An omics investigation into chronic widespread musculoskeletal pain reveals epiandrosterone sulfate as a potential biomarker.
An omics investigation into chronic widespread musculoskeletal pain reveals epiandrosterone sulfate as a potential biomarker.
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DOI：
10.1097/j.pain.0000000000000200
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发表时间：
2015-10
期刊：
影响因子：
7.4
通讯作者：
Williams FMK
中科院分区：
文献类型：
--
作者：
Livshits G;Macgregor AJ;Gieger C;Malkin I;Moayyeri A;Grallert H;Emeny RT;Spector T;Kastenmüller G;Williams FMK
一项对2个人群样本慢性广泛性疼痛的“组学”调查显示，CYP3A5基因变异是CWP患者类固醇激素异常的潜在原因。慢性广泛性肌肉骨骼疼痛（CWP）很常见，人群患病率为10%。本研究旨在通过使用系统生物学方法来定义CWP/体重关联的生物学基础。来自TwinsUK登记的成年女性双胞胎（n = 2444）具有广泛的临床、人体测量学和“组学”数据。采用双能x线吸收仪对324种代谢物进行非靶向代谢组学筛选，检测CWP和体成分。通过全基因组关联研究探索了这些关联的生物学基础，并在独立人群样本中进行了重复研究（奥格斯堡地区合作卫生研究[KORA]研究，n = 2483）。使用孟德尔随机化研究设计，在CWP中寻找已确定的遗传变异的因果作用。脂肪质量/身高2是与CWP相关性最强的体成分变量（TwinsUK: P = 2.4 × 10−15,KORA: P = 1.59 × 10−10）。在检测的324种代谢物中，硫酸表雄酮（EAS）与CWP （TwinsUK组P = 1.05 × 10−09，KORA组P = 3.70 × 10−06）和脂肪质量/身高高度相关。EAS的全基因组关联研究发现，在7q22.1处，输入的单核苷酸多态性rs1581492与EAS水平显著相关（P≤2.49 × 10−78），这一结果在KORA中得到了重复（P = 2.12 × 10−9）。rs1581492基因型的孟德尔随机化结果显示，EAS与CWP不太可能存在因果关系。使用不可知性组学方法关注CWP与体重指数的关联，我们已经证实了类固醇激素的关联，并确定了CYP基因上游的遗传变异，该基因可能控制这种反应。该研究表明，类固醇激素异常是疼痛的结果，而不是引起疼痛的原因，EAS可能提供一种识别CWP风险亚群的生物标志物。
An “omics” investigation of chronic widespread pain in 2 population samples reveals a genetic variant in CYP3A5 as underlying steroid hormone abnormalities seen in CWP. Chronic widespread musculoskeletal pain (CWP) is common, having a population prevalence of 10%. This study aimed to define the biological basis of the CWP/body mass association by using a systems biology approach. Adult female twins (n = 2444) from the TwinsUK registry who had extensive clinical, anthropometric, and “omic” data were included. Nontargeted metabolomics screening including 324 metabolites was carried out for CWP and body composition using dual-energy X-ray absorptiometry. The biological basis of these associations was explored through a genome-wide association study and replicated in an independent population sample (Cooperative Health Research in the Region of Augsburg [KORA] study, n = 2483). A causal role for the genetic variants identified was sought in CWP using a Mendelian randomisation study design. Fat mass/height2 was the body composition variable most strongly associated with CWP (TwinsUK: P = 2.4 × 10−15 and KORA: P = 1.59 × 10−10). Of 324 metabolites examined, epiandrosterone sulfate (EAS) was highly associated with both CWP (P = 1.05 × 10−09 in TwinsUK and P = 3.70 × 10−06 in KORA) and fat mass/height2. Genome-wide association study of EAS identified imputed single nucleotide polymorphism rs1581492 at 7q22.1 to be strikingly associated with EAS levels (P ≤ 2.49 × 10−78), and this result was replicated in KORA (P = 2.12 × 10−9). Mendelian randomization by rs1581492 genotype showed that EAS is unlikely to be causally related to CWP. Using an agnostic omics approach to focus on the association of CWP with body mass index, we have confirmed a steroid hormone association and identified a genetic variant upstream of the CYP genes, which likely controls this response. This study suggests that steroid hormone abnormalities result from pain rather than causing it, and EAS may provide a biomarker that identifies subgroups at risk of CWP.