SLC30A8 多态性和 BMI 补充 HLA-A*24 作为胰岛同种异体移植受者移植物功能不良的危险因素。

SLC30A8 polymorphism and BMI complement HLA-A*24 as risk factors for poor graft function in islet allograft recipients.

机构信息

Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.

Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium.

出版信息

Diabetologia. 2018 Jul;61(7):1623-1632. doi: 10.1007/s00125-018-4609-z. Epub 2018 Apr 20.

DOI:10.1007/s00125-018-4609-z

PMID:29679103

Abstract

AIMS/HYPOTHESIS: HLA-A24 carriership hampers achievement of insulin independence in islet allograft recipients. However, less than half of those who fail to achieve insulin independence carry the allele. We investigated whether genetic polymorphism at the recipients' zinc transporter 8-encoding SLC30A8 gene (rs13266634) could complement their HLA-A24 status in predicting functional graft outcome.

METHODS

We retrospectively analysed data of a hospital-based patient cohort followed for 18 months post transplantation. Forty C-peptide-negative type 1 diabetic individuals who received >2 million beta cells (>4000 islet equivalents) per kg body weight in one or two intraportal implantations under similar immunosuppression were genotyped for SLC30A8. Outcome measurements included achievement and maintenance of graft function. Metabolic benefit was defined as <25% CV of fasting glycaemia in the presence of >331 pmol/l C-peptide, in addition to achievement of insulin independence and maintenance of C-peptide positivity.

RESULTS

In multivariate analysis, HLA-A24 positivity, presence of SLC30A8 CT or TT genotypes and BMI more than or equal to the group median (23.9 kg/m) were independently associated with failure to achieve insulin independence (p = 0.015-0.046). The risk increased with the number of factors present (p < 0.001). High BMI interacted with SLC30A8 T allele carriership to independently predict difficulty in achieving graft function with metabolic benefit (p = 0.015). Maintenance of C-peptide positivity was mainly associated with older age at the time of implantation. Only HLA-A24 carriership independently predicted failure to maintain acceptable graft function once achieved (p = 0.012).

CONCLUSIONS/INTERPRETATION: HLA-A*24, the SLC30A8 T allele and high BMI are associated with poor graft outcome and should be considered in the interpretation of future transplantation trials.

TRIAL REGISTRATION

ClinicalTrials.gov NCT00798785 and NCT00623610.

摘要

目的/假设：HLA-A24 携带者阻碍胰岛同种异体移植受者实现胰岛素独立性。然而，未能实现胰岛素独立性的患者中，只有不到一半携带该等位基因。我们研究了受者锌转运体 8 编码 SLC30A8 基因（rs13266634）的遗传多态性是否可以补充其 HLA-A24 状态，从而预测功能移植物的结果。

方法

我们回顾性分析了一家医院基于患者队列的数据分析，这些患者在移植后 18 个月内接受了随访。40 名 C 肽阴性 1 型糖尿病患者在相似的免疫抑制下接受了每公斤体重超过 200 万个β细胞（超过 4000 个胰岛当量）的一次或两次门静脉内移植，这些患者的 SLC30A8 进行了基因分型。结果测量包括获得和维持移植物功能。代谢益处定义为空腹血糖变异系数（CV）小于 25%，同时 C 肽大于 331pmol/L，以及实现胰岛素独立性和维持 C 肽阳性。

结果

在多变量分析中，HLA-A24 阳性、存在 SLC30A8 CT 或 TT 基因型和 BMI 大于或等于组中位数（23.9kg/m）与未能实现胰岛素独立性独立相关（p=0.015-0.046）。存在的因素越多，风险越高（p<0.001）。高 BMI 与 SLC30A8 T 等位基因携带相互作用，独立预测具有代谢益处的移植物功能获得困难（p=0.015）。C 肽阳性的维持主要与移植时的年龄较大有关。只有 HLA-A24 携带状态独立预测一旦获得可接受的移植物功能后出现功能丧失（p=0.012）。

结论/解释：HLA-A*24、SLC30A8 T 等位基因和高 BMI 与移植物不良结果相关，在解释未来的移植试验时应予以考虑。