ABCB1 C3435T and G2677T/A polymorphism decreased the risk for steroid-induced osteonecrosis of the femoral head after kidney transplantation

Abstract

Advances in transplantation technology have brought about great benefits to patients suffering from organ failure, but the problem still remains of complications induced by steroids used for post-transplant immunosuppression. Among the side-effects caused by steroids, non-traumatic osteonecrosis of the femoral head (ONF) constitutes a serious problem. The same protocol for steroid administration induces ONF in some patients, but not in others, indicating the presence of individual difference in steroid sensitivity. We hypothesized that this difference might be mediated by the drug-transport protein, P-glycoprotein (P-gp), and investigated the relationship between single nucleotide polymorphisms in the multidrug resistance gene 1 (ABCB1, MDR1) encoding P-gp and ONF. Subjects comprised 136 patients receiving kidney transplantation. Thirty patients developed post-transplant ONF. Genomic DNA was extracted from peripheral blood, and genotypes of ABCB1 C3435T (exon 26) and G2677T/A (exon 21) were determined by direct sequencing. Multivariate analyses based on clinical information were performed to determine the relationship between ABCB1 genotypes and ONF. The dose/concentration (D/C) ratios of tacrolimus were also determined to estimate the activity of P-gp in patients with different genotypes of ABCB1 C3435T (CC, CT, TT), and in those who did and did not develop ONF. The ABCB1 3435TT genotype showed a significantly lower incidence of ONF (adjusted odds ratio = 0.10, P = 0.034). The D/C ratio in the 3435TT genotype was significantly higher than that in the 3435CC genotype. The D/C ratio in patients developing ONF was significantly higher than in those patients who did not develop ONF. The results suggest increased activity of P-gp in patients with the 3435TT genotype and in those who did not develop ONF. The ABCB1 2677 homozygous variant type also showed a lower incidence of ONF (adjusted odds ratio = 0.26, P = 0.056). The 3435T and 3435C alleles were in linkage disequilibrium with the 2677T and the 2677G alleles, respectively, in the study population. An assessment of C3435T and G2677T/A polymorphisms preceding steroid treatment could be useful for predicting the resistance to ONF development.

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

“…This SNP may therefore be linked to a high prevalence of colon cancer in the Ashkenazi population. Similarly, refractory Crohn's disease has also been found to be associated with the 2677G>T/A/C, 3435C>T, and 1236C>T SNPs [31]. This could also be linked to a high prevalence of the disease in the Ashkenazi Jewish population, as noted by the high prevalence of the 3435T allele discovered in our Ashkenazi population.…”

“…The 1236C>T and 2677G>T/A/C polymorphisms have also been linked to several diseases such as pharmacoresistant epilepsy and Parkinsons disease [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. Studies on these polymorphisms have yielded contradictory results, possibly due to small sample sizes and the isolated nature of the study populations.…”

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

“…HIV The final study 73 examined the relationship between osteonecrosis of the femoral head (ONF) associated with steroid therapy following renal transplantation, and the 3435C4T and 2677G4TA genotypes. The study included 30 patients with ONF and 106 without ONF, all of whom had undergone renal transplantation and post-transplant immunosuppression with tacrolimus or cyclosporine plus either 'large-dose' or 'small-dose' steroid protocols.…”

“…Another limitation of many of these studies 18,96,42,61,69,[72][73][74][77][78][79]84,88,89 was the absence of any attempt to detect or prevent stratification between cases and controls, either through control for ethnicity or genetic methods of detection of stratification (some studies may have been performed in ethnically homogenous populations, but this was not stated). Indeed in two of the studies, significant differences in allele frequency between groups of different ethnicity were commented upon, 42,79 and this was not taken into account when performing the statistical analysis.…”

Endothelial nitric oxide synthase gene polymorphisms in patients with nontraumatic femoral head osteonecrosis

“…[3][4][5][6] However, the relationship of genetic polymorphism of plasminogen activator inhibitor (PAI)-1 4G/5G and post-renal transplant FHON was controversial. 3,5 Nitric oxide (NO) is a multifunctional biomolecule and serves as an important signal in physiologic processes including angiogenesis, thrombosis, and bone turnover, which are known to be related to the pathogenesis of osteonecrosis. 7 It was reported that the predominant isoform of nitric oxide synthases expressed in normal adult bone is endothelial nitric oxide synthase (eNOS).…”