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Abstract：
BACKGROUND: A growing body of evidence has highlighted the interactions of lipids metabolism and immune regulation. Nevertheless, there is still a lack of evidence regarding the causality between lipids and autoimmune diseases (ADs), as well as their possibility as drug targets for ADs.
OBJECTIVE: This study was conducted to comprehensively understand the casual associations between lipid traits and ADs, and evaluate the therapeutic possibility of lipid-lowering drug targets on ADs.
METHODS: Genetic variants for lipid traits and variants encoding targets of various lipid-lowering drugs were derived from Global Lipid Genetics Consortium (GLGC) and verified in Drug Bank. Summary data of ADs were obtained from MRC Integrative Epidemiology Unit (MER-IEU) database and FinnGen consortium, respectively. The causal inferences between lipid traits/genetic agents of lipid-lowering targets and ADs were evaluated by Mendelian randomization (MR), summary data-based MR (SMR), and multivariable MR (MVMR) analyses. Enrichment analysis and protein interaction network were employed to reveal the functional characteristics and biological relevance of potential therapeutic lipid-lowering targets.
RESULTS: There was no evidence of causal effects regarding 5 lipid traits and 9 lipid-lowering drug targets on ADs. Genetically proxied 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition was associated with a reduced risk of rheumatoid arthritis (RA) in both discovery (OR [odds ratio] = 0.45, 95%CI: 0.32, 0.63, P = 6.79 × 10- 06) and replicate datasets (OR = 0.37, 95%CI: 0.23, 0.61, P = 7.81 × 10- 05). SMR analyses supported that genetically proxied HMGCR inhibition had causal effects on RA in whole blood (OR = 0.48, 95%CI: 0.29, 0.82, P = 6.86 × 10- 03) and skeletal muscle sites (OR = 0.75, 95%CI: 0.56, 0.99, P = 4.48 × 10- 02). After controlling for blood pressure, body mass index (BMI), smoking and drinking alchohol, HMGCR suppression showed a direct causal effect on a lower risk of RA (OR = 0.33, 95%CI: 0.40, 0.96, P = 0.042).
CONCLUSIONS: Our study reveals causal links of genetically proxied HMGCR inhibition (lipid-lowering drug targets) and HMGCR expression inhibition with a decreased risk of RA, suggesting that HMGCR may serve as candidate drug targets for the treatment and prevention of RA.
OBJECTIVE: This study was conducted to comprehensively understand the casual associations between lipid traits and ADs, and evaluate the therapeutic possibility of lipid-lowering drug targets on ADs.
METHODS: Genetic variants for lipid traits and variants encoding targets of various lipid-lowering drugs were derived from Global Lipid Genetics Consortium (GLGC) and verified in Drug Bank. Summary data of ADs were obtained from MRC Integrative Epidemiology Unit (MER-IEU) database and FinnGen consortium, respectively. The causal inferences between lipid traits/genetic agents of lipid-lowering targets and ADs were evaluated by Mendelian randomization (MR), summary data-based MR (SMR), and multivariable MR (MVMR) analyses. Enrichment analysis and protein interaction network were employed to reveal the functional characteristics and biological relevance of potential therapeutic lipid-lowering targets.
RESULTS: There was no evidence of causal effects regarding 5 lipid traits and 9 lipid-lowering drug targets on ADs. Genetically proxied 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition was associated with a reduced risk of rheumatoid arthritis (RA) in both discovery (OR [odds ratio] = 0.45, 95%CI: 0.32, 0.63, P = 6.79 × 10- 06) and replicate datasets (OR = 0.37, 95%CI: 0.23, 0.61, P = 7.81 × 10- 05). SMR analyses supported that genetically proxied HMGCR inhibition had causal effects on RA in whole blood (OR = 0.48, 95%CI: 0.29, 0.82, P = 6.86 × 10- 03) and skeletal muscle sites (OR = 0.75, 95%CI: 0.56, 0.99, P = 4.48 × 10- 02). After controlling for blood pressure, body mass index (BMI), smoking and drinking alchohol, HMGCR suppression showed a direct causal effect on a lower risk of RA (OR = 0.33, 95%CI: 0.40, 0.96, P = 0.042).
CONCLUSIONS: Our study reveals causal links of genetically proxied HMGCR inhibition (lipid-lowering drug targets) and HMGCR expression inhibition with a decreased risk of RA, suggesting that HMGCR may serve as candidate drug targets for the treatment and prevention of RA.
摘要：
背景：越来越多的证据强调了脂质代谢和免疫调节的相互作用。然而，仍然缺乏关于脂质与自身免疫性疾病（AD）之间因果关系的证据，以及它们作为AD药物靶标的可能性。
目的：本研究旨在全面了解脂质性状与ADs之间的偶然关联，并评估降脂药靶点对ADs的治疗可能性。
方法：脂质性状的遗传变异和编码各种降脂药物靶标的变异来自全球脂质遗传学联盟（GLGC），并在药物库中验证。AD的汇总数据来自MRC综合流行病学单位（MER-IEU）数据库和FinnGen联盟，分别。通过孟德尔随机化（MR）评估了降脂目标的脂质性状/遗传因子与AD之间的因果关系，基于数据的汇总MR(SMR)，和多变量MR(MVMR)分析。利用富集分析和蛋白质相互作用网络来揭示潜在的治疗性降脂靶标的功能特征和生物学相关性。
结果：没有证据表明5种脂质性状和9种降脂药靶点对ADs有因果关系。遗传代理3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）抑制与类风湿关节炎（RA）的风险降低相关，这两个发现（OR[比值比]=0.45，95CI：0.32，0.63，P=6.79×10-06）和重复数据集（OR=0.37，95CI：0.23，0.61，P=7.81×10-05）。SMR分析支持基因代理HMGCR抑制对全血RA（OR=0.48，95CI：0.29，0.82，P=6.86×10-03）和骨骼肌部位（OR=0.75，95CI：0.56，0.99，P=4.48×10-02）有因果关系。控制血压后,体重指数（BMI），吸烟和饮酒，HMGCR抑制对RA风险降低有直接的因果关系(OR=0.33,95CI:0.40,0.96,P=0.042)。
结论：我们的研究揭示了基因代理HMGCR抑制（降脂药靶）和HMGCR表达抑制与RA风险降低的因果关系，提示HMGCR可作为治疗和预防RA的候选药物靶点。
目的：本研究旨在全面了解脂质性状与ADs之间的偶然关联，并评估降脂药靶点对ADs的治疗可能性。
方法：脂质性状的遗传变异和编码各种降脂药物靶标的变异来自全球脂质遗传学联盟（GLGC），并在药物库中验证。AD的汇总数据来自MRC综合流行病学单位（MER-IEU）数据库和FinnGen联盟，分别。通过孟德尔随机化（MR）评估了降脂目标的脂质性状/遗传因子与AD之间的因果关系，基于数据的汇总MR(SMR)，和多变量MR(MVMR)分析。利用富集分析和蛋白质相互作用网络来揭示潜在的治疗性降脂靶标的功能特征和生物学相关性。
结果：没有证据表明5种脂质性状和9种降脂药靶点对ADs有因果关系。遗传代理3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）抑制与类风湿关节炎（RA）的风险降低相关，这两个发现（OR[比值比]=0.45，95CI：0.32，0.63，P=6.79×10-06）和重复数据集（OR=0.37，95CI：0.23，0.61，P=7.81×10-05）。SMR分析支持基因代理HMGCR抑制对全血RA（OR=0.48，95CI：0.29，0.82，P=6.86×10-03）和骨骼肌部位（OR=0.75，95CI：0.56，0.99，P=4.48×10-02）有因果关系。控制血压后,体重指数（BMI），吸烟和饮酒，HMGCR抑制对RA风险降低有直接的因果关系(OR=0.33,95CI:0.40,0.96,P=0.042)。
结论：我们的研究揭示了基因代理HMGCR抑制（降脂药靶）和HMGCR表达抑制与RA风险降低的因果关系，提示HMGCR可作为治疗和预防RA的候选药物靶点。
