PDF(Pubmed)
Abstract：
UNASSIGNED: Several observational studies suggest a possible link between lipid-lowering drugs and allergic diseases. However, inferring causality from these studies can be challenging due to issues such as bias, reverse causation, and residual confounding. To investigate the potential causal effect of lipid-lowering drugs, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, on allergic diseases (allergic asthma, allergic conjunctivitis, atopic dermatitis, allergic rhinitis, and allergic urticaria), we performed a Mendelian randomization (MR)-based study.
UNASSIGNED: We employed MR and summary-data-based MR (SMR), analyzing genome-wide association study (GWAS) data from people of European descent. Single nucleotide polymorphisms (SNPs) were employed as instrumental variables. We selected 2 types of genetic measures to represent the impact of lipid-lowering drugs, including genetic variants near or within drug target genes correlated with low-density lipoprotein cholesterol (LDL-C), and expression quantitative trait loci of drug target genes. The inverse-variance weighted (IVW)-MR approach was the primary utilized MR method, while sensitivity analyses were used to test the robustness of the results. We used SMR analysis as a supplementary analytical method, applying the heterogeneity in dependent instruments (HEIDI) test to assess if the observed correlation between gene expression and outcome was due to a linkage situation.
UNASSIGNED: The IVW-MR analysis revealed significant evidence for an association between PCSK9-mediated LDL-C reduction and a decrease in the risk of allergic asthma (odds ratio [OR] = 1.31, 95% confidence interval [CI] = 1.11-1.56; P < 0.01). Likewise, SMR analysis discovered an augmented expression of PCSK9 being linked with a heightened susceptibility to allergic asthma (OR = 1.21, 95% CI = 1.03-1.43; P = 0.02). No consistent evidence was found for other associations in either analysis.
UNASSIGNED: Our findings support a potential causal relationship between PCSK9 activity and an increased risk of allergic asthma. Thus, PCSK9 inhibitors, which reduce PCSK9 activity, might be considered a priority in future clinical trials investigating drugs for allergic asthma prevention or treatment.
UNASSIGNED: We employed MR and summary-data-based MR (SMR), analyzing genome-wide association study (GWAS) data from people of European descent. Single nucleotide polymorphisms (SNPs) were employed as instrumental variables. We selected 2 types of genetic measures to represent the impact of lipid-lowering drugs, including genetic variants near or within drug target genes correlated with low-density lipoprotein cholesterol (LDL-C), and expression quantitative trait loci of drug target genes. The inverse-variance weighted (IVW)-MR approach was the primary utilized MR method, while sensitivity analyses were used to test the robustness of the results. We used SMR analysis as a supplementary analytical method, applying the heterogeneity in dependent instruments (HEIDI) test to assess if the observed correlation between gene expression and outcome was due to a linkage situation.
UNASSIGNED: The IVW-MR analysis revealed significant evidence for an association between PCSK9-mediated LDL-C reduction and a decrease in the risk of allergic asthma (odds ratio [OR] = 1.31, 95% confidence interval [CI] = 1.11-1.56; P < 0.01). Likewise, SMR analysis discovered an augmented expression of PCSK9 being linked with a heightened susceptibility to allergic asthma (OR = 1.21, 95% CI = 1.03-1.43; P = 0.02). No consistent evidence was found for other associations in either analysis.
UNASSIGNED: Our findings support a potential causal relationship between PCSK9 activity and an increased risk of allergic asthma. Thus, PCSK9 inhibitors, which reduce PCSK9 activity, might be considered a priority in future clinical trials investigating drugs for allergic asthma prevention or treatment.
摘要：
■一些观察性研究表明，降脂药与过敏性疾病之间可能存在联系。然而,由于偏见等问题，从这些研究中推断因果关系可能是具有挑战性的，反向因果关系，和残余的混杂。探讨降脂药物的潜在因果效应,前蛋白转化酶枯草杆菌蛋白酶/kexin9型（PCSK9）抑制剂和3-羟基-3-甲基-戊二酰辅酶A还原酶（HMGCR）抑制剂，过敏性疾病（过敏性哮喘，过敏性结膜炎,特应性皮炎,过敏性鼻炎,和过敏性荨麻疹），我们进行了一项基于孟德尔随机化(MR)的研究.
■我们采用了MR和基于汇总数据的MR（SMR），分析来自欧洲人后裔的全基因组关联研究（GWAS）数据。单核苷酸多态性（SNP）用作工具变量。我们选择了两种类型的遗传措施来代表降脂药物的影响，包括与低密度脂蛋白胆固醇（LDL-C）相关的药物靶基因附近或内部的遗传变异，和药物靶基因的表达数量性状位点。逆方差加权(IVW)-MR方法是主要使用的MR方法，而敏感性分析用于测试结果的稳健性。我们使用SMR分析作为补充分析方法，应用依赖工具（HEIDI）测试的异质性来评估观察到的基因表达和结果之间的相关性是否归因于连锁情况。
■IVW-MR分析显示PCSK9介导的LDL-C降低与过敏性哮喘风险降低之间存在显著关联（比值比[OR]=1.31，95%置信区间[CI]=1.11-1.56；P<0.01）。同样，SMR分析发现PCSK9的表达增强与过敏性哮喘的易感性增加有关（OR=1.21，95％CI=1.03-1.43；P=0.02）。在任何分析中都没有发现其他关联的一致证据。
■我们的研究结果支持PCSK9活性与过敏性哮喘风险增加之间的潜在因果关系。因此，PCSK9抑制剂，减少PCSK9活性，在未来研究用于过敏性哮喘预防或治疗的药物的临床试验中，可能被视为优先事项。
■我们采用了MR和基于汇总数据的MR（SMR），分析来自欧洲人后裔的全基因组关联研究（GWAS）数据。单核苷酸多态性（SNP）用作工具变量。我们选择了两种类型的遗传措施来代表降脂药物的影响，包括与低密度脂蛋白胆固醇（LDL-C）相关的药物靶基因附近或内部的遗传变异，和药物靶基因的表达数量性状位点。逆方差加权(IVW)-MR方法是主要使用的MR方法，而敏感性分析用于测试结果的稳健性。我们使用SMR分析作为补充分析方法，应用依赖工具（HEIDI）测试的异质性来评估观察到的基因表达和结果之间的相关性是否归因于连锁情况。
■IVW-MR分析显示PCSK9介导的LDL-C降低与过敏性哮喘风险降低之间存在显著关联（比值比[OR]=1.31，95%置信区间[CI]=1.11-1.56；P<0.01）。同样，SMR分析发现PCSK9的表达增强与过敏性哮喘的易感性增加有关（OR=1.21，95％CI=1.03-1.43；P=0.02）。在任何分析中都没有发现其他关联的一致证据。
■我们的研究结果支持PCSK9活性与过敏性哮喘风险增加之间的潜在因果关系。因此，PCSK9抑制剂，减少PCSK9活性，在未来研究用于过敏性哮喘预防或治疗的药物的临床试验中，可能被视为优先事项。
