Objective To explore the clinical and genetic risk factors of steroid-induced osteonecrosis of the femoral head (ONFH). Methods A prospective cohort of patients using high-dose glucocorticoids for the first time was established, and patients who received high-dose glucocorticoid treatment for the first time from July 2015 to January 2018 were included. None of the patients had received glucocorticoid treatment before enrollment, and it was planned to receive glucocorticoid treatment with an equivalent prednisone dose ≥ 30 mg/d for ≥ 3 weeks or a pulse treatment ≥ 200 mg/d for ≥ 3 days after enrollment. Blood samples were collected before treatment for the detection of bone metabolism and lipid metabolism indexes; hip MR examinations were performed at 1, 3, 6, 12, and 24 months after enrollment to determine whether ONFH occurred. The study endpoint was the diagnosis of ONFH. Patients without ONFH were followed up for at least 2 years, and the Lasso regression model was used to evaluate the risk factors for the onset of steroid-induced ONFH. A nested case-control sub-cohort A (12 cases) was established by a 1:1 matching method, and whole blood samples of patients were detected by whole exome sequencing to screen for differential and functional single nucleotide polymorphisms (SNP)/insertion-deletion (InDel) loci. Patients diagnosed with steroid-induced ONFH and those who met the above hormone dose requirements but did not develop ONFH after more than 2 years of follow-up were retrospectively recruited to form sub-cohort B (50 cases). Whole blood samples were collected and the candidate SNP/InDels were externally verified by Sanger sequencing technology respectively. Results Ninety-six patients were enrolled, among which 88 completed the follow-up, and 8 cases (9.1%) were diagnosed with steroid-induced ONFH during the follow-up period. The time from the start of hormone treatment to diagnosis was 53.00 (34.00, 133.50) days. There was no statistically significant difference in age, gender, and body mass index between the ONFH and non-ONFH groups; the hormone dose in the first month of treatment in the steroid-induced ONFH group [32.74 (29.55, 47.05) mg/kg] was higher than that in the non-ONFH group [24.00 (21.10, 29.45) mg/kg] (Z = -2.410, P = 0.016), but there was no statistically significant difference in the proportion of patients receiving pulse treatment (37.5% and 10.0% respectively) (adjusted χ² = 2.829, P = 0.093); the ratio of apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) in the steroid-induced ONFH group was 0.95 (0.80, 1.50), which was higher than that in the non-ONFH group 0.70 (0.60, 0.80) (Z = -2.875, P < 0.001). The results of the Lasso regression model suggested that a higher ApoB/ApoA1 ratio, a lower serum β-c-terminal telopeptide (β-CTX) of type I collagen, and a higher hormone dose in the first month were the three major risk factors for the occurrence of steroid-induced ONFH, and the internal validation accuracy of the model was 0.982. Through whole exome sequencing of sub-cohort A, 7 differential SNP/InDels loci were found, and verification in sub-cohort B confirmed that carrying the COLEC12 mutation (rs2305027, G1816A) was a risk factor for steroid-induced ONFH (OR = 6.00, 95%CI: 1.17, 30.73). Conclusion A higher hormone dose in the first month, a low serum β-CTX level before treatment, a high ApoB/ApoA1 ratio, and carrying the COL-EC12 mutation (rs2305027, G1816A) can increase the risk of steroid-induced ONFH.
目的探讨激素性股骨头坏死(osteonecrosis of femoral head,ONFH)的临床与遗传风险因素。方法建立首次使用高剂量糖皮质激素患者的前瞻性队列,纳入2015年7月至2018年1月首次接受高剂量糖皮质激素治疗的患者。患者入组前均未接受过糖皮质激素治疗,计划入组后接受等效泼尼松剂量≥30 mg/d,持续≥3周;或冲击治疗≥200 mg/d,持续≥3 d的糖皮质激素治疗。治疗前采集血液样本,行骨代谢、脂代谢指标检测;入组后第1、3、6、12和24个月行髋部MR检查,判断是否发生ONFH。研究终点为诊断ONFH,对未发生ONFH的患者随访至少2年,采用Lasso回归模型评估激素性ONFH发病的风险因素。采用1:1匹配方法建立巢式病例对照子队列A(12例),采用全外显子组测序检测患者全血样本,筛选差异性和功能性单核苷酸多态性(single nucleotide polymorphism,SNP)/插入缺失(insertion-deletion,InDel)位点。回顾性招募诊断为激素性ONFH的患者及符合上述激素剂量要求但随访2年以上未发生ONFH的患者组成子队列B(50例),采集全血样本并使用Sanger测序技术分别对候选SNP/InDels进行外部验证。结果入组96例,其中88例完成随访,8例(9.1%)在随访期内被确诊为激素性ONFH,开始激素治疗至确诊的时间为53.00(34.00,133.50)d。ONFH与非ONFH组患者年龄、性别和体质指数的组间差异无统计学意义;激素性ONFH组治疗首月激素剂量[32.74(29.55,47.05)mg/kg]较非ONFH组[24.00(21.10,29.45)mg/kg]更高(Z=-2.410,P=0.016),但接受冲击治疗患者比例(分别为37.5%和10.0%)的组间差异无统计学意义(矫正χ~2=2.829,P=0.093);激素性ONFH组载脂蛋白B/载脂蛋白A1(apolipoprotein B/apolipoprotein A1,ApoB/ApoA1)比值0.95(0.80,1.50)较非ONFH组0.70(0.60,0.80)更高(Z=-2.875,P<0.001)。Lasso回归模型结果提示,较高的ApoB/ApoA1比值、较低的血清Ⅰ型胶原羧基端肽β特殊序列(β-c-terminal telopeptide,β-CTX)及较高的首月激素剂量是激素性ONFH发生的三大风险因素,模型内部验证准确性为0.982。通过对子队列A进行全外显子测序发现7个差异SNP/InDels位点,在子队列B中进行验证证实携带COLEC12突变(rs2305027,G1816A)是激素性ONFH的风险因素(OR=6.00,95%CI:1.17,30.73)。结论较高的首月激素剂量、治疗前低血清β-CTX水平、高ApoB/ApoA1比例、携带COL-EC12突变(rs2305027,G1816A)可增加激素性ONFH的发生风险。
刷新
尊享16+权益
