Genetic proxies for therapy of insulin drug targets and risk of osteoarthritis: a drug-target Mendelian randomization analysis.

IF 4.6 2区医学 Q2 IMMUNOLOGY

Inflammopharmacology Pub Date : 2024-12-01 Epub Date: 2024-08-11 DOI:10.1007/s10787-024-01542-8

Ziqin Cao, Qiangxiang Li, Jianhuang Wu, Yajia Li

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引用次数: 0

Abstract

Background: The potential effects of insulin therapy on osteoarthritis (OA) risk are poorly understood. This study aimed to explore the causal relationship between insulin therapy and OA.

Methods: Mendelian randomization (MR) analysis was performed to examine the association between genetically proxied inhibition of insulin targets and the risk of overall, hip (HOA) and knee OA (KOA). We then performed univariable MR using summary statistics regarding insulin target genes derived from the DrugBank database. Data related to blood glucose reduction levels were used as a proxy for insulin levels. Two phenotypes, type 2 diabetes, and glycosylated hemoglobin levels, were selected as positive controls to confirm the direction and validity of the proxies. The OA datasets were derived from the UK Biobank cohort. Multivariable MR was adjusted for body mass index, sedentary behavior, cigarette smoking, frequency of alcohol intake, age, and genetic sex.

Results: Genetically proxied insulin therapy was associated with an increased risk of overall OA [odds ratio (OR):1.2595; 95% confidence interval (CI):1.0810-1.4675] and HOA (OR:1.4218; 95%CI:1.1240-1.7985), which remained consistent across multiple MR methods. After adjusting for confounders, we found evidence supporting a significant causal link with a higher risk of overall OA and HOA. A further two-step MR analysis revealed no significant mediation effects from the six mediators in the associations.

Conclusion: There was a causal association between genetically proxied insulin therapy and a higher risk of OA, especially HOA.

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胰岛素药物靶点治疗和骨关节炎风险的基因代理：药物靶点孟德尔随机分析。

背景：人们对胰岛素治疗对骨关节炎（OA）风险的潜在影响知之甚少。本研究旨在探讨胰岛素治疗与 OA 之间的因果关系：方法：我们进行了孟德尔随机化（MR）分析，以研究基因代表的胰岛素靶点抑制与总体、髋关节（HOA）和膝关节OA（KOA）风险之间的关联。然后，我们使用从 DrugBank 数据库中提取的有关胰岛素靶基因的汇总统计数据进行了单变量 MR 分析。与血糖降低水平相关的数据被用作胰岛素水平的替代物。2 型糖尿病和糖化血红蛋白水平这两种表型被选为阳性对照，以确认替代物的方向和有效性。OA数据集来自英国生物库队列。多变量 MR 对体重指数、久坐行为、吸烟、饮酒频率、年龄和遗传性别进行了调整：基因代理胰岛素治疗与总体 OA [几率比（OR）：1.2595；95% 置信区间（CI）：1.0810-1.4675] 和 HOA [几率比（OR）：1.4218；95% 置信区间（CI）：1.1240-1.7985] 风险的增加有关，这在多种 MR 方法中保持一致。在对混杂因素进行调整后，我们发现有证据支持总体 OA 和 HOA 风险较高之间存在显著的因果关系。进一步的两步MR分析显示，六种中介因素在关联中没有显著的中介效应：结论：基因代胰岛素治疗与较高的 OA（尤其是 HOA）风险之间存在因果关系。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Inflammopharmacology IMMUNOLOGYTOXICOLOGY-TOXICOLOGY

CiteScore

8.00

自引率

3.40%

发文量

200

期刊介绍： Inflammopharmacology is the official publication of the Gastrointestinal Section of the International Union of Basic and Clinical Pharmacology (IUPHAR) and the Hungarian Experimental and Clinical Pharmacology Society (HECPS). Inflammopharmacology publishes papers on all aspects of inflammation and its pharmacological control emphasizing comparisons of (a) different inflammatory states, and (b) the actions, therapeutic efficacy and safety of drugs employed in the treatment of inflammatory conditions. The comparative aspects of the types of inflammatory conditions include gastrointestinal disease (e.g. ulcerative colitis, Crohn''s disease), parasitic diseases, toxicological manifestations of the effects of drugs and environmental agents, arthritic conditions, and inflammatory effects of injury or aging on skeletal muscle. The journal has seven main interest areas: -Drug-Disease Interactions - Conditional Pharmacology - i.e. where the condition (disease or stress state) influences the therapeutic response and side (adverse) effects from anti-inflammatory drugs. Mechanisms of drug-disease and drug disease interactions and the role of different stress states -Rheumatology - particular emphasis on methods of measurement of clinical response effects of new agents, adverse effects from anti-rheumatic drugs -Gastroenterology - with particular emphasis on animal and human models, mechanisms of mucosal inflammation and ulceration and effects of novel and established anti-ulcer, anti-inflammatory agents, or antiparasitic agents -Neuro-Inflammation and Pain - model systems, pharmacology of new analgesic agents and mechanisms of neuro-inflammation and pain -Novel drugs, natural products and nutraceuticals - and their effects on inflammatory processes, especially where there are indications of novel modes action compared with conventional drugs e.g. NSAIDs -Muscle-immune interactions during inflammation [...]