Background: 

Previous studies have demonstrated the influence of heritable factors on the development of nontraumatic osteonecrosis of the femoral head (ONFH). We hypothesized that genetic variation is associated with an increased risk of ONFH, and that variants could be identified by a genomewide association study (GWAS).

Methods: 

Using data collected from the MyCode Community Health Initiative, we identified 118 adult patients with radiographically confirmed nontraumatic ONFH. Study patients were statistically compared with a control population of 56,811 unrelated individuals without a diagnosis of ONFH. A case-control GWAS was performed to identify single nucleotide variants (SNVs) associated with ONFH. Sensitivity analyses were performed to evaluate the association of the top SNVs with (cortico)steroid-associated ONFH and ONFH with femoral head collapse. Gene-based analyses were performed to identify potential causal genes.

Results: 

Of the 118 patients, 114 (96.6%) had bilateral ONFH at a median of 5 years of follow-up; 90.7% had at least one 3-week steroid prescription compared with 68.3% in controls. A GWAS identified 4 SNVs reaching genomewide significance. rs116468452 near CACNA1E was significantly associated with ONFH (p = 3.26 × 10⁻⁹, odds ratio [OR] = 5.6, 95% confidence interval [CI] = 3.21 to 9.76). rs10953090 in SAMD9 was significantly associated with ONFH in the steroid-exposed subset (p = 2.96 × 10⁻⁸, OR = 2.57, 95% CI = 1.84 to 3.58). rs112467115 in PI4K1B showed enhanced association in the collapsed subset (p = 7.82 × 10⁻⁸, OR = 4.5, 95% CI = 2.60 to 7.79). Gene-based analyses identified PPARGC1B as the only gene significantly associated with ONFH after Bonferroni correction (p = 1 × 10⁻⁶), with the lead SNV being rs78814834 (OR = 2.86, 95% CI = 1.87 to 4.38).

Conclusions: 

We identified 4 SNVs and 1 gene, PPARGC1B, associated with ONFH.

Level of Evidence: 

Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

中文翻译：

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PPARGC1B与股骨头非创伤性骨坏死相关：一项图表审查队列的全基因组关联研究。

背景： 

先前的研究已证明遗传因素对股骨头非创伤性骨坏死（ONFH）的发展的影响。我们假设遗传变异与ONFH的风险增加有关，并且可以通过全基因组关联研究（GWAS）识别变异。

方法： 

使用从MyCode社区健康计划收集的数据，我们确定了118名经射线照相证实为非创伤性ONFH的成年患者。将研究患者与没有诊断为ONFH的56811个无关个体的对照人群进行统计学比较。进行病例对照GWAS以鉴定与ONFH相关的单核苷酸变异体（SNV）。进行敏感性分析以评估与（皮质）类固醇相关的ONFH和ONFH与股骨头塌陷相关的顶级SNV。进行了基于基因的分析，以确定潜在的因果基因。

结果： 

在118例患者中，有114例（96.6％）接受了双侧ONFH治疗，中位随访时间为5年。90.7％的人至少有3周的类固醇处方，而对照组为68.3％。GWAS确定了4个达到全基因组重要性的SNV。CACNA1E附近的rs116468452与ONFH显着相关（p = 3.26×10 ^-9，优势比[OR] = 5.6，95％置信区间[CI] = 3.21至9.76）。SAMD9中的rs10953090与类固醇暴露的亚组中的ONFH显着相关（p = 2.96×10 ^-8，OR = 2.57，95％CI = 1.84至3.58）。PI4K1B中的rs112467115在折叠子集中显示出增强的关联性（p = 7.82×10 ^-8，OR = 4.5，95％CI = 2.60至7.79）。确定基于基因的分析PPARGC1B是在Bonferroni校正后与ONFH显着相关的唯一基因（p = 1×10 ^-6），其中SNV领先是rs78814834（OR = 2.86，95％CI = 1.87至​​4.38）。

结论： 

我们确定了4个SNV和1个基因，PPARGC1B ，与ONFH相关。

证据级别： 

预后IV级。有关证据水平的完整说明，请参见《作者说明》。