Influence of TGFB1 and CTLA4 polymorphisms on calcineurin inhibitors dose and risk of acute rejection in renal transplantation

Abstract

Organ transplant is often the treatment of choice as it extends and improves patient life. Immunosuppressive treatment, which prevents acute rejection of the organ, is used in transplant patients to prevent the loss of transplant. The aim of the study was to determine the impact of the CTLA4 (+49A>G, rs231775) and the TGF-β1 (−800G>A, rs1800468) polymorphisms on the therapeutic effect of immunosuppressive drugs (cyclosporine—CsA, tacrolimus—TAC) and the risk of acute rejection in renal transplant patients. The analysis of the CTLA4 +49A>G and the TGF-β1 −800G>A polymorphisms was carried out in 392 patients after kidney transplant using real-time PCR. The CTLA4 +49A>G polymorphism did not affect CsA or TAC dose, ratio of drug concentration to dose (C/D), and blood concentrations. As for the TGF-β1 -800G>A polymorphism, patients with the GA genotype required lower TAC doses compared to the GG genotype (TAC 12 h: 3.63 mg vs 5.3 mg, TAC 24 h: 2.38 mg vs 3.29 mg). Comparing the C/D ratio in both groups (TAC 12 h and TAC 24 h), higher C/D ratio was observed in patients with the GA genotype. These results indicate that patients with the A allele require slightly lower doses of TAC. The results suggest that the TGF-β1 −800 G>A polymorphism may influence the TAC dose, while the +49A>G polymorphism of the CTLA4 gene does not correlate with the dose of CsA or TAC. The analysis of the biochemical parameters of the renal profile showed no impact of the CTLA4 and the TGF-β1 polymorphisms on the risk of organ rejection.

Serum Transforming Growth Factor β1 and Its Genetic Variants Are Associated with Increased Macrophage Inflammatory Protein 1β and Susceptibility to Idiopathic Carpal Tunnel Syndrome

“…Regarding rs1800468 (−800G/A), CTS patients had an increased frequency of major allele G. It is controversial that minor allele A > G is associated with the occurrence of cervical cancer [ 42 ] and coronary heart disease [ 43 ]. In addition, our results showed that the minor protective A allele (GA and AA) resulted in a significant increase in serum TGF-β1 and MIP-1β levels compared with those carrying the major risk allele, G. Bogacz et al [ 44 ], reported that renal transplant patients with the A allele rs1800468 required a slightly lower dose of the immunosuppressant tacrolimus-TAC than patients with the G allele. Therefore, the TGF-β1 SNPs are potential targets for CTS therapy.…”

CC Genotype of GNAS c.393C>T (rs7121) Polymorphism Has a Protective Effect against Development of BK Viremia and BKV-Associated Nephropathy after Renal Transplant

“…Although Gαs-mediated signaling participates in a number of pathophysiological processes by initiating diverse intracellular signaling cascades, until now no studies have elucidated the role of the functional GNAS c.393C>T polymorphism in the clinical outcome of renal transplant recipients. However, increasing evidence suggests that inherited factors may affect renal allograft survival [ 18 , 19 , 20 , 21 ]. Regarding the relationship with the renal allograft outcome, G-protein-mediated receptor signaling is a promising candidate because it is a part of angiotensin II, chemokine, and adrenergic receptor signaling, which is involved in the immunological processes of the formation of donor-specific antibodies (DSAs) and the development of rejections [ 4 , 22 , 23 ].…”

“…Up to now, over 50 studies investigated the role of this polymorphism mainly in neoplasm and arterial hypertension. Besides the GNAS c.393C>T polymorphism, somatic missense mutations such as R201H, R201L, R201s, and R201C in the exon 8 of the GNAS gene and mutations in the exon 9 such as Q227R and Q227L were identified to have a clinical significance in several tumor entities [ 8 , 16 , 17 , 18 ]. These mutations occur in pituitary tumors, appendiceal mucinous adenocarcinoma, duodenal adenocarcinoma, intraductal papillary mucinous neoplasm, and bone tumors [ 8 , 24 , 25 , 26 ].…”