New target-HMGCR inhibitors for the treatment of primary sclerosing cholangitis: A drug Mendelian randomization study.

IF 1.7 4区医学 Q2 MEDICINE, GENERAL & INTERNAL

Open Medicine Pub Date : 2024-07-19 eCollection Date: 2024-01-01 DOI:10.1515/med-2024-0994

Jie Zhou, Yixin Xu, Haitao Wang, Zhilin Liu

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引用次数: 0

Abstract

Background: No intervention definitively extends transplant-free survival in primary sclerosing cholangitis (PSC). Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), may enhance PSC prognosis, but their efficacy is debated.

Methods: We analyzed HMGCR single-nucleotide polymorphisms from published genome-wide association studies using Mendelian randomization to assess the causal relationship between HMGCR and PSC risk. Effects of HMGCR were compared with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, common lipid-lowering drugs, using coronary heart disease risk as a positive control. The inverse-variance weighted (IVW) method was the primary analysis, complemented by the weighted median method. Heterogeneity analysis, examination of horizontal pleiotropy, and leave-one-out sensitivity analysis were conducted for result robustness.

Results: Genetically predicted HMGCR exhibited a pronounced detrimental effect on PSC in both the IVW method (odds ratio [OR] [95%] = 2.43 [1.23-4.78], P = 0.010) and the weighted median method (OR [95%] = 2.36 [1.02-5.45], P = 0.044). However, PCSK9 did not reach statistical significance. Moreover, all analyses passed through heterogeneity analysis, horizontal pleiotropy analysis, and leave-one-out sensitivity analysis.

Conclusion: This study has confirmed a causal relationship between HMGCR and PSC risk, suggesting statins targeting HMGCR could enhance PSC patient outcomes.

查看原文本刊更多论文

治疗原发性硬化性胆管炎的新靶点-HMGCR 抑制剂：药物孟德尔随机化研究。

背景：没有任何干预措施能明确延长原发性硬化性胆管炎（PSC）患者的无移植生存期。他汀类药物是3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）的抑制剂，可改善PSC的预后，但其疗效尚存争议：我们采用孟德尔随机法分析了已发表的全基因组关联研究中的HMGCR单核苷酸多态性，以评估HMGCR与PSC风险之间的因果关系。以冠心病风险为阳性对照，比较了HMGCR与常见降脂药物丙蛋白转化酶亚基克星9（PCSK9）抑制剂的影响。主要分析方法为反方差加权法（IVW），辅以加权中位数法。为了保证结果的稳健性，还进行了异质性分析、横向多义性检查和排除敏感性分析：在 IVW 法（比值比 [OR] [95%] = 2.43 [1.23-4.78]，P = 0.010）和加权中值法（比值比 [95%] = 2.36 [1.02-5.45]，P = 0.044）中，遗传预测的 HMGCR 对 PSC 有明显的不利影响。然而，PCSK9 并未达到统计学意义。此外，所有分析均通过了异质性分析、水平多向性分析和撇除敏感性分析：本研究证实了 HMGCR 与 PSC 风险之间的因果关系，提示针对 HMGCR 的他汀类药物可改善 PSC 患者的预后。

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

Open Medicine Medicine-General Medicine

CiteScore

3.00

自引率

0.00%

发文量

153

审稿时长

20 weeks

期刊介绍： Open Medicine is an open access journal that provides users with free, instant, and continued access to all content worldwide. The primary goal of the journal has always been a focus on maintaining the high quality of its published content. Its mission is to facilitate the exchange of ideas between medical science researchers from different countries. Papers connected to all fields of medicine and public health are welcomed. Open Medicine accepts submissions of research articles, reviews, case reports, letters to editor and book reviews.