Multi-Omics Mendelian Randomization Study Investigating the Impact of PCSK9 and HMGCR Inhibition on Type 2 Diabetes Across Five Populations

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2024-10-17 DOI:10.2337/db24-0451

Daniel B. Rosoff, Josephin Wagner, Jeesun Jung, Pal Pacher, Constantinos Christodoulides, George Davey Smith, David Ray, Falk W. Lohoff

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引用次数: 0

Abstract

The prevalence of type 2 diabetes (T2D) varies among populations of different race/ethnicity. The influence of genetically-proxied lipoprotein cholesterol (LDL-C) lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA Reductase (HMGCR) on T2D in non-European populations is not well established.A drug-target Mendelian randomization (MR) approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and European (EUR). Our study did not find relationships between genetically-proxied PCSK9 inhibition and T2D risk in EAS (odds ratio [OR]=1.02, [0.95-1.10]), SAS (OR=1.05, [0.97-1.14]), HISP (OR=1.03, [0.94-1.12]), or EUR (OR=1.04, [0.98-1.11]). However, in AFR, primary analyses suggested an increased risk of T2D due to PCSK9 inhibition (OR=1.53, [1.058-2.22], P-value=0.024), although this was not supported in sensitivity analyses. Genetically-proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR=1.44, [1.30-1.61], P-value=9.8×10−12), EAS (OR=1.36, [1.22-1.51], P-value=4.2×10−10), and EUR (OR=1.52, [1.21-1.90], P-value=3.3×10−4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-European populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in South Asian, East Asian, and European cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases.

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调查 PCSK9 和 HMGCR 抑制对五类人群 2 型糖尿病影响的多指标孟德尔随机化研究

2 型糖尿病（T2D）的发病率在不同种族/民族的人群中存在差异。在非欧洲人群中，通过丙蛋白转化酶枯草酶/kexin 9（PCSK9）和HMG-CoA还原酶（HMGCR）降低脂蛋白胆固醇（LDL-C）对T2D的影响尚未得到很好的确定：这些人群包括东亚人 (EAS)、南亚人 (SAS)、西班牙裔人 (HISP)、非洲人 (AFR) 和欧洲人 (EUR)。我们的研究在东亚裔（EAS）、南亚裔（SAS）、西班牙裔（HISP）、非洲裔（AFR）和欧洲裔（EUR）人群中均未发现PCSK9抑制基因与T2D风险之间的关系（几率比[OR]=1.02，[0.95-1.10]），在南亚裔（SAS）、西班牙裔（HISP）、非洲裔（AFR）和欧洲裔（EUR）人群中也未发现PCSK9抑制基因与T2D风险之间的关系（几率比[OR]=1.05，[0.97-1.14]）。然而，在 AFR 中，主要分析表明 PCSK9 抑制增加了 T2D 风险（OR=1.53，[1.058-2.22]，P-value=0.024），但敏感性分析未支持这一观点。在 SAS（OR=1.44，[1.30-1.61]，P-value=9.8×10-12）、EAS（OR=1.36，[1.22-1.51]，P-value=4.2×10-10）和 EUR（OR=1.52，[1.21-1.90]，P-value=3.3×10-4）中，基因型 HMGCR 抑制与 T2D 风险增加相关。这些结果在各种敏感性分析（包括同位分析）中都是一致的，表明研究结果是可靠的。研究结果表明，在大多数非欧洲人群中，长期 PCSK9 抑制剂对 T2D 和血糖指标的影响是中性的，但在非洲裔人群中可能会增加风险。相比之下，在南亚、东亚和欧洲队列中，HMGCR 抑制增加了 T2D 的风险，这强调了在代谢性疾病基因研究中考虑多样性的必要性。

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.