Meng m. Liu ¹ Xiang Chen ^2* Chuan w. Yu ³ Jin w. Chen ¹ Pu x. Zhen ⁴ zhipeng liu ⁵

• ¹ Department of Physical Education, Dongshin University, Naju, North Jeolla, Republic of Korea
• ² Department of Bone and Joint Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Region, China
• ³ School of Physical Education and Health, Heze University, Heze, China
• ⁴ Hubei University of Science and Technology, Xianning, China
• ⁵ Department of Hepatobiliary Surgery, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi Zhuang Region, China

Previous research has suggested that dyslipidemia may be a risk factor for rotator cuff syndrome (RCS), and lipid-lowering drugs may aid in its treatment, though conclusions have not been definitive. Mendelian randomization is a statistical method that explores the causal relationships between exposure factors and diseases. It overcomes the confounding issues inherent in traditional observational studies, thereby providing more reliable causal inferences. We employed this method to investigate whether hyperlipidemia is a risk factor for rotator cuff syndrome and whether lipid-lowering drugs can effectively treat this condition.Genetic variations linked to lipid traits low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and total cholesterol (TC) were acquired from the UK Biobank and the Global Lipids Genetics Consortium (GLGC). Data on genetic variation in rotator cuff syndrome were obtained from FinnGen, including 24,061 patients and 275,212 controls. In the next step, we carried out two-sample Mendelian randomization analyses to determine whether lipid traits correlate with rotator cuff syndrome risk. Additionally, we performed drug-target Mendelian randomization (MR) analyses on 10 drug targets related to rotator cuff syndrome. For the drug targets that showed significant results, further analysis was done using Summary-data-based Mendelian Randomization (SMR) and colocalization techniques. We performed a mediation analysis to identify potential mediators between HMG-CoA reductase (HMGCR) and RCS.No causative link was established between these lipid traits and rotator cuff syndrome. However, a significant association has been identified where HMGCR inhibition corresponds to a reduced risk of rotator cuff disease(OR=0.68, [95% CI,0.56-0.83]， P = 1.510x10 -4 ). Additionally, enhanced expression of HMGCR in muscle tissues is also linked to a decreased risk of rotator cuff syndrome(OR=0.88,[95% CI， 0.76-0.99]， P = 0.03). Body mass index (BMI) mediated 22.97% of the total effect of HMGCR on RCS.This study does not support low-density LDL-C, TG, and TC as risk factors for rotator cuff syndrome. HMGCR represents a potential pharmaceutical target for preventing and treating rotator cuff syndrome. The protective action of statins on the rotator cuff syndrome might not be associated with their lipid-lowering properties.