Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects
Background: Observational studies suggest that statins may affect amyotrophic lateral sclerosis (ALS). However, they are limited by confounding and reverse causality biases. Therefore, we aimed to investigate the potential causal associations between statins and ALS using a mendelian randomization (...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-05-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/11/5/1359 |
| _version_ | 1827742007695507456 |
|---|---|
| author | Wenjing Wang Linjing Zhang Kailin Xia Tao Huang Dongsheng Fan |
| author_facet | Wenjing Wang Linjing Zhang Kailin Xia Tao Huang Dongsheng Fan |
| author_sort | Wenjing Wang |
| collection | DOAJ |
| description | Background: Observational studies suggest that statins may affect amyotrophic lateral sclerosis (ALS). However, they are limited by confounding and reverse causality biases. Therefore, we aimed to investigate the potential causal associations between statins and ALS using a mendelian randomization (MR) approach. Methods: Two-sample MR and drug-target MR were performed. Exposure sources included GWAS summary statistics of statin use, low-density-lipoprotein cholesterol (LDL-C), HMGCR-mediated LDL-C and LDL-C response to statins. Results: Genetic predisposition to statin medication was associated with increased ALS risk (OR = 1.085, 95% CI = 1.025–1.148, <i>p</i> = 0.005). After removing SNPs significantly associated with statin use from the instrumental variables (IVs), LDL-C-related higher ALS risk was absent (before removing: OR = 1.075, 95% CI = 1.013–1.141, <i>p</i> = 0.017; after removing: OR = 1.036, 95% CI = 0.949–1.131, <i>p</i> = 0.432). HMGCR-mediated LDL-C (OR = 1.033, 95% CI = 0.823–1.296, <i>p</i> = 0.779) and blood LDL-C response to statins (OR = 0.998, 95% CI = 0.991–1.005, <i>p</i> = 0.538) had no association with ALS. Conclusions: Here, we show that statins may be a risky exposure that increases ALS risk independent of the lowering effect of LDL-C in peripheral circulation. This provides insights into ALS development and prevention. |
| first_indexed | 2024-03-11T03:55:11Z |
| format | Article |
| id | doaj.art-dd3fd8b016d54e3b84062bed4025f274 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T03:55:11Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-dd3fd8b016d54e3b84062bed4025f2742023-11-18T00:35:53ZengMDPI AGBiomedicines2227-90592023-05-01115135910.3390/biomedicines11051359Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering EffectsWenjing Wang0Linjing Zhang1Kailin Xia2Tao Huang3Dongsheng Fan4Department of Neurology, Peking University Third Hospital, Beijing 100191, ChinaDepartment of Neurology, Peking University Third Hospital, Beijing 100191, ChinaDepartment of Neurology, Peking University Third Hospital, Beijing 100191, ChinaDepartment of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, ChinaDepartment of Neurology, Peking University Third Hospital, Beijing 100191, ChinaBackground: Observational studies suggest that statins may affect amyotrophic lateral sclerosis (ALS). However, they are limited by confounding and reverse causality biases. Therefore, we aimed to investigate the potential causal associations between statins and ALS using a mendelian randomization (MR) approach. Methods: Two-sample MR and drug-target MR were performed. Exposure sources included GWAS summary statistics of statin use, low-density-lipoprotein cholesterol (LDL-C), HMGCR-mediated LDL-C and LDL-C response to statins. Results: Genetic predisposition to statin medication was associated with increased ALS risk (OR = 1.085, 95% CI = 1.025–1.148, <i>p</i> = 0.005). After removing SNPs significantly associated with statin use from the instrumental variables (IVs), LDL-C-related higher ALS risk was absent (before removing: OR = 1.075, 95% CI = 1.013–1.141, <i>p</i> = 0.017; after removing: OR = 1.036, 95% CI = 0.949–1.131, <i>p</i> = 0.432). HMGCR-mediated LDL-C (OR = 1.033, 95% CI = 0.823–1.296, <i>p</i> = 0.779) and blood LDL-C response to statins (OR = 0.998, 95% CI = 0.991–1.005, <i>p</i> = 0.538) had no association with ALS. Conclusions: Here, we show that statins may be a risky exposure that increases ALS risk independent of the lowering effect of LDL-C in peripheral circulation. This provides insights into ALS development and prevention.https://www.mdpi.com/2227-9059/11/5/1359amyotrophic lateral sclerosisstatinsmendelian randomizationcausalityHydroxymethylglutaryl-CoA reductase inhibitorslipids |
| spellingShingle | Wenjing Wang Linjing Zhang Kailin Xia Tao Huang Dongsheng Fan Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects Biomedicines amyotrophic lateral sclerosis statins mendelian randomization causality Hydroxymethylglutaryl-CoA reductase inhibitors lipids |
| title | Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects |
| title_full | Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects |
| title_fullStr | Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects |
| title_full_unstemmed | Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects |
| title_short | Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects |
| title_sort | mendelian randomization analysis reveals statins potentially increase amyotrophic lateral sclerosis risk independent of peripheral cholesterol lowering effects |
| topic | amyotrophic lateral sclerosis statins mendelian randomization causality Hydroxymethylglutaryl-CoA reductase inhibitors lipids |
| url | https://www.mdpi.com/2227-9059/11/5/1359 |
| work_keys_str_mv | AT wenjingwang mendelianrandomizationanalysisrevealsstatinspotentiallyincreaseamyotrophiclateralsclerosisriskindependentofperipheralcholesterolloweringeffects AT linjingzhang mendelianrandomizationanalysisrevealsstatinspotentiallyincreaseamyotrophiclateralsclerosisriskindependentofperipheralcholesterolloweringeffects AT kailinxia mendelianrandomizationanalysisrevealsstatinspotentiallyincreaseamyotrophiclateralsclerosisriskindependentofperipheralcholesterolloweringeffects AT taohuang mendelianrandomizationanalysisrevealsstatinspotentiallyincreaseamyotrophiclateralsclerosisriskindependentofperipheralcholesterolloweringeffects AT dongshengfan mendelianrandomizationanalysisrevealsstatinspotentiallyincreaseamyotrophiclateralsclerosisriskindependentofperipheralcholesterolloweringeffects |