Diagram of the study design.

BackgroundOsteoarthritis (OA), a prevalent musculoskeletal disorder, has been suggested to have a potential association with metabolic syndrome, particularly lipid metabolism. Studies exploring the effects of lipid-lowering drugs on OA have yielded conflicting results.ObjectiveThis study employed a drug-targeted Mendelian randomization approach to investigate the association between genetically predicted lipid-modulating effects of commonly targeted lipid-lowering agents and the risk of OA, with the aim of providing a theoretical foundation for the use of lipid-lowering drugs in OA treatment.MethodsEmploying Mendelian randomization (MR) analysis, we examined the potential causal relationship between lipid-lowering drugs and OA. Genetic variants associated with LDL cholesterol levels were selected from the GWAS summary data, and a series of statistical analyses, including inverse-variance weighted (IVW), weighted median (WM), and MR-Egger, were performed to estimate causal effects.ResultsWe observed significant associations between genetically proxied lipid-lowering drug targets and OA risk. Notably, HMGCR-mediated LDL cholesterol showed an association with overall OA of the hip or knee (OR = 0.865, 95%CI: 0.762 to 0.983, p = 0.026, q = 0.07) and knee osteoarthritis specifically (OR = 0.746, 95%CI: 0.639 to 0.871, p = 2.180×10−4, q = 0.004). PCSK9-mediated LDL cholesterol also demonstrated an association with OA of the hip or knee (OR = 0.915, 95%CI: 0.847 to 0.988, p = 0.023, q = 0.07) and knee osteoarthritis (OR = 0.901, 95%CI: 0.821 to 0.990, p = 0.03, q = 0.07). NPC1L1-mediated LDL cholesterol showed a positive association with OA of the hip or knee (OR = 1.460, 95%CI: 1.127 to 1.890, p = 0.004, q = 0.033). Furthermore, LDLR-mediated LDL cholesterol demonstrated an association with OA of the hip or knee (OR = 0.882, 95%CI: 0.788 to 0.988, p = 0.03, q = 0.07) and hip osteoarthritis (OR = 0.867, 95%CI: 0.769 to 0.978, p = 0.02, q = 0.07).ConclusionsThese findings provide preliminary evidence for the potential therapeutic use of lipid-lowering drugs in OA treatment. Further investigation is needed to validate these findings and explore the precise mechanisms underlying the observed associations.</div

STROBE-MR checklist of recommended items to address in reports of Mendelian randomization studies^{1 2}.

STROBE-MR checklist of recommended items to address in reports of Mendelian randomization studies1 2.</p

S1 Data -

BackgroundOsteoarthritis (OA), a prevalent musculoskeletal disorder, has been suggested to have a potential association with metabolic syndrome, particularly lipid metabolism. Studies exploring the effects of lipid-lowering drugs on OA have yielded conflicting results.ObjectiveThis study employed a drug-targeted Mendelian randomization approach to investigate the association between genetically predicted lipid-modulating effects of commonly targeted lipid-lowering agents and the risk of OA, with the aim of providing a theoretical foundation for the use of lipid-lowering drugs in OA treatment.MethodsEmploying Mendelian randomization (MR) analysis, we examined the potential causal relationship between lipid-lowering drugs and OA. Genetic variants associated with LDL cholesterol levels were selected from the GWAS summary data, and a series of statistical analyses, including inverse-variance weighted (IVW), weighted median (WM), and MR-Egger, were performed to estimate causal effects.ResultsWe observed significant associations between genetically proxied lipid-lowering drug targets and OA risk. Notably, HMGCR-mediated LDL cholesterol showed an association with overall OA of the hip or knee (OR = 0.865, 95%CI: 0.762 to 0.983, p = 0.026, q = 0.07) and knee osteoarthritis specifically (OR = 0.746, 95%CI: 0.639 to 0.871, p = 2.180×10−4, q = 0.004). PCSK9-mediated LDL cholesterol also demonstrated an association with OA of the hip or knee (OR = 0.915, 95%CI: 0.847 to 0.988, p = 0.023, q = 0.07) and knee osteoarthritis (OR = 0.901, 95%CI: 0.821 to 0.990, p = 0.03, q = 0.07). NPC1L1-mediated LDL cholesterol showed a positive association with OA of the hip or knee (OR = 1.460, 95%CI: 1.127 to 1.890, p = 0.004, q = 0.033). Furthermore, LDLR-mediated LDL cholesterol demonstrated an association with OA of the hip or knee (OR = 0.882, 95%CI: 0.788 to 0.988, p = 0.03, q = 0.07) and hip osteoarthritis (OR = 0.867, 95%CI: 0.769 to 0.978, p = 0.02, q = 0.07).ConclusionsThese findings provide preliminary evidence for the potential therapeutic use of lipid-lowering drugs in OA treatment. Further investigation is needed to validate these findings and explore the precise mechanisms underlying the observed associations.</div

S1 File -

BackgroundOsteoarthritis (OA), a prevalent musculoskeletal disorder, has been suggested to have a potential association with metabolic syndrome, particularly lipid metabolism. Studies exploring the effects of lipid-lowering drugs on OA have yielded conflicting results.ObjectiveThis study employed a drug-targeted Mendelian randomization approach to investigate the association between genetically predicted lipid-modulating effects of commonly targeted lipid-lowering agents and the risk of OA, with the aim of providing a theoretical foundation for the use of lipid-lowering drugs in OA treatment.MethodsEmploying Mendelian randomization (MR) analysis, we examined the potential causal relationship between lipid-lowering drugs and OA. Genetic variants associated with LDL cholesterol levels were selected from the GWAS summary data, and a series of statistical analyses, including inverse-variance weighted (IVW), weighted median (WM), and MR-Egger, were performed to estimate causal effects.ResultsWe observed significant associations between genetically proxied lipid-lowering drug targets and OA risk. Notably, HMGCR-mediated LDL cholesterol showed an association with overall OA of the hip or knee (OR = 0.865, 95%CI: 0.762 to 0.983, p = 0.026, q = 0.07) and knee osteoarthritis specifically (OR = 0.746, 95%CI: 0.639 to 0.871, p = 2.180×10−4, q = 0.004). PCSK9-mediated LDL cholesterol also demonstrated an association with OA of the hip or knee (OR = 0.915, 95%CI: 0.847 to 0.988, p = 0.023, q = 0.07) and knee osteoarthritis (OR = 0.901, 95%CI: 0.821 to 0.990, p = 0.03, q = 0.07). NPC1L1-mediated LDL cholesterol showed a positive association with OA of the hip or knee (OR = 1.460, 95%CI: 1.127 to 1.890, p = 0.004, q = 0.033). Furthermore, LDLR-mediated LDL cholesterol demonstrated an association with OA of the hip or knee (OR = 0.882, 95%CI: 0.788 to 0.988, p = 0.03, q = 0.07) and hip osteoarthritis (OR = 0.867, 95%CI: 0.769 to 0.978, p = 0.02, q = 0.07).ConclusionsThese findings provide preliminary evidence for the potential therapeutic use of lipid-lowering drugs in OA treatment. Further investigation is needed to validate these findings and explore the precise mechanisms underlying the observed associations.</div

Characteristics of GWAS data for exposure and outcomes.

Characteristics of GWAS data for exposure and outcomes.</p

Inverse-variance weighted Mendelian randomization (IVW-MR) association between low- density lipoprotein (LDL) cholesterol mediated by gene 3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMGCR), Niemann-Pick C1-Like 1 (NPC1L1, proprotein convertase subtilisin/kexin type 9 (PCSK9), cholesterylester transfer protein (CETP), low-density lipoprotein receptor (LDLR,), or apolipoprotein B (APOB) and OA outcomes.

IVW- MR method was used to assess the association.</p

A3H HapI had a reduced ability to associate with 7SL and Y RNAs.

<p>Single mutation G105R restored its RNA binding activity. A) To compare RNA binding activities between A3H HapII and HapI, 293T cells were transfected with HA-tagged A3H HapII and HapI, and the cell lysates were immunoprecipitated using anti-HA affinity matrix agarose beads. Immunoprecipitated RNA were purified and reverse transcribed, and the relative amounts of 7SL, Y RNAs, GAPDH, β-actin and 5s RNA were measured using qRT-PCR. B) Relative RNA binding activities of A3H HapI and HapI105R compared to HapII.</p

The Δ15N deletion abolished A3H HapII anti-viral activity and virion incorporation.

<p>To compare anti-viral activity and packaging of A3H HapII and HapIIΔ15N, pNL4–3Δvif was transfected with decreasing doses of A3H HapII and HapIIΔ15N. A) A3H HapIIΔ15N had no anti-viral activity compared to A3H HapII. B) Even when expressed at similar levels as A3H HapII (cell lysates in lane 3 and 5), A3H HapIIΔ15N completely lost its ability to be packaged into HIV-1.</p

Single point mutation on 115W impairs A3H HapII RNA binding activity and viral packaging.

<p>A) A3H HapII115A showed no anti-viral activity against HIV-1 NL4-3ΔVif compared to A3H HapII. B) A3H HapII115A had reduced protein expression level compared to A3H HapII (compare cell lysates in lanes 2 and 5), but even when expressed at similar levels (compare cell lysates in lanes 3 and 5), HapII 115A lost its ability to be packaged into the virus (viral lysate lane 5). C) A3H HapII115A had impaired ability to bind to 7SL, Y RNAs as well as GAPDH RNA.</p

A3H HapIIΔ15N has little RNA binding affinity.

<p>A) To compare the RNA binding activity between A3H HapII and HapI, 293T cells were transfected with HA-tagged A3H HapII and HapI, and the cell lystes were immunoprecipitated using anti-HA affinity matrix. Immunoprecipitated RNA were purified and reverse transcribed, and the relative amounts of 7SL, Y RNAs and GAPDH were measured. B) Homology modeling of A3H HapII showing that 15N lies close to the putative RLYYHW RNA binding motif.</p