Causal effects of lipid-lowering therapies on aging-related outcomes and risk of cancers: a drug-target Mendelian randomization study

Chen, Han; Tang, Xinyu; Su, Wei; Li, Shuo; Yang, Ruoyun; Cheng, Hong; Zhang, Guoxin; Zhou, Xiaoying

doi:10.18632/aging.205347

Cited by 2 publications

(2 citation statements)

References 34 publications

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“…Ioannou and colleagues suggested that disparities in liver cancer outcomes may stem from varying cholesterol levels in the liver [25]. In another MR study [38], inconsistent findings regarding the impact of PCSK9 inhibitors on tumors, particularly gastric cancer, lung cancer, and hepatocellular carcinoma, were noted. We attribute these differences to two factors: (1) our study used more recent and larger LDL data sets from 2020 and 2022, unlike previous studies that relied on 2013 data, and (2) we employed an additional LDL data set for validation and rigorously excluded reverse causality effects, enhancing the robustness of our results.…”

Section: Discussionmentioning

confidence: 99%

The Causal Relationship between PCSK9 Inhibitors and Malignant Tumors: A Mendelian Randomization Study Based on Drug Targeting

Wang,

Li,

Zhang

et al. 2024

Genes

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Objective: This study explores the potential causal association between proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors and tumor development using Mendelian randomization (MR) based on drug targets. Methods: Instrumental variables within ±100 kb of the PCSK9 gene locus, impacting low-density lipoprotein cholesterol (LDL-C), were utilized for MR analysis. Coronary heart disease (CHD) served as a positive control to validate the causal relationship between PCSK9 inhibitors and various cancers. We employed reverse MR to address the reverse causation concerns. Data from positive controls and tumors were sourced from OpenGWAS. Results: MR analysis suggested a negative causal relationship between PCSK9 inhibitors and both breast and lung cancers (95%CIBreast cancer 0.81~0.99, p = 2.25 × 10−2; 95%CILung cancer 0.65~0.94, p = 2.55 × 10−3). In contrast, a positive causal link was observed with gastric, hepatic, and oral pharyngeal cancers and cervical intraepithelial neoplasia (95%CIGastric cancer 1.14~1.75, p = 1.88 × 10−2; 95%CIHepatic cancer 1.46~2.53, p = 1.16 × 10−2; 95%CIOral cavity and pharyngeal cancer 4.49~6.33, p = 3.36 × 10−4; 95%CICarcinoma in situ of cervix uteri 4.56~7.12, p = 6.91 × 10−3), without heterogeneity or pleiotropy (p > 0.05). Sensitivity analyses confirmed these findings. The results of MR of drug targets suggested no causal relationship between PCSK9 inhibitors and bladder cancer, thyroid cancer, pancreatic cancer, colorectal cancer, malignant neoplasms of the kidney (except for renal pelvis tumors), malignant neoplasms of the brain, and malignant neoplasms of the esophagus (p > 0.05). Reverse MR helped mitigate reverse causation effects. Conclusions: The study indicates a divergent causal relationship of PCSK9 inhibitors with certain cancers. While negatively associated with breast and lung cancers, a positive causal association was observed with gastric, hepatic, oral cavity, and pharyngeal cancers and cervical carcinoma in situ. No causal links were found with bladder, thyroid, pancreatic, colorectal, certain kidney, brain, and esophageal cancers.

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Section: Discussionmentioning

confidence: 99%

The Causal Relationship between PCSK9 Inhibitors and Malignant Tumors: A Mendelian Randomization Study Based on Drug Targeting

Wang,

Li,

Zhang

et al. 2024

Genes

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“…Instrumental Variables (IVs) targeting IL6R were obtained by identifying SNPs in the ±100-kb range of the IL6R locus and are associated with CRP serum levels (association P- value < 5 × 10 −8 ), i.e., they could mimic the effects of IL6R inhibitors since CRP serum levels are a reliable downstream biomarker of IL-6 signaling ( 16 ). To ensure that a sufficient number of SNPs representative of the traits analyzed in this drug-targeted MR analysis were included and to minimize the effect of strong linkage disequilibrium (LD) to a certain extent, we finally fixed the critical value of LD ( r 2 < 0.3) by referring to the literature wherein excellent results have been achieved in the past ( 17 – 19 ). In addition, to prevent weak instrumental bias, only SNPs with F -statistic >10 were included in the analysis.…”

Section: Methodsmentioning

confidence: 99%

Therapeutic potential of single-nucleotide polymorphism-mediated IL6R inhibitors in ankylosing spondylitis treatment

Chen,

Xu,

Que

et al. 2024

Front. Med.

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ObjectiveInterleukin-6 (IL-6) is a multiple-effect cell factor implicated in the etiopathogenesis of several rheumatologic disorders. The blockade of the IL-6 pathway via IL6R inhibitors effectively treats these disorders. However, the clinical significance of the IL6R blockade for ankylosing spondylitis (AS) therapy remains controversial. With advances in genomics, increasing evidence has revealed the role of heritability in the etiology of disease, and Mendelian randomization (MR) analyses are being used more broadly to infer causation. Therefore, this MR study aims to evaluate the potential therapeutic utility of IL6R-targeted approaches in AS.MethodsThe C-reactive protein (CRP) level was used as an exposure factor, and rheumatoid arthritis (RA) was used as a positive control. As-related genome-wide association study (GWAS) data were used as the primary outcome of drug-targeted MR analyses to test the relation between IL6R blockers and AS. Inverse variance weighting (IVW) is the primary analytical approach. Various sensitivity tests were performed to check the robustness and trustworthiness of the causality estimation, including consistency, heterogeneity, and pleiotropy analyses. In addition, repeated analysis was conducted using different GWAS data related to exposures and outcomes to examine the results for stability.ResultsAccording to the IVW results, IL6R inhibitors significantly reduced the risk of AS in ukb-b-18194 (OR: 0.995, 95% CI 0.993–0.996, P = 5.12 × 10−08) and ukb-a-88 (OR: 0.994, 95% CI 0.993–0.996, P = 6.25 × 10−15). Moreover, repeated analyses were performed using different exposure-related GWAS data, yielding similar results, ukb-b-18194 (OR: 0.995, 95% CI 0.993–0.997, P = 1.25 × 10−06) and ukb-a-88 (OR: 0.995, 95% CI 0.994–0.997, P = 7.81 × 10−09). Heterogeneity analyses and pleiotropy analyses indicated no significant heterogeneity or pleiotropy.ConclusionThis MR analysis result further validates that the IL-6 pathway may contribute to the pathogenesis of AS and that the inhibition of IL6R reduces the risk of AS. These findings may guide future studies and provide more favorable drug treatment options for people at high risk of AS.

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Causal effects of lipid-lowering therapies on aging-related outcomes and risk of cancers: a drug-target Mendelian randomization study

Cited by 2 publications

References 34 publications

The Causal Relationship between PCSK9 Inhibitors and Malignant Tumors: A Mendelian Randomization Study Based on Drug Targeting

The Causal Relationship between PCSK9 Inhibitors and Malignant Tumors: A Mendelian Randomization Study Based on Drug Targeting

Therapeutic potential of single-nucleotide polymorphism-mediated IL6R inhibitors in ankylosing spondylitis treatment

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