Livshits Gregory, Macgregor Alexander J, Gieger Christian, Malkin Ida, Moayyeri Alireza, Grallert Harald, Emeny Rebecca T, Spector Tim, Kastenmüller Gabi, Williams Frances M K
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Norwich Medical School, University of East Anglia, Norwich, United Kingdom Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany Institute of Health Informatics, University College London (UCL), London, United Kingdom Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany German Center for Diabetes Research, Neuherberg, Germany Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Pain. 2015 Oct;156(10):1845-1851. doi: 10.1097/j.pain.0000000000000200.
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.
慢性广泛性肌肉骨骼疼痛（CWP）很常见，在人群中的患病率为10%。本研究旨在通过系统生物学方法确定CWP与体重关联的生物学基础。纳入了来自英国双胞胎登记处的成年女性双胞胎（n = 2444），她们拥有广泛的临床、人体测量和“组学”数据。使用双能X线吸收法对CWP和身体成分进行了包括324种代谢物的非靶向代谢组学筛查。通过全基因组关联研究探索了这些关联的生物学基础，并在一个独立的人群样本（奥格斯堡地区合作健康研究[KORA]，n = 2483）中进行了重复验证。使用孟德尔随机化研究设计在CWP中寻找已鉴定的基因变异的因果作用。脂肪量/身高²是与CWP关联最密切的身体成分变量（英国双胞胎队列：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（英国双胞胎队列中P = 1.05×10⁻⁰⁹，KORA中P = 3.70×10⁻⁰⁶）和脂肪量/身高²均高度相关。对EAS的全基因组关联研究确定，7q22.1处的推定单核苷酸多态性rs1581492与EAS水平显著相关（P≤2.49×10⁻⁷⁸），该结果在KORA中得到重复验证（P = 2.12×10⁻⁹）。rs1581492基因型的孟德尔随机化分析表明，EAS不太可能与CWP存在因果关系。通过一种无假设的组学方法关注CWP与体重指数的关联，我们证实了一种甾体激素关联，并鉴定出CYP基因上游的一个基因变异，它可能控制这种反应。本研究表明，甾体激素异常是由疼痛导致而非引起疼痛所致，EAS可能提供一种生物标志物，用于识别有CWP风险的亚组人群。
