Association of ABCB1 and CYP450 Gene Polymorphisms and their DNA Methylation Status with Steroid-Induced Osteonecrosis of the Femoral Head in the Chinese Population

Abstract

Osteonecrosis of the femoral head (ONFH) is a severe pathological state with multiple etiologies. Steroid hormone metabolism-related genes play an important role in ONFH. The aim of this study was to investigate the relationships between polymorphisms of the drug-metabolizing enzyme gene, cytochrome P450 (CYP450), and the drug transporter gene, ATP-binding cassette subfamily B member 1 (ABCB1), as well as their DNA methylation status with the pathogenesis of steroid-induced ONFH. Methods: In this case-control study, we evaluated five single nucleotide polymorphisms (SNPs) in two genes in a Han Chinese population, including 79 patients with steroid-induced ONFH and 114 persons who took steroids but did not develop steroid-induced ONFH. SNPs were genotyped by the improved multiplex ligation detection reaction. MethylTarget technology was used to ascertain the methylation status at two CpG islands in the ABCB1 gene for statistical analysis. Finally, interactions between the SNPs and the CpG site's methylation levels were statistically analyzed by methylation quantitative trait locus. Results: We found that the T allele of the CYP450 rs2242480 locus was associated with steroid-induced ONFH risk reduction (odds ratio [OR] = 0.598, 95% confidence interval [CI]: 0.360-0.992, p = 0.046). In the genetic model analysis, the T allele of the rs2032582 locus in the ABCB1 gene was associated with a reduced risk of steroid-induced ONFH under the dominant model (OR = 0.465, 95% CI: 0.223-0.972, p = 0.042). The CpG sites with significant differences (p < 0.05) in methylation levels between the cases and controls were ABCB1_1_192 .ABCB1_2_43. A total of 14 pairs of linear regression tests between SNPs and methylation sites demonstrated statistical significance ( p < 0.05). Conclusions: This study provides evidence for two steroid-induced ONFH susceptibility genes (ABCB1, CYP450) in the Han Chinese population.

DNA methylation in the OPG/RANK/RANKL pathway is associated with steroid-induced osteonecrosis of the femoral head

“…There were no healthy people receiving steroid treatment. The control group included healthy subjects who were widely used in most of the studies, rather than patients receiving steroid treatment with other conditions [ 27 ]. The reason is that even if the patients with SLE and ONFH, which accounted for the highest proportion of the disease, were taken as the control group, the resulting statistical conclusion could only prove the difference between the two diseases.…”

Steroid-induced osteonecrosis

“…Other SNPs with an impact on steroid-induced osteonecrosis have been demonstrated for cytochrome P450 and associated with lower risk [ 25 ], whereas different IL1B polymorphisms influence the risk for steroid-induced osteonecrosis [ 26 ]. Metalloproteinase 2, 8, and 10 polymorphisms contribute to susceptibility [ 27 , 28 ], as RETN (coding for resistin, an adipokine involved in metabolic disorders) and ApoA 5 and APOE (involved in lipid metabolism) SNP [ [29] , [30] , [31] ].…”

“… Gene Risk Ref. ATP-binding cassette subfamily B member 1 (ABCB1) Reduced [ 24 ] Cytochrome P450 Reduced [ 25 ] IL1B Increased or reduced [ 26 ] Metalloproteinase 2, 8, and 10 Increased [ 27 , 28 ] Metalloproteinase 9 Reduced [ 32 ] RETN Increased [ 29 ] APOA5 Increased [ 30 ] APOE Increased [ 31 ] TIMP4 Reduced [ 33 ] PAI-1 Increased [ 34 ] LncRNA LINC-PINT Increased [ 35 ] VEGF Increased [ 13 ] NO Increased [ 13 ] …”

“…Epigenetic mechanisms have also been observed to impact the risk associated with systemic glucocorticoids. Significant methylation level differences between patients and controls were found in ABCB1 gene, with patients having higher methylation levels [ 25 ]. Micro RNAs (MIR) were also found to be implicated in risk of diseases, and the transcripts of MIR17HG and MIR155HG gene variants, which regulate bone metabolism among other functions, are associated with steroid-induced osteonecrosis [ 36 ].…”

FTO rs62033406 A>G associated with the risk of osteonecrosis of the femoral head among the Chinese Han population

“…In recent studies, emerging lines of evidence have suggested genetic factors and hereditary forms play a pivotal role in ONFH development [ 5 ]. For example, NOS3 , IL-1B , ABCB1 and CYP450 single nucleotide polymorphisms (SNPs) were closely related to the susceptibility of ONFH [ 6 – 8 ]. However, many variants contributed to ONFH remain to be identified.…”