Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, UK.
Primula Group Ltd., London N8 0RL, UK.
Genes (Basel). 2024 Aug 12;15(8):1059. doi: 10.3390/genes15081059.
Adenosine triphosphate-citrate lyase (ACLY) inhibition has proven clinically efficacious for low-density lipoprotein cholesterol (LDL-c) lowering and cardiovascular disease (CVD) risk reduction. Clinical and genetic evidence suggests that some LDL-c lowering strategies, such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibition with statin therapy increase body weight and the risk of developing type 2 diabetes mellitus (T2DM). However, whether ACLY inhibition affects metabolic risk factors is currently unknown. We aimed to investigate the effects of ACLY inhibition on glycaemic and anthropometric traits using Mendelian randomization (MR). As genetic instruments for ACLY inhibition, we selected weakly correlated single-nucleotide polymorphisms at the gene associated with lower gene expression in the eQTLGen study (N = 31,684) and lower LDL-c levels in the Global Lipid Genetic Consortium study (N = 1.65 million). Two-sample Mendelian randomization was employed to investigate the effects of ACLY inhibition on T2DM risk, and glycaemic and anthropometric traits using summary data from large consortia, with sample sizes ranging from 151,013 to 806,834 individuals. Findings for genetically predicted ACLY inhibition were compared to those obtained for genetically predicted HMGCR inhibition using the same instrument selection strategy and outcome data. Primary MR analyses showed that genetically predicted ACLY inhibition was associated with lower waist-to-hip ratio (β per 1 standard deviation lower LDL-c: -1.17; 95% confidence interval (CI): -1.61 to -0.73; < 0.001) but not with risk of T2DM (odds ratio (OR) per standard deviation lower LDL-c: 0.74, 95% CI = 0.25 to 2.19, = 0.59). In contrast, genetically predicted HMGCR inhibition was associated with higher waist-to-hip ratio (β = 0.15; 95%CI = 0.04 to 0.26; = 0.008) and T2DM risk (OR = 1.73, 95% CI = 1.27 to 2.36, < 0.001). The MR analyses considering secondary outcomes showed that genetically predicted ACLY inhibition was associated with a lower waist-to-hip ratio adjusted for body mass index (BMI) (β = -1.41; 95%CI = -1.81 to -1.02; < 0.001). In contrast, genetically predicted HMGCR inhibition was associated with higher HbA1c (β = 0.19; 95%CI = 0.23 to 0.49; < 0.001) and BMI (β = 0.36; 95%CI = 0.23 to 0.49; < 0.001). Human genetic evidence supports the metabolically favourable effects of ACLY inhibition on body weight distribution, in contrast to HMGCR inhibition. These findings should be used to guide and prioritize ongoing clinical development efforts.
三磷酸腺苷-柠檬酸裂解酶 (ACLY) 抑制已被证明在降低低密度脂蛋白胆固醇 (LDL-c) 和降低心血管疾病 (CVD) 风险方面具有临床疗效。临床和遗传证据表明，一些 LDL-c 降低策略，如他汀类药物治疗抑制 3-羟-3-甲基戊二酰基辅酶 A 还原酶 (HMGCR)，会增加体重和患 2 型糖尿病 (T2DM) 的风险。然而，ACLY 抑制是否会影响代谢风险因素目前尚不清楚。我们旨在使用孟德尔随机化 (MR) 研究 ACLY 抑制对血糖和人体测量特征的影响。作为 ACLY 抑制的遗传工具，我们选择了与 eQTLGen 研究中基因表达降低相关的基因 (N = 31,684) 和全球脂质遗传联盟研究中 LDL-c 水平降低相关的基因 (N = 1.65 百万) 的弱相关单核苷酸多态性。采用两样本孟德尔随机化研究，使用来自大型联盟的汇总数据，对 ACLY 抑制对 T2DM 风险以及血糖和人体测量特征的影响进行了研究，样本量从 151,013 到 806,834 人不等。使用相同的工具选择策略和结果数据，将基于遗传预测的 ACLY 抑制与基于遗传预测的 HMGCR 抑制的结果进行了比较。主要 MR 分析表明，遗传预测的 ACLY 抑制与较低的腰围-臀围比相关 (每标准偏差 LDL-c 降低 1 个单位：-1.17；95%置信区间 (CI)：-1.61 至-0.73；< 0.001)，但与 T2DM 风险无关 (每标准偏差 LDL-c 降低 1 个单位的比值比 (OR)：0.74，95%CI = 0.25 至 2.19， = 0.59)。相比之下，遗传预测的 HMGCR 抑制与较高的腰围-臀围比相关 (β = 0.15；95%CI = 0.04 至 0.26；< 0.001) 和 T2DM 风险相关 (OR = 1.73，95%CI = 1.27 至 2.36，< 0.001)。考虑次要结果的 MR 分析表明，遗传预测的 ACLY 抑制与经体重指数 (BMI) 调整后的腰围-臀围比相关 (β = -1.41；95%CI = -1.81 至-1.02；< 0.001)。相比之下，遗传预测的 HMGCR 抑制与较高的 HbA1c (β = 0.19；95%CI = 0.23 至 0.49；< 0.001) 和 BMI (β = 0.36；95%CI = 0.23 至 0.49；< 0.001) 相关。人类遗传证据支持 ACLY 抑制对体重分布的代谢有益影响，而不是 HMGCR 抑制。这些发现应该用于指导和优先考虑正在进行的临床开发工作。
