一项针对接受阿片类药物治疗的欧洲晚期癌症患者的全基因组关联研究发现，20号染色体上的调节变异与疼痛强度相关

IF 3.5 2区医学 Q1 ANESTHESIOLOGY

European Journal of Pain Pub Date : 2024-12-04 DOI:10.1002/ejp.4764

Francesca Minnai, Morena Shkodra, Sara Noci, Martina Esposito, Cinzia Brunelli, Alessandra Pigni, Ernesto Zecca, Frank Skorpen, Pål Klepstad, Stein Kaasa, Oscar Corli, Maria C. Pallotti, Marco C. Maltoni, Augusto T. Caraceni, Francesca Colombo

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引用次数: 0

摘要

世卫组织镇痛阶梯第三级中的阿片类药物是治疗癌性疼痛的护理标准。然而，有相当一部分患者并没有从治疗中获益。基因可能在使患者对阿片类药物产生良好或不良反应方面发挥作用。在这里，我们通过进行全基因组关联研究（GWAS）来调查这个问题。方法对2057例接受吗啡、丁丙诺啡、芬太尼和羟考酮治疗的欧洲晚期癌症患者进行基因分型。我们（使用REGENIE软件）在基因型和阿片反应表型之间进行了全基因组回归模型，阿片反应表型被定义为测量患者疼痛强度的数值评分。结果GWAS在20号染色体上鉴定出5个非编码变异，p值为5.0 × 10−8。对所有人来说，次要等位基因与较低的疼痛强度有关。这些变异是PCMTD2基因的内含子，位于OPRL1（阿片相关痛觉肽受体1）下游200 kbp。值得注意的是，根据eQTLGen数据库，这些变异作为表达数量性状位点，主要调节PCMTD2的表达，但也调节OPRL1的表达。最近有报道称，在不同慢性疼痛条件的受试者中进行的GWAS中，同一染色体区域的变异与疼痛强度显著相关。结论：我们的研究结果支持遗传学在晚期癌症患者阿片类药物反应中的作用。需要进一步的功能分析来了解观察到的关联背后的生物学机制，并导致个性化疼痛治疗计划的发展，最终提高癌症患者的生活质量。这项针对接受阿片类药物治疗的欧洲晚期癌症患者的全基因组关联研究发现了与疼痛强度相关的20号染色体（靠近PCMTD2和OPRL1基因）上的新调控变异。这些发现增强了我们对阿片类药物反应的遗传基础的理解，为阿片类药物疗效提供了新的潜在标记。该研究是药物基因组学的重大进展，为影响疼痛强度的遗传因素提供了一个强大的数据集和新的见解，这可能导致个性化的癌症疼痛管理。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

A genome-wide association study of European advanced cancer patients treated with opioids identifies regulatory variants on chromosome 20 associated with pain intensity

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A genome-wide association study of European advanced cancer patients treated with opioids identifies regulatory variants on chromosome 20 associated with pain intensity

Background

Opioids in step III of the WHO analgesic ladder are the standard of care for treating cancer pain. However, a significant minority of patients do not benefit from therapy. Genetics might play a role in predisposing patients to a good or poor response to opioids. Here, we investigated this issue by conducting a genome-wide association study (GWAS).

Methods

We genotyped 2057 European advanced cancer patients treated with morphine, buprenorphine, fentanyl and oxycodone. We carried out a whole-genome regression model (using REGENIE software) between genotypes and the opioid response phenotype, defined as a numerical score measuring patient pain intensity.

Results

The GWAS identified five non-coding variants on chromosome 20 with a p-value <5.0 × 10⁻⁸. For all of them, the minor allele was associated with lower pain intensity. These variants were intronic to the PCMTD2 gene and were 200 kbp downstream of OPRL1, the opioid related nociceptin receptor 1. Notably according to the eQTLGen database, these variants act as expression quantitative trait loci, modulating the expression mainly of PCMTD2 but also of OPRL1. Variants in the same chromosomal region were recently reported to be significantly associated with pain intensity in a GWAS conducted in subjects with different chronic pain conditions.

Conclusions

Our results support the role of genetics in the opioid response in advanced cancer patients. Further functional analyses are needed to understand the biological mechanism underlying the observed association and lead to the development of individualized pain treatment plans, ultimately improving the quality of life for cancer patients.

Significance Statement

This genome-wide association study on European advanced cancer patients treated with opioids identifies novel regulatory variants on chromosome 20 (near PCMTD2 and OPRL1 genes) associated with pain intensity. These findings enhance our understanding of the genetic basis of opioid response, suggesting new potential markers for opioid efficacy. The study is a significant advancement in pharmacogenomics, providing a robust dataset and new insights into the genetic factors influencing pain intensity, which could lead to personalized cancer pain management.

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来源期刊

European Journal of Pain 医学-临床神经学

CiteScore

7.50

自引率

5.60%

发文量

163

审稿时长

4-8 weeks

期刊介绍： European Journal of Pain (EJP) publishes clinical and basic science research papers relevant to all aspects of pain and its management, including specialties such as anaesthesia, dentistry, neurology and neurosurgery, orthopaedics, palliative care, pharmacology, physiology, psychiatry, psychology and rehabilitation; socio-economic aspects of pain are also covered. Regular sections in the journal are as follows: • Editorials and Commentaries • Position Papers and Guidelines • Reviews • Original Articles • Letters • Bookshelf The journal particularly welcomes clinical trials, which are published on an occasional basis. Research articles are published under the following subject headings: • Neurobiology • Neurology • Experimental Pharmacology • Clinical Pharmacology • Psychology • Behavioural Therapy • Epidemiology • Cancer Pain • Acute Pain • Clinical Trials.