HLA-G启动子及14碱基对插入缺失变异与急性移植物排斥反应和终末期肾病的关联
Association of HLA-G promoter and 14-bp insertion-deletion variants with acute allograft rejection and end-stage renal disease.
作者信息
Misra M K, Prakash S, Kapoor R, Pandey S K, Sharma R K, Agrawal S
机构信息
Department of Medical genetics, Sanjay Gandhi Post-graduate Institute of Medical Sciences, Lucknow, India; Department of Anatomy, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
出版信息
Tissue Antigens. 2013 Nov;82(5):317-26. doi: 10.1111/tan.12210.
The aim of this study was to investigate the HLA-G 14-bp insertion/deletion (I/D) polymorphism among end-stage renal disease (ESRD) patients. Cytomegalovirus (CMV) infection, acute allograft rejection (AR) and overall survival after renal transplantation was investigated in 300 ESRD patients and 302 age, sex and ethnicity-matched controls. Sequencing was performed to evaluate the impact of HLA-G promoter region single-nucleotide polymorphisms (SNPs) whereas semi-quantitative PCR method was used to determine the probable HLA-G expression pattern among ESRD and AR cases. Further, soluble human leukocyte antigen (HLA)-G (sHLA-G) expression levels were compared in AR vs non-AR cases in the light of HLA-G 14-bp I/D polymorphism. Increased risk was found for 14-bp D/D (deletion-DD) genotype and 14-bp D allele [DD: odds ratio (OR) = 1.46, 95% confidence interval (CI) = 1.03-2.06, P value = 0.0358; D: OR = 1.29, 95% CI = 1.03-1.62, P value = 0.0277], respectively for ESRD and CMV infection (DD: OR = 2.70, 95% CI = 1.45-5.05, P value = 0.0021; D: OR = 1.94, 95% CI = 1.22-3.08, P value = 0.0052). Nearly fourfold (OR = 3.62, 95%CI = 1.61-8.14, p = 0.0039) risk was observed for 14-bp I/I (insertion-II) genotype for AR. Survival analysis showed increased overall survival (OS) (AR or death) for 14-bp D/D genotype. HLA-G promoter region sequencing was carried out among 60 ESRD patients and 100 normal controls which showed increased risk for -964 G>A, -725 C>G/T and -486 A>C SNPs. -964 G>A and -725 C>G/T SNPs showed risk association for AR patients. High level of HLA-G transcripts was observed among non-AR patients. Further soluble HLA-G (sHLA-G) showed increased levels in ESRD patients (mean ± SEM; 62.16 ± 2.43 U/ml) as compared to controls (mean ± SEM; 21.06 ± 3.89 U/ml) (P = <0.0001). The 14-bp I/I, 14-bp I/D and 14-bp D/D genotypes showed significantly higher levels of sHLA-G among non-AR as compared to AR patients.
本研究旨在调查终末期肾病（ESRD）患者中HLA - G 14碱基对插入/缺失（I/D）多态性。对300例ESRD患者以及302例年龄、性别和种族匹配的对照者，研究了肾移植后的巨细胞病毒（CMV）感染、急性移植排斥反应（AR）和总体生存率。采用测序法评估HLA - G启动子区域单核苷酸多态性（SNP）的影响，而采用半定量PCR法确定ESRD和AR病例中可能的HLA - G表达模式。此外，根据HLA - G 14碱基对I/D多态性，比较了AR与非AR病例中可溶性人类白细胞抗原（HLA）- G（sHLA - G）的表达水平。发现14碱基对D/D（缺失 - DD）基因型和14碱基对D等位基因与ESRD和CMV感染的风险增加有关[DD：比值比（OR）= 1.46，95%置信区间（CI）= 1.03 - 2.06，P值 = 0.0358；D：OR = 1.29，95% CI = 1.03 - 1.62，P值 = 0.0277]，分别对应ESRD和CMV感染（DD：OR = 2.70，95% CI = 1.45 - 5.05，P值 = 0.0021；D：OR = 1.94，95% CI = 1.22 - 3.08，P值 = 0.0052）。观察到14碱基对I/I（插入 - II）基因型的AR风险增加近四倍（OR = 3.62，95% CI = 1.61 - 8.14，p = 0.0039）。生存分析显示，14碱基对D/D基因型的总体生存率（OS）（AR或死亡）增加。对60例ESRD患者和100例正常对照者进行了HLA - G启动子区域测序，结果显示 - 964 G>A、 - 725 C>G/T和 - 486 A>C SNP的风险增加。 - 964 G>A和 - 725 C>G/T SNP与AR患者的风险相关。在非AR患者中观察到高水平的HLA - G转录本。此外，与对照者（平均值±标准误；21.06±3.89 U/ml）相比，ESRD患者中可溶性HLA - G（sHLA - G）水平升高（平均值±标准误；62.16±2.43 U/ml）（P = <0.0001）。与AR患者相比，14碱基对I/I、14碱基对I/D和14碱基对D/D基因型在非AR患者中显示出显著更高的sHLA - G水平。
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