MDR1 Polymorphisms and Idiopathic Nephrotic Syndrome in Slovak Children: Preliminary Results

Abstract

BackgroundThe role of the multidrug resistance-1 (MDR1 or ABCB1) gene polymorphisms 1236T>C, 2677T>G, and 3435T>C was studied in relation to susceptibility, demographics, and pathological characteristics, as well as their role in the therapeutic response (TR) to prednisone treatment in children with idiopathic nephrotic syndrome (INS).Material/MethodsThe polymorphisms were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method in 46 children with INS and in 100 healthy controls. Different genetic models (codominant, dominant, recessive, and overdominant) were used for testing of associations between polymorphisms and phenotypes.ResultsStatistical analysis showed a significantly increased chance of TR in children carrying 3435TC genotype (OR=5.13, 95% CI=1.18–22.25; overdominant model). Moreover, INS patients under 6 years of age had significantly decreased frequencies of MDR1 1236CC (7.7% vs. 35%, p=0.029) or 2677GG (3.8% vs. 30.0%, p=0.033) genotypes. We also observed that patients with minimal change in disease and patients under 6 years of age at the onset of INS were initial responders more frequently when compared with children with focal segmental glomerulosclerosis and patients ≥6 years old at the onset (p=0.0001, p=0.027, respectively).ConclusionsThese data suggest that prednisone TR may be influenced by histology, age at the onset of INS, and MDR1 3435T>C polymorphism. The MDR1 1236T>C and 2677T>G polymorphisms were significantly associated with age at onset. Larger multicenter studies and studies across other ethnic groups are needed to elucidate the contradictory implications of MDR1 polymorphisms with INS in children.

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

“…This is the first meta-analysis of MDR1 polymorphisms and INS, which consisted of 9 case-control studies including 928 patients with INS and 879 healthy controls to assess disease susceptibility, and 724 affected individuals consisting of 236 patients with SR and 488 patients with SS to evaluate steroid responsiveness. Our meta-analysis showed no evidence of a correlation between the 3 polymorphisms investigated and susceptibility to INS, which was consistent with the findings from the studies by Choi et al, [ 35 ] Cizmarikova et al, [ 15 ] and Suvanto et al [ 32 ] Because P-gp affects the pharmacokinetics of GCs, the occurrence of idiopathic NS is unlikely to be related to MDR1 variants, which is in accordance with our findings. However, because Youssef et al [ 14 ] and Jafar et al [ 16 ] reported that rs1045642 and rs2032582 were associated with INS susceptibility, additional studies are warranted.…”

“…The subjects in 4 studies were Asian [ 16 , 17 , 34 , 35 ] and those from the other 5 were Caucasian. [ 14 , 15 , 31 – 33 ] Seven studies reported genotype frequencies between patients with INS and healthy controls, [ 14 – 16 , 31 , 32 , 34 , 35 ] and 7 studies showed the genotype data of SS and SR groups. [ 14 – 17 , 32 , 33 , 35 ] Haplotype frequencies of both case and control cohorts were described in part in 4 studies.…”

“…[ 14 – 17 , 32 , 33 , 35 ] Haplotype frequencies of both case and control cohorts were described in part in 4 studies. [ 14 , 15 , 32 , 35 ] SS and SR groups were also compared in 4 studies (details provided in Table 1 ). [ 14 – 16 , 35 ] Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping in 6 studies, [ 14 – 16 , 31 , 34 , 35 ] the TaqMan genotyping assay was performed in 1 study, [ 17 ] and the 2 remaining studies used real-time PCR.…”

“…However, these studies yielded inconsistent results. Youssef et al [ 14 ] reported that the T allele and TT genotype of rs1045642, and the T allele and GT, TT, and TT + AA genotypes of rs2032582 were significantly increased in patients with INS, but no significant evidence of association was found with any of these 3 SNPs in the cohort tested by Cizmarikova et al [ 15 ] Jafar et al [ 16 ] showed that the frequencies of homozygous mutant TT/AA genotypes of rs2032582 were significantly increased in affected children with steroid resistance, whereas Chiou et al [ 17 ] observed a trend with the T allele of rs1128503 in their cohort.…”

Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome

“…Several studies have been conducted to evaluate the association of P-glycoprotein polymorphisms with the responsiveness to glucocorticoids in patients with nephrotic syndrome. The results of these studies on the significance of the genetic polymorphisms are contradictory [ 71 , 82 – 84 , 86 , 104 , 120 , 121 ]. A recent meta-analysis concluded that there is evidence of an association between rs1128503 and increased risk of steroid resistance in children with nephrotic syndrome [ 122 ].…”