Department of Biomedical Science and Therapeutics, Faculty of Medicine & Health Science, Universiti Malaysia Sabah, Jalan UMS, 88400, Kota Kinabalu, Sabah, Malaysia.
Infectious Diseases Research Group, School of Medical & Applied Sciences, Central Queensland University, Rockhampton, QLD, 4702, Australia.
BMC Nephrol. 2020 Sep 7;21(1):388. doi: 10.1186/s12882-020-02052-9.
New-onset diabetes after transplantation (NODAT) is associated with reduced patient and graft survival. This study examined the clinical and selected genetic factors associated with NODAT among renal-transplanted Malaysian patients.
This study included 168 non-diabetic patients (58% males, 69% of Chinese ethnicity) who received renal transplantation between 1st January 1994 to 31st December 2014, and were followed up in two major renal transplant centres in Malaysia. Fasting blood glucose levels were used to diagnose NODAT in patients who received renal transplantation within 1 year. Two single nucleotide polymorphisms (SNPs), namely; rs1494558 (interleukin-7 receptor, IL-7R) and rs2232365 (mannose-binding leptin-2, MBL2) were selected and genotyped using Sequenom MassArray platform. Cox proportional hazard regression analyses were used to examine the risk of developing NODAT according to the different demographics and clinical covariates, utilizing four time-points (one-month, three-months, six-months, one-year) post-transplant.
Seventeen per cent of patients (n = 29, 55% males, 69% Chinese) were found to have developed NODAT within one-year of renal transplantation based on their fasting blood glucose levels. NODAT patients had renal transplantation at an older age compared to non-NODAT (39.3 ± 13.4 vs 33.9 ± 11.8 years, p = 0.03). In multivariate analysis, renal-transplanted patients who received a higher daily dose of cyclosporine (mg) were associated with increased risk of NODAT (Hazard ratio (HR) =1.01 per mg increase in dose, 95% confidence interval (CI) 1.00-1.01, p = 0.002). Other demographic (gender, ethnicities, age at transplant) and clinical factors (primary kidney disease, type of donor, place of transplant, type of calcineurin inhibitors, duration of dialysis pre-transplant, BMI, creatinine levels, and daily doses of tacrolimus and prednisolone) were not found to be significantly associated with risk of NODAT. GA genotype of rs1494558 (HR = 3.15 95% CI 1.26, 7.86) and AG genotype of rs2232365 (HR = 2.57 95% CI 1.07, 6.18) were associated with increased risk of NODAT as compared to AA genotypes.
The daily dose of cyclosporine and SNPs of IL-7R (rs1494558) and MBL2 (rs2232365) genes are significantly associated with the development of NODAT in the Malaysian renal transplant population.
移植后新发糖尿病（NODAT）与患者和移植物存活率降低有关。本研究旨在探讨马来西亚肾移植患者中与 NODAT 相关的临床和部分遗传因素。
本研究纳入了 168 名非糖尿病患者（58%为男性，69%为华人），他们于 1994 年 1 月 1 日至 2014 年 12 月 31 日期间在马来西亚的两个主要肾移植中心接受了肾移植，并接受了随访。在肾移植后 1 年内，通过检测空腹血糖水平来诊断 NODAT。选择了两个单核苷酸多态性（SNP），即 rs1494558（白细胞介素-7 受体，IL-7R）和 rs2232365（甘露糖结合凝集素-2，MBL2），并使用 Sequenom MassArray 平台进行基因分型。采用 Cox 比例风险回归分析，利用四个时间点（移植后一个月、三个月、六个月和一年），根据不同的人口统计学和临床协变量，评估发生 NODAT 的风险。
根据空腹血糖水平，17%的患者（n=29，55%为男性，69%为华人）在肾移植后一年内被诊断为 NODAT。与非 NODAT 患者相比，NODAT 患者的肾移植年龄较大（39.3±13.4 岁 vs 33.9±11.8 岁，p=0.03）。多变量分析显示，接受较高日剂量环孢素（mg）的肾移植患者发生 NODAT 的风险增加（风险比（HR）=1.01/剂量增加 1mg，95%置信区间（CI）为 1.00-1.01，p=0.002）。其他人口统计学因素（性别、种族、移植时年龄）和临床因素（原发病、供体类型、移植地点、钙调神经磷酸酶抑制剂类型、移植前透析时间、BMI、肌酐水平以及他克莫司和泼尼松龙的日剂量）与 NODAT 的风险均无显著相关性。与 AA 基因型相比，rs1494558 的 GA 基因型（HR=3.15，95%CI 1.26-7.86）和 rs2232365 的 AG 基因型（HR=2.57，95%CI 1.07-6.18）与 NODAT 风险增加相关。
环孢素的日剂量和 IL-7R（rs1494558）和 MBL2（rs2232365）基因的 SNP 与马来西亚肾移植人群中 NODAT 的发生显著相关。
