biomarkers of disease severity.
鉴于C1抑制剂缺乏所致遗传性血管性水肿（C1-INH-HAE）临床表现存在巨大异质性，人们正在大力探寻可用于改善疾病管理的、能检测到的疾病严重程度生物学决定因素。考虑到血浆激肽释放酶在缓激肽生成中起核心作用，我们研究了功能性多态性KLKB1-428G/A对疾病表型的影响。
我们研究了来自114个欧洲家庭的249例C1-INH-HAE患者，探讨了C1-INH-HAE临床特征与携带KLKB1-428G/A（联合或不联合功能性F12-46C/T多态性）之间的可能关联。
KLKB1-428G/A多态性G等位基因携带者的疾病发病明显延迟（即延迟4.1年[p < 0.001]，取决于合子状态），而同时携带KLKB1-428G/A和F12-46C/T多态性的携带者疾病发病延迟8.8年（p < 0.001），且需要长期预防性治疗的概率降低64%（p = 0.019）。
这些发现支持了我们最初的假设，即参与缓激肽代谢和功能的蛋白质基因的功能改变会影响临床表型，并可能促成C1-INH-HAE的发病机制。鉴于症状出现较早与疾病的后续病程及最终对长期预防的需求呈负相关，这些多态性可能是有用的疾病严重程度预后生物标志物。
