Jacob Marius, Ohl Kim, Goodarzi Tannaz, Harendza Sigrid, Eggermann Thomas, Fitzner Christina, Hilgers Ralf-Dieter, Bolte Anna, Floege Jürgen, Rauen Thomas, Tenbrock Klaus
RWTH Aachen University, Dept. of Pediatrics, Aachen, Germany.
Universitätsklinikum Hamburg-Eppendorf, Zentrum für Innere Medizin, III. Medizinische Klinik, Hamburg, Germany.
Kidney Blood Press Res. 2018;43(2):360-366. doi: 10.1159/000488069. Epub 2018 Mar 8.
BACKGROUND/AIMS: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and still constitutes one of the most important causes of end-stage renal disease. Abnormal T cell responses may play a role in IgAN pathogenesis. Co-stimulatory molecules such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are important for naive T cells to initiate and terminate immune responses. Single nucleotide polymorphisms (SNPs) in the CTLA4 gene locus are associated with several autoimmune diseases.
We aimed to investigate the occurrence of the SNPs -318C/T, +49A/G and CT60 G/A within the CTLA4 locus in healthy blood donors (n=455) and IgAN patients (n=252) recruited from the recently published STOP-IgAN trial. The presence of these SNPs was then associated with baseline proteinuria in IgAN patients.
We observed a significantly increased frequency of the CTLA4 -318C/T genotype in IgAN patients as compared to controls (CC vs. CT+TT: OR 1.65, 95%-CI 1.03-2.65, p=0.035). No significant associations, neither with the +49A/G nor for the CT60 G/A SNP, were detected. However, when we stratified for proteinuria at time of inclusion into the STOP-IgAN trial (<1 g/day vs. >1 g/day), we observed significant differences in the frequencies of the CT60 G/A genotype, i.e. a significantly increased risk for higher proteinuria in patients carrying the G allele (OR 2.81, 95%-CI 1.03-7.64, p=0.042).
The CTLA4 -318/C/T SNP was associated with an increased risk to develop IgAN, while the CT60 G/A genotype significantly associated with the risk for higher proteinuria suggesting a possible role for CTLA-4 in IgAN.
背景/目的：IgA肾病（IgAN）是原发性肾小球肾炎最常见的形式，仍是终末期肾病的最重要病因之一。异常的T细胞反应可能在IgAN发病机制中起作用。共刺激分子如细胞毒性T淋巴细胞相关抗原4（CTLA-4）对于初始T细胞启动和终止免疫反应很重要。CTLA4基因座中的单核苷酸多态性（SNP）与几种自身免疫性疾病相关。
我们旨在研究从最近发表的STOP-IgAN试验中招募的健康献血者（n = 455）和IgAN患者（n = 252）中CTLA4基因座内SNP -318C/T、+49A/G和CT60 G/A的发生情况。然后将这些SNP的存在与IgAN患者的基线蛋白尿相关联。
与对照组相比，我们观察到IgAN患者中CTLA4 -318C/T基因型的频率显著增加（CC与CT+TT：OR 1.65，95%置信区间1.03 - 2.65，p = 0.035）。未检测到与+49A/G或CT60 G/A SNP有显著关联。然而，当我们根据纳入STOP-IgAN试验时的蛋白尿情况进行分层（<1 g/天与>1 g/天）时，我们观察到CT60 G/A基因型频率存在显著差异，即携带G等位基因的患者蛋白尿增加的风险显著增加（OR 2.81，95%置信区间1.03 - 7.64，p = 0.042）。
CTLA4 -318/C/T SNP与发生IgAN的风险增加相关，而CT60 G/A基因型与蛋白尿增加的风险显著相关，提示CTLA-4在IgAN中可能起作用。
