Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects
Abstract
:1. Introduction
2. Materials and Methods
2.1. Exposure Data
2.2. Outcome Data: GWAS Summary Statistics for ALS
2.3. MR Analysis
3. Results
3.1. Genetically Determined Statin Use Was Associated with a Higher Risk of ALS
3.2. Statin Use Potentially Mediates LDL-C Associated ALS Risk
3.3. Peripheral Effect of Statin Was Not Associated with ALS Risk
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Tang, L.; Fan, D. Amyotrophic lateral sclerosis: New era, new challenges. Lancet Neurol. 2022, 21, 400–401. [Google Scholar] [CrossRef]
- Hardiman, O.; Al-Chalabi, A.; Chio, A.; Corr, E.M.; Logroscino, G.; Robberecht, W.; Shaw, P.J.; Simmons, Z.; van den Berg, L.H. Amyotrophic lateral sclerosis. Nat. Rev. Dis. Prim. 2017, 3, 17071. [Google Scholar] [CrossRef]
- Ingre, C.; Roos, P.M.; Piehl, F.; Kamel, F.; Fang, F. Risk factors for amyotrophic lateral sclerosis. Clin. Epidemiol. 2015, 7, 181–193. [Google Scholar] [CrossRef]
- Zufiría, M.; Gil-Bea, F.J.; Fernández-Torrón, R.; Poza, J.J.; Muñoz-Blanco, J.L.; Rojas-García, R.; Riancho, J.; López de Munain, A. Als: A bucket of genes, environment, metabolism and unknown ingredients. Prog. Neurobiol. 2016, 142, 104–129. [Google Scholar] [CrossRef]
- Al-Chalabi, A.; Hardiman, O. The epidemiology of als: A conspiracy of genes, environment and time. Nat. Rev. Neurol. 2013, 9, 617–628. [Google Scholar] [CrossRef]
- Sini, P.; Dang, T.B.C.; Fais, M.; Galioto, M.; Padedda, B.M.; Lugliè, A.; Iaccarino, C.; Crosio, C. Cyanobacteria, cyanotoxins, and neurodegenerative diseases: Dangerous liaisons. Int. J. Mol. Sci. 2021, 22, 8726. [Google Scholar] [CrossRef]
- Tanaka, M.; Toldi, J.; Vécsei, L. Exploring the etiological links behind neurodegenerative diseases: Inflammatory cytokines and bioactive kynurenines. Int. J. Mol. Sci. 2020, 21, 2431. [Google Scholar] [CrossRef]
- Tanaka, M.; Szabó, Á.; Spekker, E.; Polyák, H.; Tóth, F.; Vécsei, L. Mitochondrial impairment: A common motif in neuropsychiatric presentation? The link to the tryptophan–kynurenine metabolic system. Cells 2022, 11, 2607. [Google Scholar] [CrossRef]
- Tanaka, M.; Vécsei, L. Editorial of special issue ‘dissecting neurological and neuropsychiatric diseases: Neurodegeneration and neuroprotection’. Int. J. Mol. Sci. 2022, 23, 6991. [Google Scholar] [CrossRef]
- Adhyaru, B.B.; Jacobson, T.A. Safety and efficacy of statin therapy. Nat. Rev. Cardiol. 2018, 15, 757–769. [Google Scholar] [CrossRef]
- Alfaqih, M.A.; Allott, E.H.; Hamilton, R.J.; Freeman, M.R.; Freedland, S.J. The current evidence on statin use and prostate cancer prevention: Are we there yet? Nat. Rev. Urol. 2017, 14, 107–119. [Google Scholar] [CrossRef]
- Nielsen, S.F.; Nordestgaard, B.G.; Bojesen, S.E. Statin use and reduced cancer-related mortality. N. Engl. J. Med. 2012, 367, 1792–1802. [Google Scholar] [CrossRef]
- Gazzerro, P.; Proto, M.C.; Gangemi, G.; Malfitano, A.M.; Ciaglia, E.; Pisanti, S.; Santoro, A.; Laezza, C.; Bifulco, M. Pharmacological actions of statins: A critical appraisal in the management of cancer. Pharmacol. Rev. 2012, 64, 102–146. [Google Scholar] [CrossRef]
- Golomb, B.A.; Verden, A.; Messner, A.K.; Koslik, H.J.; Hoffman, K.B. Amyotrophic lateral sclerosis associated with statin use: A disproportionality analysis of the fda’s adverse event reporting system. Drug Saf. 2018, 41, 403–413. [Google Scholar] [CrossRef]
- Mariosa, D.; Kamel, F.; Bellocco, R.; Ronnevi, L.-O.; Almqvist, C.; Larsson, H.; Ye, W.; Fang, F. Antidiabetics, statins and the risk of amyotrophic lateral sclerosis. Eur. J. Neurol. 2020, 27, 1010–1016. [Google Scholar] [CrossRef]
- Skajaa, N.; Bakos, I.; Horváth-Puhó, E.; Henderson, V.W.; Lash, T.L.; Sørensen, H.T. Statin initiation and risk of amyotrophic lateral sclerosis: A danish population-based cohort study. Epidemiology 2021, 32, 756–762. [Google Scholar] [CrossRef]
- Toft Sørensen, H.; Lash, T.L. Statins and amyotrophic lateral sclerosis—The level of evidence for an association. J. Intern. Med. 2009, 266, 520–526. [Google Scholar] [CrossRef]
- Armon, C. An evidence-based medicine approach to the evaluation of the role of exogenous risk factors in sporadic amyotrophic lateral sclerosis. Neuroepidemiology 2003, 22, 217–228. [Google Scholar] [CrossRef]
- Emdin, C.A.; Khera, A.V.; Kathiresan, S. Mendelian randomization. JAMA 2017, 318, 1925–1926. [Google Scholar] [CrossRef]
- Hartwig, F.P.; Davies, N.M.; Hemani, G.; Davey Smith, G. Two-sample mendelian randomization: Avoiding the downsides of a powerful, widely applicable but potentially fallible technique. Int. J. Epidemiol. 2017, 45, 1717–1726. [Google Scholar] [CrossRef]
- Davey Smith, G.; Ebrahim, S. ‘Mendelian randomization’: Can genetic epidemiology contribute to understanding environmental determinants of disease? Int. J. Epidemiol. 2003, 32, 1–22. [Google Scholar] [CrossRef] [PubMed]
- Davey Smith, G.; Hemani, G. Mendelian randomization: Genetic anchors for causal inference in epidemiological studies. Hum. Mol. Genet. 2014, 23, R89–R98. [Google Scholar] [CrossRef] [PubMed]
- Hartmann, H.; Ho, W.Y.; Chang, J.C.; Ling, S.C. Cholesterol dyshomeostasis in amyotrophic lateral sclerosis: Cause, consequence, or epiphenomenon? FEBS J. 2022, 289, 7688–7709. [Google Scholar] [CrossRef]
- Lawlor, D.A. Commentary: Two-sample mendelian randomization: Opportunities and challenges. Int. J. Epidemiol. 2016, 45, 908–915. [Google Scholar] [CrossRef]
- Schmidt, A.F.; Finan, C.; Gordillo-Marañón, M.; Asselbergs, F.W.; Freitag, D.F.; Patel, R.S.; Tyl, B.; Chopade, S.; Faraway, R.; Zwierzyna, M. Genetic drug target validation using mendelian randomisation. Nat. Commun. 2020, 11, 3255. [Google Scholar] [CrossRef]
- Huang, W.; Xiao, J.; Ji, J.; Chen, L. Association of lipid-lowering drugs with COVID-19 outcomes from a mendelian randomization study. eLife 2021, 10, e73873. [Google Scholar] [CrossRef]
- Wu, Y.; Byrne, E.M.; Zheng, Z.; Kemper, K.E.; Yengo, L.; Mallett, A.J.; Yang, J.; Visscher, P.M.; Wray, N.R. Genome-wide association study of medication-use and associated disease in the UK biobank. Nat. Commun. 2019, 10, 1891. [Google Scholar] [CrossRef]
- Santos, R.; Ursu, O.; Gaulton, A.; Bento, A.P.; Donadi, R.S.; Bologa, C.G.; Karlsson, A.; Al-Lazikani, B.; Hersey, A.; Oprea, T.I. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 2017, 16, 19–34. [Google Scholar] [CrossRef]
- Rosoff, D.B.; Smith, G.D.; Lohoff, F.W. Prescription opioid use and risk for major depressive disorder and anxiety and stress-related disorders: A multivariable mendelian randomization analysis. JAMA Psychiatry 2021, 78, 151–160. [Google Scholar] [CrossRef]
- Cai, J.; He, L.; Wang, H.; Rong, X.; Chen, M.; Shen, Q.; Li, X.; Li, M.; Peng, Y. Genetic liability for prescription opioid use and risk of cardiovascular diseases: A multivariable mendelian randomization study. Addiction 2022, 117, 1382–1391. [Google Scholar] [CrossRef]
- Guo, X.; Chong, L.; Zhang, X.; Li, R. Immunosuppressants contribute to a reduced risk of parkinson’s disease in rheumatoid arthritis. Int. J. Epidemiol. 2022, 51, 1328–1338. [Google Scholar] [CrossRef] [PubMed]
- Klimentidis, Y.C.; Arora, A.; Newell, M.; Zhou, J.; Ordovas, J.M.; Renquist, B.J.; Wood, A.C. Phenotypic and genetic characterization of lower ldl cholesterol and increased type 2 diabetes risk in the UK biobank. Diabetes 2020, 69, 2194–2205. [Google Scholar] [CrossRef] [PubMed]
- Postmus, I.; Trompet, S.; Deshmukh, H.A.; Barnes, M.R.; Li, X.; Warren, H.R.; Chasman, D.I.; Zhou, K.; Arsenault, B.J.; Donnelly, L.A. Pharmacogenetic meta-analysis of genome-wide association studies of ldl cholesterol response to statins. Nat. Commun. 2014, 5, 5068. [Google Scholar] [CrossRef] [PubMed]
- Nicolas, A.; Kenna, K.P.; Renton, A.E.; Ticozzi, N.; Faghri, F.; Chia, R.; Dominov, J.A.; Kenna, B.J.; Nalls, M.A.; Keagle, P.; et al. Genome-wide analyses identify kif5a as a novel als gene. Neuron 2018, 97, 1268–1283.e6. [Google Scholar] [CrossRef] [PubMed]
- Mayerhofer, E.; Malik, R.; Parodi, L.; Burgess, S.; Harloff, A.; Dichgans, M.; Rosand, J.; Anderson, C.D.; Georgakis, M.K. Genetically predicted on-statin ldl response is associated with higher intracerebral haemorrhage risk. Brain 2022, 145, 2677–2686. [Google Scholar] [CrossRef] [PubMed]
- Smit, R.A.; Trompet, S.; Leong, A.; Goodarzi, M.O.; Postmus, I.; Warren, H.; Theusch, E.; Barnes, M.R.; Arsenault, B.J.; Li, X. Statin-induced ldl cholesterol response and type 2 diabetes: A bidirectional two-sample mendelian randomization study. Pharm. J. 2020, 20, 462–470. [Google Scholar] [CrossRef]
- Hemani, G.; Zheng, J.; Elsworth, B.; Wade, K.H.; Haberland, V.; Baird, D.; Laurin, C.; Burgess, S.; Bowden, J.; Langdon, R.; et al. The mr-base platform supports systematic causal inference across the human phenome. eLife 2018, 7, e34408. [Google Scholar] [CrossRef]
- Burgess, S.; Thompson, S.G.; Collaboration, C.C.G. Avoiding bias from weak instruments in mendelian randomization studies. Int. J. Epidemiol. 2011, 40, 755–764. [Google Scholar] [CrossRef]
- Burgess, S.; Bowden, J.; Fall, T.; Ingelsson, E.; Thompson, S.G. Sensitivity analyses for robust causal inference from mendelian randomization analyses with multiple genetic variants. Epidemiology 2017, 28, 30–42. [Google Scholar] [CrossRef]
- Bowden, J.; Davey Smith, G.; Haycock, P.C.; Burgess, S. Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genet. Epidemiol. 2016, 40, 304–314. [Google Scholar] [CrossRef]
- Burgess, S.; Thompson, S.G. Interpreting findings from mendelian randomization using the mr-egger method. Eur. J. Epidemiol. 2017, 32, 377–389. [Google Scholar] [CrossRef] [PubMed]
- Hemani, G.; Bowden, J.; Davey Smith, G. Evaluating the potential role of pleiotropy in mendelian randomization studies. Hum. Mol. Genet. 2018, 27, R195–R208. [Google Scholar] [CrossRef] [PubMed]
- Zeng, P.; Zhou, X. Causal effects of blood lipids on amyotrophic lateral sclerosis: A mendelian randomization study. Hum. Mol. Genet. 2019, 28, 688–697. [Google Scholar] [CrossRef] [PubMed]
- Bandres-Ciga, S.; Noyce, A.J.; Hemani, G.; Nicolas, A.; Calvo, A.; Mora, G.; Consortium, I.; Arosio, A.; Barberis, M.; Bartolomei, I. Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis. Ann. Neurol. 2019, 85, 470–481. [Google Scholar] [CrossRef] [PubMed]
- Su, X.W.; Nandar, W.; Neely, E.B.; Simmons, Z.; Connor, J.R. Statins accelerate disease progression and shorten survival in sod1g93a mice. Muscle Nerve 2016, 54, 284–291. [Google Scholar] [CrossRef]
- Murinson, B.B.; Haughey, N.J.; Maragakis, N.J. Selected statins produce rapid spinal motor neuron loss in vitro. BMC Musculoskelet. Disord. 2012, 13, 100. [Google Scholar] [CrossRef]
- Daneman, R.; Prat, A. The blood–brain barrier. Cold Spring Harb. Perspect. Biol. 2015, 7, a020412. [Google Scholar] [CrossRef]
- Ward, N.C.; Watts, G.F.; Eckel, R.H. Statin toxicity: Mechanistic insights and clinical implications. Circ. Res. 2019, 124, 328–350. [Google Scholar] [CrossRef]
- Paganoni, S.; Deng, J.; Jaffa, M.; Cudkowicz, M.E.; Wills, A.-M. Body mass index, not dyslipidemia, is an independent predictor of survival in amyotrophic lateral sclerosis. Muscle Nerve 2011, 44, 20–24. [Google Scholar] [CrossRef]
- Rafiq, M.K.; Lee, E.; Bradburn, M.; McDermott, C.J.; Shaw, P.J. Effect of lipid profile on prognosis in the patients with amyotrophic lateral sclerosis: Insights from the olesoxime clinical trial. Amyotroph. Lateral Scler. Front. Degener. 2015, 16, 478–484. [Google Scholar] [CrossRef]
- Ingre, C.; Chen, L.; Zhan, Y.; Termorshuizen, J.; Yin, L.; Fang, F. Lipids, apolipoproteins, and prognosis of amyotrophic lateral sclerosis. Neurology 2020, 94, e1835–e1844. [Google Scholar] [CrossRef] [PubMed]
- Wang, W.; Bian, J.; Li, Z. Internalized activation of membrane receptors: From phenomenon to theory. Trends Cell Biol. 2021, 31, 428–431. [Google Scholar] [CrossRef] [PubMed]
- Wang, W.; Bian, J.; Sun, Y.; Li, Z. The new fate of internalized membrane receptors: Internalized activation. Pharmacol. Ther. 2021, 233, 108018. [Google Scholar] [CrossRef] [PubMed]
- Ahmed, R.M.; Irish, M.; Piguet, O.; Halliday, G.M.; Ittner, L.M.; Farooqi, S.; Hodges, J.R.; Kiernan, M.C. Amyotrophic lateral sclerosis and frontotemporal dementia: Distinct and overlapping changes in eating behaviour and metabolism. Lancet Neurol. 2016, 15, 332–342. [Google Scholar] [CrossRef] [PubMed]
- Cooper-Knock, J.; Zhang, S.; Kenna, K.P.; Moll, T.; Franklin, J.P.; Allen, S.; Nezhad, H.G.; Iacoangeli, A.; Yacovzada, N.Y.; Eitan, C.; et al. Rare variant burden analysis within enhancers identifies cav1 as an als risk gene. Cell Rep. 2020, 33, 108456. [Google Scholar] [CrossRef]
- Park, E.-J.; Seong, E.; Kim, Y.; Lee, K. Ammonium lauryl sulfate-induced apoptotic cell death may be due to mitochondrial dysfunction triggered by caveolin-1. Toxicol. Vitr. 2019, 57, 132–142. [Google Scholar] [CrossRef]
- Sawada, A.; Wang, S.; Jian, M.; Leem, J.; Wackerbarth, J.; Egawa, J.; Schilling, J.M.; Platoshyn, O.; Zemljic-Harpf, A.; Roth, D.M. Neuron-targeted caveolin-1 improves neuromuscular function and extends survival in sod1g93a mice. FASEB J. 2019, 33, 7545–7554. [Google Scholar] [CrossRef]
- Graaf, M.R.; Richel, D.J.; van Noorden, C.J.F.; Guchelaar, H.-J. Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer. Cancer Treat. Rev. 2004, 30, 609–641. [Google Scholar] [CrossRef]
- Weber, M.J.; Gioeli, D. Ras signaling in prostate cancer progression. J. Cell. Biochem. 2004, 91, 13–25. [Google Scholar] [CrossRef]
- Tang, Z.; Ma, Q.; Wang, L.; Liu, C.; Gao, H.; Yang, Z.; Liu, Z.; Zhang, H.; Ji, L.; Jiang, G. A brief review: Some compounds targeting yap against malignancies. Future Oncol. 2019, 15, 1535–1543. [Google Scholar] [CrossRef]
- Liu, D.; Lv, H.; Liu, Q.; Sun, Y.; Hou, S.; Zhang, L.; Yang, M.; Han, B.; Wang, G.; Wang, X.; et al. Atheroprotective effects of methotrexate via the inhibition of yap/taz under disturbed flow. J. Transl. Med. 2019, 17, 378. [Google Scholar] [CrossRef] [PubMed]
- Sorrentino, G.; Ruggeri, N.; Specchia, V.; Cordenonsi, M.; Mano, M.; Dupont, S.; Manfrin, A.; Ingallina, E.; Sommaggio, R.; Piazza, S.; et al. Metabolic control of yap and taz by the mevalonate pathway. Nat. Cell Biol. 2014, 16, 357–366. [Google Scholar] [CrossRef] [PubMed]
- Wang, W.; Li, W.; Liu, K.; Niu, X.; Guan, K.; Jiang, Y.; Li, Z.; Dong, E. Src mediates β-adrenergic receptor induced yap tyrosine phosphorylation. Sci. China Life Sci. 2020, 63, 697–705. [Google Scholar] [CrossRef] [PubMed]
- Lee, N.; Tilija Pun, N.; Jang, W.-J.; Bae, J.W.; Jeong, C.-H. Pitavastatin induces apoptosis in oral squamous cell carcinoma through activation of foxo3a. J. Cell. Mol. Med. 2020, 24, 7055–7066. [Google Scholar] [CrossRef] [PubMed]
- Wood, W.G.; Igbavboa, U.; Muller, W.E.; Eckert, G.P. Statins, bcl-2, and apoptosis: Cell death or cell protection? Mol. Neurobiol. 2013, 48, 308–314. [Google Scholar] [CrossRef]
- Sudlow, C.; Gallacher, J.; Allen, N.; Beral, V.; Burton, P.; Danesh, J.; Downey, P.; Elliott, P.; Green, J.; Landray, M. Uk biobank: An open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015, 12, e1001779. [Google Scholar] [CrossRef]
- Wild, C.P. Complementing the genome with an “exposome”: The outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol. Biomark. Prev. 2005, 14, 1847–1850. [Google Scholar] [CrossRef]
- Power, M.C.; Weuve, J.; Sharrett, A.R.; Blacker, D.; Gottesman, R.F. Statins, cognition, and dementia—Systematic review and methodological commentary. Nat. Rev. Neurol. 2015, 11, 220–229. [Google Scholar] [CrossRef]
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Wang, W.; Zhang, L.; Xia, K.; Huang, T.; Fan, D. Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects. Biomedicines 2023, 11, 1359. https://doi.org/10.3390/biomedicines11051359
Wang W, Zhang L, Xia K, Huang T, Fan D. Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects. Biomedicines. 2023; 11(5):1359. https://doi.org/10.3390/biomedicines11051359
Chicago/Turabian StyleWang, Wenjing, Linjing Zhang, Kailin Xia, Tao Huang, and Dongsheng Fan. 2023. "Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects" Biomedicines 11, no. 5: 1359. https://doi.org/10.3390/biomedicines11051359