CTLA-4 Polymorphisms in Patients with IgA Nephropathy Correlate with Proteinuria

Abstract

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. Methods: 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. Results: 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). Conclusion: 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.

T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target

“…However, some studies reported the contrary results [39]. Another factor affecting the function of Tregs in IgAN is an expression of CTLA-4; Jacob et al reported that polymorphisms attributed to decreased CTLA-4 gene expression were associated with higher proteinuria in IgAN patients [40]. However, the actual Treg’s CTLA-4 protein level was not investigated.…”

“…Proteinuria-positive patients have a higher frequency of Th22 cells than proteinuria-negative IgAN patients and healthy people [14]. Moreover, higher proteinuria was observed in the patients possessing polymorphisms that caused a decreased expression of CTLA-4, immunosuppressive protein expressed on Tregs [40]. On the other hand, negative correlations were observed between the severity of 24-h proteinuria and tonsillar Th1/Th2 ratio [21], miR-155 level in PBMC [15], and frequency of activated Tregs [13].…”

CTLA-4 Expression Inversely Correlates with Kidney Function and Serum Immunoglobulin Concentration in Patients with Primary Glomerulonephritides

“…The CTLA-4 rs231726 gene is associated with a higher risk of developing IgA nephropathy (Wang et al 2014), and the CTLA-4 rs231779 gene is associated with proteinuria, podocyte foot process effacement, and advanced mesangial proliferation (Kim et al 2011). Additionally, data obtained by Jacob et al (2018) support the hypothesis that CTLA-4 may be involved in the development and progression of IgA nephropathy. They found that frequencies of the –318/C/T SNP within the CTLA-4 gene locus appreciably differ between IgA nephropathy patients and healthy controls.…”

Association of Immune and Inflammatory Gene Polymorphism With the Risk of IgA Nephropathy: A Systematic Review and Meta-Analysis of 45 Studies

“…CTLA4 is a negative regulator in CD28 signaling and plays a key role in the initiation and termination of immune responses, whereas ICOS regulates the activation and tolerance of T cells. The G allele in CTLA4 rs231779 significantly increased the risk and was related to the prevalence of proteinuria ( 15 , 56 ). As for the correlation between SNPs and clinical symptoms, HLA-DQB1/DRB1 had a high association with a minor allele in rs2856717 that cannot be covered by adjustment of LD structure, protective haplotype (ACAT) and at-risk haplotypes (ATAT, GCGT).…”