Causal Effects of Lipid-lowering Drugs on Skin Diseases: a Two-sample Mendelian Randomization Study

Overview

Journal Front Med (Lausanne)

Specialty General Medicine

Date 2024 Oct 10

PMID 39386745

Authors

Yong Liu

Hui Liu

Queqiao Bian

Affiliations

Soon will be listed here.

Abstract

Background: Although previous studies have indicated an association between low-density lipoprotein (LDL) and skin diseases, their causal effects remain inconclusive. This study aimed to assess the causal relationship between genetically proxied lipid-lowering drugs and skin cancers and psoriasis.

Methods: Two-sample Mendelian randomization (MR) analysis was performed using single-nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS). The inverse-variance weighted (IVW) method was used to determine causal relationships. The "leave-one-out" sensitivity test, Cochran's Q-statistic and MR-Egger intercept were used to assess heterogeneity and horizontal pleiotropy.

Results: We identified 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and proprotein convertase subtilisin-kexin type 9 (PCSK9) as genetically proxied lipid-lowering drugs. Genetically proxied inhibition of HMGCR (stains) was causally associated with reduced risk of nonmelanoma skin cancer (OR 0.982, 95% CI 0.967-0.997, = 0.016 by weighted median; OR 0.977, 95% CI 0.966-0.989, < 0.001 by IVW) and psoriasis (OR 0.585, 95% CI 0.378-0.905, = 0.016 by IVW), while PCSK9 inhibition (alirocumab) was causally associated with reduced risk of psoriasis (OR 0.560, 95% CI 0.413-0.761 by weighted median; OR 0.564, 95% CI 0.447-0.712 by IVW; < 0.001) in the ieu-b-5089 dataset. Similar results were observed in the ieu-b-110 dataset for HMGCR and PCSK9. Sensitivity analysis revealed no evidence of heterogeneity or horizontal pleiotropy.

Conclusion: This study revealed the existing HMGCR inhibitors (stains) might be protective for reducing nonmelanoma skin cancer risk, and HMGCR inhibitors (stains) and PCSK9 inhibitor (alirocumab) might be promising for reducing psoriasis risk in the European population.

References

Gesto D, Pereira C, Cerqueira N, Sousa S . An Atomic-Level Perspective of HMG-CoA-Reductase: The Target Enzyme to Treat Hypercholesterolemia. Molecules. 2020; 25(17). PMC: 7503714. DOI: 10.3390/molecules25173891. View

Jia N, Dong L, Lu Q, Li X, Jin M, Yin X . The causal effect of schizophrenia on fractures and bone mineral density: a comprehensive two-sample Mendelian randomization study of European ancestry. BMC Psychiatry. 2023; 23(1):692. PMC: 10518911. DOI: 10.1186/s12888-023-05196-8. View

Karimkhani C, Dellavalle R, Coffeng L, Flohr C, Hay R, Langan S . Global Skin Disease Morbidity and Mortality: An Update From the Global Burden of Disease Study 2013. JAMA Dermatol. 2017; 153(5):406-412. PMC: 5817488. DOI: 10.1001/jamadermatol.2016.5538. View

Burgess S, Thompson S . Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017; 32(5):377-389. PMC: 5506233. DOI: 10.1007/s10654-017-0255-x. View

Horie Y, Makihara H, Horikawa K, Takeshige F, Ibuki A, Satake T . Reduced skin lipid content in obese Japanese women mediated by decreased expression of rate-limiting lipogenic enzymes. PLoS One. 2018; 13(3):e0193830. PMC: 5843255. DOI: 10.1371/journal.pone.0193830. View

Knox C, Wilson M, Klinger C, Franklin M, Oler E, Wilson A . DrugBank 6.0: the DrugBank Knowledgebase for 2024. Nucleic Acids Res. 2023; 52(D1):D1265-D1275. PMC: 10767804. DOI: 10.1093/nar/gkad976. View

Cao J, Wang Z, Zhu M, Huang Y, Jin Z, Xiong Z . Low-density lipoprotein cholesterol and risk of hepatocellular carcinoma: a Mendelian randomization and mediation analysis. Lipids Health Dis. 2023; 22(1):110. PMC: 10388495. DOI: 10.1186/s12944-023-01877-1. View

Zhao S, Yiu Z, Barton A, Bowes J . Association of Lipid-Lowering Drugs With Risk of Psoriasis: A Mendelian Randomization Study. JAMA Dermatol. 2023; 159(3):275-280. PMC: 9878432. DOI: 10.1001/jamadermatol.2022.6051. View

Wu T, Ye L, Wang S, Huang J, Zhang J . Association of lipid lowering drugs and the risk of systemic lupus erythematosus: a drug target Mendelian randomization. Front Pharmacol. 2023; 14:1258018. PMC: 10642506. DOI: 10.3389/fphar.2023.1258018. View

10.

Bull C, Bell J, Murphy N, Sanderson E, Davey Smith G, Timpson N . Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study. BMC Med. 2020; 18(1):396. PMC: 7745469. DOI: 10.1186/s12916-020-01855-9. View

11.

Aggarwal P, Knabel P, Fleischer Jr A . United States burden of melanoma and non-melanoma skin cancer from 1990 to 2019. J Am Acad Dermatol. 2021; 85(2):388-395. DOI: 10.1016/j.jaad.2021.03.109. View

12.

Ascierto P, Schadendorf D . Update in the treatment of non-melanoma skin cancers: the use of PD-1 inhibitors in basal cell carcinoma and cutaneous squamous-cell carcinoma. J Immunother Cancer. 2022; 10(12). PMC: 9716987. DOI: 10.1136/jitc-2022-005082. View

13.

Lawlor D . Commentary: Two-sample Mendelian randomization: opportunities and challenges. Int J Epidemiol. 2016; 45(3):908-15. PMC: 5005949. DOI: 10.1093/ije/dyw127. View

14.

Michalek I, Loring B, John S . A systematic review of worldwide epidemiology of psoriasis. J Eur Acad Dermatol Venereol. 2016; 31(2):205-212. DOI: 10.1111/jdv.13854. View

15.

Rubatto M, Sciamarrelli N, Borriello S, Pala V, Mastorino L, Tonella L . Classic and new strategies for the treatment of advanced melanoma and non-melanoma skin cancer. Front Med (Lausanne). 2023; 9:959289. PMC: 9947410. DOI: 10.3389/fmed.2022.959289. View

16.

Boehncke W, Schon M . Psoriasis. Lancet. 2015; 386(9997):983-94. DOI: 10.1016/S0140-6736(14)61909-7. View

17.

Solak Tekin N, Tekin I, Barut F, Sipahi E . Accumulation of oxidized low-density lipoprotein in psoriatic skin and changes of plasma lipid levels in psoriatic patients. Mediators Inflamm. 2007; 2007:78454. PMC: 1804297. DOI: 10.1155/2007/78454. View

18.

Burgess S, Foley C, Zuber V . Inferring Causal Relationships Between Risk Factors and Outcomes from Genome-Wide Association Study Data. Annu Rev Genomics Hum Genet. 2018; 19:303-327. PMC: 6481551. DOI: 10.1146/annurev-genom-083117-021731. View

19.

Reid C, Griffiths C . Psoriasis and Treatment: Past, Present and Future Aspects. Acta Derm Venereol. 2020; 100(3):adv00032. PMC: 9128930. DOI: 10.2340/00015555-3386. View

20.

Liang J, Yu D, Luo C, Bennett C, Jedrychowski M, Gygi S . Epigenetic suppression of PGC1α (PPARGC1A) causes collateral sensitivity to HMGCR-inhibitors within BRAF-treatment resistant melanomas. Nat Commun. 2023; 14(1):3251. PMC: 10241879. DOI: 10.1038/s41467-023-38968-7. View