■肾脏手术耐受是在没有免疫抑制的情况下延长肾脏同种异体移植功能的一种罕见且有益的状态。潜在的机制是未知的。我们假设耐受性可能是由遗传蛋白质编码遗传变异驱动的,具有很大的影响,至少在一些病人身上。
■我们对超过218,000名肾移植受者进行了一项欧洲调查,并从40名移植受者中收集了DNA,这些受者在没有免疫抑制的情况下保持良好的同种异体移植功能至少1年。我们进行了一项全外显子组关联研究,比较了36例耐受患者中至高影响变异的分布情况。使用主成分分析选择遗传同质性,和192个控件,使用针对小样本调整的最佳序列-核关联检验。
■我们确定了HOMER2的罕见变体(3/36,FDR0.0387),IQCH(5/36,FDR0.0362),10例耐受患者的LCN2(3/36,FDR0.102)与0控件。一名患者携带HOMER2和LCN2的变体。此外,这三个基因在两名患者中显示出相同的变异。这三个基因在初级纤毛表达,免疫反应的关键结构。
■稀有蛋白质编码变异与相当一部分患者的手术耐受性相关。我们的发现对于更好地理解移植和其他医学领域的免疫耐受具有重要意义。ClinicalTrials.gov,标识符:NCT0512444。
UNASSIGNED: Renal operational tolerance is a rare and beneficial state of prolonged renal allograft function in the absence of immunosuppression. The underlying mechanisms are unknown. We hypothesized that tolerance might be driven by inherited protein coding genetic variants with large effect, at least in some patients.
UNASSIGNED: We set up a European survey of over 218,000 renal transplant recipients and collected DNAs from 40 transplant recipients who maintained good allograft function without immunosuppression for at least 1 year. We performed an exome-wide association
study comparing the distribution of moderate to high impact variants in 36 tolerant patients, selected for genetic homogeneity using principal component analysis, and 192 controls, using an optimal sequence-kernel association test adjusted for small samples.
UNASSIGNED: We identified rare variants of HOMER2 (3/36, FDR 0.0387), IQCH (5/36, FDR 0.0362), and LCN2 (3/36, FDR 0.102) in 10 tolerant patients vs. 0 controls. One patient carried a variant in both HOMER2 and LCN2. Furthermore, the three genes showed an identical variant in two patients each. The three genes are expressed at the primary cilium, a key structure in immune responses.
UNASSIGNED: Rare protein coding variants are associated with operational tolerance in a sizable portion of patients. Our findings have important implications for a better understanding of immune tolerance in transplantation and other fields of medicine.ClinicalTrials.gov, identifier: NCT05124444.