Polymorphisms of the MDR1 and MIF genes in children with nephrotic syndrome

Abstract

Oral steroid treatment is the first line of therapy for childhood nephrotic syndrome (NS). Nonetheless, some patients are resistant to this treatment. Many efforts have been made to explain the differences in the response to steroid treatment in patients with NS based on the genetic background. We have investigated single nucleotide polymorphisms of the MDR1 [C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642)] and MIF (G-173C, rs755622) genes in 170 children with NS. Of these children, 69 (40.6%) were initial steroid non-responders, and 23 (13.5% of total) developed chronic kidney disease. Renal biopsy findings, which were available for 101 patients, showed that 35 patients had minimal change lesion and 66 had focal segmental glomerulosclerosis. The frequencies of the MDR1 1236 CC (18.8 vs 7.2%) or TC (53.5 vs 43.5%) genotype and C allele (45.5 vs 29.0%) were significantly higher in the initial steroid responders than in the non-responders. Analysis of MDR1 three-marker haplotypes revealed that the frequency of the TGC haplotype was significantly lower in the initial steroid responders than in the non-responders (15.8 vs 29.0%). There was no association between the MIF G-173C polymorphism and clinical parameters, renal histological findings, and steroid responsiveness. These data suggest that the initial steroid response in children with NS may be influenced by genetic variations in the MDR1 gene.

A PRISMA-compliant meta-analysis of MDR1 polymorphisms and idiopathic nephrotic syndrome

“…1). [14–17,31–35] All of the participants in these studies were children consisting of 928 patients with INS and 879 healthy controls; moreover, steroid resistance data were available for 724 patients comprising 488 patients with SS and 236 patients with SR, which were compared. The subjects in 4 studies were Asian [16,17,34,35] and those from the other 5 were Caucasian.…”

Association between Macrophage Migration Inhibitory Factor Gene Variation and Response to Glucocorticoid Treatment in Sudden Sensorineural Hearing Loss

“…Choi et al [2011] found no association between the MIF (-173 G/C) polymorphism and steroid responsiveness in Italian patients with nephrotic syndrome, although another study revealed contrary data [Berdeli et al, 2005]. The MIF (-173 G/C) polymorphism did not contribute to prednisone and glucocorticoid poor response in vivo in childhood acute lymphoblastic leukemia [Ziino et al, 2005] and idiopathic thrombocytopenic purpura [Lao et al, 2013], respectively.…”

“…In contrast to other proinflammatory cytokines that are generally suppressed by glucocorticoids, MIF has a very specific counterregulatory effect on glucocorticoids. On the one hand, MIF expression and secretion are increased by low physiological concentrations of glucocorticoids [Choi et al, 2011]. Evidence of MIF upregulation as a result of endogenous glucocorticoid effect has been reported in rat adjuvant-induced arthritis.…”

Regulatory Pathways for ATP-binding Cassette Transport Proteins in Kidney Proximal Tubules

“…Such mutations do not always lead to renal function problems but can have systemic effects as well. Recently, an association between ABCB1 polymorphisms and the resistance against steroid treatment of nephrotic syndrome in children was found (17), suggesting a gain of function in P-gp. In addition, we showed that the P-gpdeficient mice (Mdr1a/1b( −/− )) exhibit a generalized disturbed renal tubular function caused by decreased intracellular levels of ATP and altered morphology of mitochondria (18).…”