Poppelaars Felix, Gaya da Costa Mariana, Faria Bernardo, Eskandari Siawosh K, Damman Jeffrey, Seelen Marc A
Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Nephrology and Infectious Disease R&D Group, INEB, Institute of Investigation and Innovation in Health (i3S), University of Porto, Porto, Portugal.
Clin Kidney J. 2021 Sep 17;15(2):278-286. doi: 10.1093/ckj/sfab175. eCollection 2022 Feb.
Improvement of long-term outcomes in kidney transplantation remains one of the most pressing challenges, yet drug development is stagnating. Human genetics offers an opportunity for much-needed target validation in transplantation. Conflicting data exist about the effect of transforming growth factor-beta 1 (TGF-β1) on kidney transplant survival, since TGF-β1 has pro-fibrotic and protective effects. We investigated the impact of a recently discovered functional polymorphism on kidney graft survival.
We performed an observational cohort study analysing recipient and donor DNA in 1271 kidney transplant pairs from the University Medical Centre Groningen in The Netherlands, and associated a low-producing polymorphism (rs1800472-C > T) with 5-, 10- and 15-year death-censored kidney graft survival.
Donor genotype frequencies of rs1800472 in differed significantly between patients with and without graft loss (P = 0.014). Additionally, the low-producing polymorphism in the donor was associated with an increased risk of graft loss following kidney transplantation (hazard ratio = 2.12 for the T-allele; 95% confidence interval 1.18-3.79; P = 0.012). The incidence of graft loss within 15 years of follow-up was 16.4% in the CC-genotype group and 31.6% in the CT-genotype group. After adjustment for transplant-related covariates, the association between the polymorphism in the donor and graft loss remained significant. In contrast, there was no association between the polymorphism in the recipient and graft loss.
Kidney allografts possessing a low-producing polymorphism have a higher risk of late graft loss. Our study adds to a growing body of evidence that TGF-β1 is beneficial, rather than harmful, for kidney transplant survival.
改善肾移植的长期预后仍然是最紧迫的挑战之一，然而药物研发却停滞不前。人类遗传学为移植领域急需的靶点验证提供了契机。关于转化生长因子β1（TGF-β1）对肾移植存活的影响，存在相互矛盾的数据，因为TGF-β1具有促纤维化和保护作用。我们研究了一种新发现的功能性多态性对肾移植存活的影响。
我们进行了一项观察性队列研究，分析了荷兰格罗宁根大学医学中心1271对肾移植受者和供者的DNA，并将一种低表达多态性（rs1800472 - C>T）与5年、10年和15年死亡删失的肾移植存活情况相关联。
rs1800472的供者基因型频率在有和没有移植肾丢失的患者之间存在显著差异（P = 0.014）。此外，供者中的低表达多态性与肾移植后移植肾丢失风险增加相关（T等位基因的风险比 = 2.12；95%置信区间1.18 - 3.79；P = 0.012）。随访15年内，CC基因型组移植肾丢失发生率为16.4%，CT基因型组为31.6%。在对移植相关协变量进行调整后，供者中的多态性与移植肾丢失之间的关联仍然显著。相比之下，受者中的多态性与移植肾丢失之间没有关联。
具有低表达多态性的同种异体肾移植后期移植肾丢失风险更高。我们的研究进一步证明了TGF-β1对肾移植存活有益而非有害。
