Department of Orthopaedics, First Affiliated Hospital of Guangzhou, University of Traditional Chinese Medicine, BaiYun District, Guangzhou, China.
Acta Orthop. 2009 Jun;80(3):325-9. doi: 10.3109/17453670903025378.
BACKGROUND AND PURPOSE Corticosteroid treatment is associated with osteonecrosis of the femoral head (ON) in certain patients. The degree of drug sensitivity in general is governed by genetic variation between individuals. We investigated the relationship between ON and the presence of different alleles of the cytochrome P450 gene (CYP3A4), the product of which metabolizes corticosteroids, and of the P-glycoprotein (P-gp) gene (ABCBI), the product of which modulates cellular uptake of corticosteroids, to determine whether patients with certain alleles may be at higher risk of ON after corticosteroid treatment.
We studied 31 patients from Guangdong, China who were both treated with corticosteroid therapy and developed ON, and 17 corticosteroid-therapy patients without ON. Patient DNA was screened for known polymorphisms in the CYP3A4 gene (CYP3A44, CYP3A45, CYP3A4*6) and the P-gp gene ABCB1 (mutations C3435T, G2677T/A).
The majority (20/31) of the corticosteroid-treated patients who developed ON were heterozygous for ABCB1, whereas only 3/17 without ON were heterozygous. Statistical significance was observed between the ON and the control groups for the ABCB1 G2677T/A polymorphism. Analysis of haplotypic frequencies indicated significant linkage disequilibrium between the two ABCB1 polymorphisms, C3435T and G2677T/A (D' = 0.034). No CYP3A4 polymorphisms were detected in any of the patients.
Patients carrying an ABCB1 polymorphism had a higher risk of having corticosteroid-associated ON than those with wild-type genotypes. This statistically significant association conflicts with previous studies, possibly due to different sampling methods. Knowing which genetic backgrounds are most strongly associated with corticosteroid-associated ON provides a method of screening for patients who are most at risk of developing ON.
皮质类固醇治疗与某些患者的股骨头坏死（ON）有关。一般来说，药物敏感性的程度受个体之间遗传变异的控制。我们研究了细胞色素 P450 基因（CYP3A4）的不同等位基因的存在与 P-糖蛋白（P-gp）基因（ABCB1）的存在之间与 ON 的关系，CYP3A4 的产物代谢皮质类固醇，ABCB1 的产物调节皮质类固醇的细胞摄取，以确定接受皮质类固醇治疗后具有某些等位基因的患者是否有更高的发生 ON 的风险。
我们研究了 31 名来自中国广东的患者，他们都接受了皮质类固醇治疗并发生了 ON，并且有 17 名接受皮质类固醇治疗的患者没有发生 ON。对患者的 DNA 进行了 CYP3A4 基因（CYP3A44、CYP3A45、CYP3A4*6）和 P-gp 基因 ABCB1（突变 C3435T、G2677T/A）的已知多态性筛查。
20/31 名发生 ON 的皮质类固醇治疗患者中，大多数为 ABCB1 杂合子，而无 ON 的 17 名患者中仅有 3 名杂合子。ON 组和对照组之间 ABCB1 G2677T/A 多态性存在统计学意义。单倍型频率分析表明，两个 ABCB1 多态性 C3435T 和 G2677T/A 之间存在显著的连锁不平衡（D'=0.034）。未在任何患者中检测到 CYP3A4 多态性。
携带 ABCB1 多态性的患者发生皮质类固醇相关 ON 的风险高于具有野生型基因型的患者。这种统计学上显著的关联与以前的研究相冲突，可能是由于不同的采样方法。了解哪些遗传背景与皮质类固醇相关 ON 关系最密切，为筛选最易发生 ON 的患者提供了一种方法。
