Genomic Insights Into Statin Therapy: Differential Expression Analysis of Key Genes

Mahjoubin-Tehran, Maryam; Sukhorukov, Vasily N.; Jmaialahmadi, Tannaz; Sahebkar, Amirhossein

doi:10.1016/j.cpcardiol.2023.102103

Current Problems in Cardiology

2024

DOI: 10.1016/j.cpcardiol.2023.102103

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Genomic Insights Into Statin Therapy: Differential Expression Analysis of Key Genes

Maryam Mahjoubin-Tehran,

Vasily N. Sukhorukov,

Tannaz Jmaialahmadi

et al.

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Cited by 4 publications

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Association between insulin‐associated gene polymorphisms and new‐onset diabetes mellitus in statin‐treated patients

Park,

Kim,

Park

et al. 2024

Eur J Clin Investigation

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BackgroundWhile statins are effective at managing lipid levels, there is growing evidence for new‐onset diabetes mellitus (NODM). The insulin signalling pathway (ISP) inhibited by statins is one of the potential mechanisms; however, most studies have been limited to in vitro settings. Therefore, this study aimed to identify the genetic associations within the ISP‐related genes and NODM.MethodsWe performed a retrospective analysis of samples collected prospectively from February 2021 to May 2021. Among ISP‐related genes, we selected 11 candidate genes (IGF1, IGF2, IGF1R, INSR, IRS1, IRS2, PIK3CA, PIK3CB, PIK3R1, AKT1 and AKT2). An additional analysis was conducted comparing patients with DM prior to statin therapy and controls to determine whether the single nucleotide polymorphisms (SNPs) are specific to statin.ResultsA total of 602 patients were analysed, including 71 (11.8%) with statin‐induced NODM. After adjustment, IGF1R rs2715439, INSR rs1799817, INSR rs2059807 and PIK3R1 rs3730089 were found to be independently associated with NODM. In an additional analysis, all SNPs that demonstrated an association with statin‐induced NODM lost their significance in patients with DM prior to statin therapy.ConclusionThis study revealed the ISP‐related genetic effects, specifically involving genes such as INSR, IGF1R and PIK3R1, in the development of statin‐induced NODM. Our findings suggest a potential mechanism of statin‐induced NODM related to ISP‐related genetic variants.

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Association between insulin‐associated gene polymorphisms and new‐onset diabetes mellitus in statin‐treated patients

Park,

Kim,

Park

et al. 2024

Eur J Clin Investigation

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Causal effects of lipid‐lowering drugs on inflammatory skin diseases: Evidence from drug target Mendelian randomisation

Zang,

Li,

Zhang

et al. 2024

Experimental Dermatology

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Clinical research has revealed that inflammatory skin diseases are associated with dyslipidaemia. Modulating lipids is also a rising potential treatment option. However, there is heterogeneity in the existing evidence and a lack of large‐scale clinical trials. Observational research is prone to bias, making it difficult to determine causality. This study aimed to evaluate the causal association between lipid‐lowering drugs and inflammatory skin diseases. A drug target Mendelian randomisation (MR) analysis was conducted. Genetic targets of lipid‐lowering drugs, including proprotein convertase subtilis kexin 9 (PCSK9) and 3‐hydroxy‐3‐methylglutaryl‐assisted enzyme A reductase (HMGCR) inhibitor, were screened. Common inflammatory skin diseases, including psoriasis, allergic urticaria, rosacea, atopic dermatitis, systemic sclerosis and seborrhoeic dermatitis, were considered as outcomes. Gene‐predicted inhibition of PCSK9 was causally associated with a decreased risk of psoriasis (ORIVW [95%CI] = 0.600 [0.474–0.761], p = 2.48 × 10−5) and atopic dermatitis (ORIVW [95%CI] = 0.781 [0.633–0.964], p = 2.17 × 10−2). Gene‐predicted inhibition of HMGCR decreased the risk of seborrhoeic dermatitis (ORIVW [95%CI] = 0.407 [0.168–0.984], p = 4.61 × 10−2) but increased the risk of allergic urticaria (ORIVW [95%CI] = 3.421 [1.374–8.520], p = 8.24 × 10−3) and rosacea (ORIVW [95%CI] = 3.132 [1.260–7.786], p = 1.40 × 10−2). Among all causal associations, only PCSK9 inhibition demonstrated a robust causal effect on psoriasis after a more rigorous Bonferroni test (p < 4.17 × 10−3, which is 0.05/12). Modulating lipids via PCSK9 inhibition may offer potential therapeutic targets for psoriasis and atopic dermatitis. Given the potential cutaneous side effects associated with HMGCR inhibitors, PCSK9 inhibitors could be considered viable alternatives in lipid‐lowering medication.

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Association of lipid-lowering drugs with risk of sarcopenia: a drug target mendelian randomization study and meta-analysis

Li,

Zang,

et al. 2024

Hum Genomics

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Background Lipid-lowering drugs are widely used among the elderly, with some studies suggesting links to muscle-related symptoms. However, the causality remains uncertain. Methods Using the Mendelian randomization (MR) approach, we assessed the causal effects of genetically proxied reduced low-density lipoprotein cholesterol (LDL-C) through inhibitions of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1) on sarcopenia-related traits, including low hand grip strength, appendicular lean mass, and usual walking pace. A meta-analysis was conducted to combine the causal estimates from different consortiums. Results Using LDL-C pooled data predominantly from UK Biobank, genetically proxied inhibition of HMGCR was associated with higher appendicular lean mass (beta = 0.087, P = 7.56 × 10− 5) and slower walking pace (OR = 0.918, P = 6.06 × 10− 9). In contrast, inhibition of PCSK9 may reduce appendicular lean mass (beta = -0.050, P = 1.40 × 10− 3), while inhibition of NPC1L1 showed no causal impact on sarcopenia-related traits. These results were validated using LDL-C data from Global Lipids Genetics Consortium, indicating that HMGCR inhibition may increase appendicular lean mass (beta = 0.066, P = 2.17 × 10− 3) and decelerate walking pace (OR = 0.932, P = 1.43 × 10− 6), whereas PCSK9 inhibition could decrease appendicular lean mass (beta = -0.048, P = 1.69 × 10− 6). Meta-analysis further supported the robustness of these causal associations. Conclusions Genetically proxied HMGCR inhibition may increase muscle mass but compromise muscle function, PCSK9 inhibition could result in reduced muscle mass, while NPC1L1 inhibition is not associated with sarcopenia-related traits and this class of drugs may serve as viable alternatives to sarcopenia individuals or those at an elevated risk.

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Genomic Insights Into Statin Therapy: Differential Expression Analysis of Key Genes

Cited by 4 publications

References 39 publications

Association between insulin‐associated gene polymorphisms and new‐onset diabetes mellitus in statin‐treated patients

Association between insulin‐associated gene polymorphisms and new‐onset diabetes mellitus in statin‐treated patients

Causal effects of lipid‐lowering drugs on inflammatory skin diseases: Evidence from drug target Mendelian randomisation

Association of lipid-lowering drugs with risk of sarcopenia: a drug target mendelian randomization study and meta-analysis

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