高密度脂蛋白胆固醇与肝癌发病的孟德尔随机化研究

目的 验证高密度脂蛋白胆固醇与肝癌发生之间是否存在因果关联。方法 本研究基于公开的全基因组关联分析（GWAS）数据库，其暴露因素为高密度脂蛋白胆固醇（HDL-C），来源于为期随访12年的韩国基因组与流行病学研究队列（Ko GES），其结局变量为肝癌，来源于为期随访10年的日本生物样本库（BBJ）。分别用IVW、MR-Egger、WME三种方法对其进行两样本孟德尔随机化分析，并利用Cochran Q检验和MR PRESSO进行MR前提假设验证，以及leave-one-out法进行敏感性分析。结果 两样本孟德尔随机化的IVW显示，HDL-C与肝癌发生（OR=0.938, 95%CI:0.779～1.129, P=0.496）无统计学意义。MR-Egger回归法（OR=1.167, 95%CI:0.858～1.587, P=0.329）、加权中位数（OR=0.921, 95%CI:0.722～1.175, P=0.508）分析也有相似的结果。经检验得分析结果中未发现存在多效性偏倚（截距项为-0.019, P=0.089），异质性较小；敏感性分析显示MR分析结果稳健。本次所选的52个工具变量均...     

酒精依赖和肌萎缩侧索硬化因果关系的孟德尔随机化分析

目的采用孟德尔随机化方法探索饮酒行为和肌萎缩侧索硬化发病风险的因果关系。方法利用大样本全基因组关联研究数据,确定与酒精依赖密切相关的遗传位点作为工具变量,通过逆方差加权法、MR-Egger回归法等两样本孟德尔随机化方法,以比值比(OR值)作为结局指标对因果关系进行评价。结果本研究共纳入476例男性酒精依赖患者和1358例男性对照,IVW方法估计的OR值为1.12(95%可信区间:1.02-1.24,P=0.021),MR-Egger回归结果表明遗传多效性不会对结果造成偏倚(截距=-0.036,P=0.755)。结论本研究采用两样本孟德尔随机化的方法,表明在男性中严重的酒精依赖会增加肌萎缩侧索硬化的风险。     

血糖特征与结直肠良性肿瘤因果关联的孟德尔随机化研究

目的 探索血糖特征（空腹血糖、空腹胰岛素、糖化血红蛋白、胰岛素抵抗)与结直肠良性肿瘤（结直肠腺瘤、直肠良性肿瘤、结肠良性肿瘤）发病之间的因果关系。方法 血糖特征的工具变量数据来自MAGIC和GLGCL联盟,结直肠良性肿瘤的全基因组数据来源于Finn Gen联盟。研究采用随机效应逆方差加权法(inverse-variance weighted, IVW)、MR-Egger回归、加权中位数法(weighted median method,WMM)三种回归模型对四项血糖特征与结直肠良性肿瘤的因果关系进行孟德尔随机化分析。结果 IVW模型计算结果显示空腹血糖（OR=0.999,95%CI:0.997～1.001）、空腹胰岛素（OR=1.002,95%CI:0.998～1.006）、糖化血红蛋白（OR=1.001,95%CI:0.999～1.004）、胰岛素抵抗（OR=0.999,95%CI:0.997～1.002）与结直肠腺瘤之间无因果关系;空腹血糖（OR=0.909,95%CI:0.684～1.209）、空腹胰岛素（OR=1.220,95%CI:0.706～2.107）、糖化血红蛋白（OR=...     

两样本孟德尔随机化法分析抑郁症与间质性肺病关系的研究

目的 采用孟德尔随机化方法分析抑郁症与间质性肺病(ILD)之间的因果关系，为ILD的预防、治疗及预后评估提供新的思路。方法 利用大样本全基因关联研究汇总数据，选择与抑郁症密切相关的遗传位点作为工具变量，逆方差加权法为主，加权中位数法和MR-Egger回归为辅对数据进行两样本孟德尔随机化分析。以OR值评价抑郁症与ILD之间的因果关系，异质性检验、基因多效性检验和敏感性分析3种方法评估结果的稳定性和可靠性。结果 共纳入37个单核苷酸多态性(SNP)位点作为工具变量，逆方差加权法估计抑郁症患者患ILD的风险(OR)是健康人群的1.21倍(95%CI:1.075～1.361,P=0.002)。加权中位数法同样支持抑郁症和ILD之间存在因果效应(95%CI:1.118～1.564,P=0.001)。逆方差加权法和MR-Egger回归的异质性检验结果表明不存在异质性，MR-Egger回归截距项和MR-PRESSO方法检验表明结果受基因多效性影响的可能性较小，leave-one-out分析未发现非特异性SNP。结论 抑郁症与ILD之间可能存在正向因果关联。     

年龄相关听力损失与阿尔茨海默病相关性的两样本孟德尔随机化分析

目的 本研究通过双样本孟德尔随机化分析探讨年龄相关性听力损失与阿尔茨海默病之间的因果关系。方法 采用逆方差加权、MR-Egger回归、加权中位数、简单模型和加权模型五种方法来评估年龄相关性听力损失与阿尔茨海默病风险之间的关系,采用敏感性分析（多效性、异质性和留一性检验）来评估结果的稳健性。结果 统计结果显示与年龄相关的听力损失和阿尔茨海默病之间未见因果关联（逆方差加权法：OR=1.052 6,95%CI:0.715 5～1.548 5;MR-Egger:OR=1.134 7,95%CI:0.212 3～6.066 0;加权中位数法：OR=0.890 8,95%CI:0.528 1～1.502 5;简单模型法：OR=0.715 7,95%CI:0.250 5～2.044 5;加权模型法：OR=0.747 0,95%CI:0.315 3～1.769 8）,这些结果与阿尔茨海默病代理数据相一致(逆方差加权法：OR=0.956 0,95%CI:0.900 8～1.014 6;MR-Egger:OR=0.988 7,95%CI:0.772 9～1.264 7;加权中位数法：OR=0.948 7,...     

基于两样本孟德尔随机化的克罗恩病与胰腺癌发病的因果关系研究

目的 本文通过两样本孟德尔随机化的方法探究克罗恩病与胰腺癌发病之间的因果关系。方法 从全基因组关联分析研究数据中筛出与胰腺癌相关的单核苷酸多态性作为基因工具变量,用逆方差加权分析方法、加权中值方法和MR-Egger方法三种孟德尔随机化方法研究克罗恩病与胰腺癌发病的因果关联。比值比和95%可信区间作结果,OR值评价克罗恩病与胰腺癌发病的因果关系。结果 筛选到80个相关SNPs。逆方差加权分析法显示克罗恩病是胰腺癌发病的危险因素（OR=1.106;95%CI:1.009～1.213;P<0.05）,MR-Egger效应估计值（OR=1.328;95%CI:1.042～1.693;P<0.05）的统计结果与之类似;加权中值法（OR=1.140;95%CI:0.996～1.305;P>0.05）的统计结果无统计学意义。敏感性分析显示研究结果没有产生偏倚,异质性检验表明SNPs不存在异质性。结论 克罗恩病与胰腺癌发病存在正向因果关联。加强克罗恩患者胰腺癌相关的筛查、预防对降低克罗恩患者发生胰腺癌的风险具有重要意义。     

外周血白细胞与高脂血症的关联性：一项孟德尔随机化和观察性研究

目的 探究外周血白细胞及分类计数与血脂间的关联,旨在为高脂血症的防控提供依据。方法 回顾性分析2017—2020年于某医院进行健康体检者的资料。采用限制性立方样条模型拟合外周血白细胞及分类计数与血脂间的剂量-反应关系。基于全基因组关联研究(Genome-wide association study, GWAS)的汇总数据,运用两样本孟德尔随机化探究白细胞分类计数与血脂指标间的因果关联。采用白细胞分类计数相关的遗传位点作为工具变量,使用逆方差加权、MR-Egger回归和加权中位数法进行孟德尔随机化分析;采用异质性检验、多效性检验和逐个剔除检验进行敏感性分析。结果 共纳入18 647例体检者进行横断面分析,高脂血症患病率为42.70%,且患者的白细胞及分类计数均高于非高脂血症者(P<0.05)。白细胞及分类计数增加可导致高脂血症患病风险增加(P<0.05);且与总胆固醇、低密度脂蛋白胆固醇和甘油三酯升高有关(单核细胞、中性粒细胞和嗜酸性粒细胞除外),与高密度脂蛋白胆固醇降低有关(P<0.05)。遗传预测的淋巴细胞与低密度脂蛋白胆固醇(OR=1.04, 95%CI:1.01...     

基于两样本孟德尔随机化方法分析血液代谢物与慢性肾病的因果关系

目的 利用孟德尔随机化方法,探究486种血液代谢物与慢性肾病的因果关系.方法 血液代谢物和慢性肾病全基因组关联分析汇总数据均来自于网络公开数据库,主要采用逆方差加权分析法(inverse-variance weighting,IVW),探究每种血液代谢物与慢性肾病之间的因果关系,并以MR-Egger回归、加权中位数法、...     

系统性红斑狼疮与心力衰竭：两样本孟德尔随机化研究

目的 系统性红斑狼疮(systemic lupus erythematosus, SLE)与心力衰竭之间的关系已受广泛关注,但观察性研究中二者的因果关联是不清楚的,因此本研究旨在使用两样本孟德尔随机化(Mendelian randomization, MR)研究来探究SLE和心力衰竭之间的因果关联。方法 从全基因组关联研究(Genome-wide association study, GWAS)汇总数据中提取与SLE相关的单核苷酸多态性(single nucleotide polymorphisms, SNPs),并选择符合标准的工具变量。然后,主要用逆方差加权法(inverse variance-weighted, IVW)进行两样本孟德尔随机化分析,并用MR-PRESSO、加权中值法、MR-Egger法和最大似然比来评估结果的稳健性。另外采用MR-Egger截距项评估工具变量的水平多效性,Cochran Q检验及留一法用来评估异质性。此外,多变量MR研究被用于进一步验证结果的稳健性。结果 IVW结果显示SLE的遗传易感性与心力衰竭相对风险增加呈正相关(OR=1.024, 95%CI...     

体力活动与卵巢癌因果关联的孟德尔随机化研究

目的 采用两样本孟德尔随机化研究方法分析体力活动与卵巢癌发生风险的因果关联。方法 体力活动和卵巢癌的数据分别来自两项公开发表的最新最大的欧洲人群全基因组关联研究汇总数据。从体力活动汇总数据中筛选出16个高度相关的单核苷酸多态性位点作为工具变量。利用逆方差加权法、MR-Egger回归和加权中位数估计法评估体力活动与卵巢癌之间的因果效应。另外采用排除回文结构工具变量、排除多效性工具变量和“留一法”进行敏感性分析。结果 逆方差加权法发现遗传预测的体力活动与卵巢癌发生风险无关（OR=0.91, 95%CI:0.66～1.24）,MR-Egger回归（OR=0.61, 95%CI:0.13～2.87）和加权中位数估计法（OR=1.16, 95%CI:0.79～1.69）与逆方差加权法得到的结果一致。敏感性分析表明结果具有稳健性。结论 未有充分的证据支持体力活动与卵巢癌发生风险之间存在因果关联。     

Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator

Developments in genome‐wide association studies and the increasing availability of summary genetic association data have made application of Mendelian randomization relatively straightforward. However, obtaining reliable results from a Mendelian randomization investigation remains problematic, as the conventional inverse‐variance weighted method only gives consistent estimates if all of the genetic variants in the analysis are valid instrumental variables. We present a novel weighted median estimator for combining data on multiple genetic variants into a single causal estimate. This estimator is consistent even when up to 50% of the information comes from invalid instrumental variables. In a simulation analysis, it is shown to have better finite‐sample Type 1 error rates than the inverse‐variance weighted method, and is complementary to the recently proposed MR‐Egger (Mendelian randomization‐Egger) regression method. In analyses of the causal effects of low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol on coronary artery disease risk, the inverse‐variance weighted method suggests a causal effect of both lipid fractions, whereas the weighted median and MR‐Egger regression methods suggest a null effect of high‐density lipoprotein cholesterol that corresponds with the experimental evidence. Both median‐based and MR‐Egger regression methods should be considered as sensitivity analyses for Mendelian randomization investigations with multiple genetic variants.     

Extending the MR‐Egger method for multivariable Mendelian randomization to correct for both measured and unmeasured pleiotropy

Methods have been developed for Mendelian randomization that can obtain consistent causal estimates while relaxing the instrumental variable assumptions. These include multivariable Mendelian randomization, in which a genetic variant may be associated with multiple risk factors so long as any association with the outcome is via the measured risk factors (measured pleiotropy), and the MR‐Egger (Mendelian randomization‐Egger) method, in which a genetic variant may be directly associated with the outcome not via the risk factor of interest, so long as the direct effects of the variants on the outcome are uncorrelated with their associations with the risk factor (unmeasured pleiotropy). In this paper, we extend the MR‐Egger method to a multivariable setting to correct for both measured and unmeasured pleiotropy. We show, through theoretical arguments and a simulation study, that the multivariable MR‐Egger method has advantages over its univariable counterpart in terms of plausibility of the assumption needed for consistent causal estimation and power to detect a causal effect when this assumption is satisfied. The methods are compared in an applied analysis to investigate the causal effect of high‐density lipoprotein cholesterol on coronary heart disease risk. The multivariable MR‐Egger method will be useful to analyse high‐dimensional data in situations where the risk factors are highly related and it is difficult to find genetic variants specifically associated with the risk factor of interest (multivariable by design), and as a sensitivity analysis when the genetic variants are known to have pleiotropic effects on measured risk factors.     

绝经后妇女冠心病患者性激素水平与脂质代谢的临床观察

目的:观察绝经后妇女冠心病(CHD)患者血清性激素水平与脂质代谢关系。方法:58例绝经后妇女CHD患者作为观察组,58例绝经后健康妇女作为对照组,测定两组性激素相关指标(血清雌二醇(E2)、孕酮(P)、睾酮(T)、催乳素(PRL)、黄体生成素(LH)、促卵泡激素(FSH)、E/T)及脂质代谢相关指标(总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、载脂蛋白B(ApoB)、HDL-C/LDL-C、HDL-C/TC)水平,并进行相关性分析。结果:观察组患者E2、HDL-C、E/T、HDL-C/LDL-C、HDL-C/TC水平明显低于对照组,TC、TG、LDL-C、ApoB水平均明显高于对照组,差异有统计学意义(P<0.01或P<0.05);经多元回归分析观察组患者E2、E/T与TC、TG、LDL-C、ApoB水平呈负相关。结论:绝经后妇女CHD患者血脂异常与性激素下降密切相关,且共同参与CHD发生、发展。     

The Relationship between Blood Lipids and Risk of Atrial Fibrillation: Univariable and Multivariable Mendelian Randomization Analysis

We performed univariable and multivariable Mendelian randomization (MR) analysis to evaluate the association between blood lipids and risk of atrial fibrillation (AF), including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), Apolipoprotein A1, and Apolipoprotein B. Methods: Data on the single nucleotide polymorphisms (SNPs) related to blood lipids were obtained from the UK Biobank study with more than 300,000 subjects of White British European ancestry, and data for AF were from the latest meta-analysis of Genome-wide association study (GWASs) with six independent cohorts with more than 1,000,000 subjects of European ancestry. The univariable MR analysis was conducted to explore whether genetic evidence of individual lipid-related traits was significantly associated with AF risks and multivariable MR analysis with three models was performed to assess the independent effects of lipid-related traits. Results: The IVW estimate showed that genetically predicted LDL-C (OR: 1.016, 95% CI: 0.962–1.073, p = 0.560), HDL-C (OR: 0.951, 95% CI: 0.895–1.010, p = 0.102), TG (OR: 0.961, 95% CI: 0.889–1.038, p = 0.313), Apolipoprotein A1 (OR: 0.978, 95% CI: 0.933–1.025, p = 0.356), and Apolipoprotein B (OR: 1.008, 95% CI: 0.959–1.070, p = 0.794) were not causally associated with the risk of AF. Sample mode (OR: 0.852, 95% CI: 0.731–0.993, p = 0.043) and weighted mode (OR: 0.907, 95% CI: 0.841–0.979, p = 0.013) showed that a 1-unit increase in TG (mmol/L) was causally associated with a 14.8% and 9.3% relative decrease in AF risk, respectively. The multivariable MR analysis with model 1, 2, and 3 indicated that TG, LDL-C, HDL-C, Apolipoprotein A1, and Apolipoprotein B were not associated with the lower risk for AF. Conclusions: Our multivariable Mendelian randomization analysis (MVMR) finding suggested no genetic evidence of lipid traits was significantly associated with AF risk. Furthermore, more work is warranted to confirm the potential association between lipid traits and AF risks.     

Investigating Effects of Plasma Apolipoprotein E on Ischemic Heart Disease Using Mendelian Randomization Study

Background: Observationally plasma apolipoprotein E (apoE) is positively associated with ischemic heart disease (IHD). A Mendelian randomization (MR) study suggesting apoE is unrelated to cardiovascular mortality did not consider specific isoforms. We used MR to obtain estimates of plasma apoE2, apoE3 and apoE4 on IHD, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides and apolipoprotein B (apoB). Methods: We obtained independent genetic instruments from proteome genome-wide association studies (GWAS) and applied them to large outcome GWAS. We used univariable MR to assess the role of each isoform and multivariable MR to assess direct effects. Results: In univariable MR, apoE4 was positively associated with IHD (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01 to 1.09), but apoE2 and apoE3 were less clearly associated. Using multivariable MR an association of apoE2 with IHD (OR 1.16, 95% CI 0.98 to 1.38) could not be excluded, and associations of apoE3 and apoE4 with IHD were not obvious. In univariable MR, apoE2 and apoE4 were positively associated with apoB, and a positive association of apoE2 with LDL cholesterol could not be excluded. Using multivariable MR apoE2 was positively associated with LDL cholesterol, and associations with apoB could not be excluded. After adjusting for apoB, no direct effects of apoE isoforms on IHD were evident. Conclusions: Plasma apoE2 and apoE4 may play a role in lipid modulation and IHD. Whether apoE could be a potential therapeutic target requires further clarification when larger genetic studies of apoE isoforms are available.     

基于孟德尔随机化方法分析尿酸与慢性肾脏病的因果关系

目的 基于孟德尔随机化方法探究尿酸（uric acid,UA）与慢性肾脏病（chronic kidney disease,CKD）之间的因果关系。方法 以UA与CKD形成的全基因组关联研究数据库为基础,筛选出单核苷酸多态性位点(single nucleotide polymorphisms,SNPs),参数设为P＜5×10-8、连锁不平衡r2＜0.01、kb = 10 000,运用逆方差加权法(inverse - variance weighted,IVW)、MR - Egger回归法、加权中位数法、基于众数的简单估计和基于众数的加权估计5种互补的方法进行孟德尔随机化分析,以OR值及95%CI评价UA与CKD之间的因果关系,利用异质性检验、水平多效性、逐个剔除检验等进行敏感性分析。设UA与痛风（GOUT）之间的因果关系为阳性对照。结果 共筛选24个与UA和CKD均相关的SNPs,IVW结果显示UA与CKD之间具有相关性,但不存在因果关系,UA升高不是CKD发生的危险因素（OR = 0.95,95%CI: 0.78～1.16）。以GOUT作为阳性对照,IVW结果显示UA与GOUT之间具有显著的因果关系（OR = 1.60,95%CI: 1.22～2.10）,随着UA水平的不断升高GOUT的患病率逐渐增加。敏感性分析表明MR结果具有稳健性。结论 UA与CKD之间有相关性,但未有充分的证据表明UA与CKD之间存在因果关系,故单纯降低UA不能减少CKD的发生风险。     

伴有代谢综合征的冠心病患者外周血小板平均体积变化的研究

目的:探讨伴有代谢综合征(MS)的冠心病患者外周血小板平均体积的变化及其临床意义。方法:选择95例心绞痛型冠心病患者为冠心病组,根据冠心病组患者是否伴有MS分为2个亚组,伴MS组(25例)和不伴MS组(70例),同期选择健康体检者70例为正常对照组。测量身高、体重、血压,测定血糖、血脂和血小板参数如血小板计数(PLT)、血小板平均体积(MPV)等相关指标,分析MPV与伴有MS的冠心病之间的关系。结果:冠心病组患者外周血MPV(11.0±3.5)fl较正常对照组(8.9±0.50)fl明显增高(P<0.05)。伴MS组和不伴MS组的外周血MPV(11.6±5.3)fl和(10.7±5.3)fl均明显高于正常对照组(P<0.05),相关分析表明,MPV与BM I(r=0.371,P<0.01)、SBP(r=0.231,P<0.05)、DBP(r=0.211,P<0.05)、TC(r=0.292,P<0.01)、TG(r=0.268,P<0.05)、FPG(r=0.210,P<0.05)呈明显正相关,而与HDL-C呈明显负相关(r=-0.212,P<0.05);随着MS的组分增加,外周血MPV未表现出同步性增高,差...     

Are post-treatment low-density lipoprotein subclass pattern analyses potentially misleading?

Background  

Some patients administered cholesterol-lowering therapies may experience an increase in the proportion of small LDL particles, which may be misinterpreted as a worsening of atherosclerotic coronary heart disease risk. This study assessed the lipid effects of adding ezetimibe to atorvastatin or doubling the atorvastatin dose on low-density lipoprotein cholesterol (LDL-C) levels (and the cholesterol content of LDL subclasses), LDL particle number (approximated by apolipoprotein B), and LDL particle size. This was a multicenter, double-blind, randomized, parallel-group study of hypercholesterolemic, high atherosclerotic coronary heart disease risk patients. After stabilization of atorvastatin 40 mg, 579 patients with LDL-C >70 mg/dL were randomized to 6 weeks of ezetimibe + atorvastatin 40 mg or atorvastatin 80 mg. Efficacy parameters included changes from baseline in LDL-C, apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein subclasses (Vertical Auto Profile II) and pattern for the overall population, as well as patient subgroups with baseline triglyceride levels <150 mg/dL or ≥150 mg/dL.     

Increases in serum lipid and lipoprotein levels with movement from the supine to standing position in adult men and women

The effect of movement from the supine to the standing position on the magnitude of change in serum lipid and lipoprotein levels and its impact on the prediction of risk for coronary heart disease was investigated in 23 male and 18 female subjects. The mean age and body weight of the men was 34 years and 93 kg, respectively, while those of women were 36 years and 71 kg. Thirty minutes of standing following thirty minutes in the supine position was associated with hemoconcentration and a significant (P less than 0.05) plasma volume reduction of -13.8% for men and women combined. Posture-related increases in serum lipids and lipoproteins were similar among both men and women and averaged +12% for triglycerides, +9.3% for total cholesterol, +9.0% for low-density lipoprotein + very low-density lipoprotein cholesterol, and +10.4% for high-density lipoprotein cholesterol. Among men, the latter increased from 41.4 to 45.6 mg X dl-1 while among women, the increase was from 58.0 to 64.3 mg X dl-1. The total cholesterol/high-density lipoprotein cholesterol ratio was unaffected by the change in body position, thus strengthening the reliability of this ratio as a coronary heart disease risk measure. Our findings indicate that body position at time of blood withdrawal significantly influences lipid and lipoprotein levels, and, depending on the absolute concentration values of total or high-density lipoprotein cholesterol, can alter the predictive risk for coronary heart disease. Heart disease. Heart disease risk based on the Framingham probability tables and the multiplier for high-density lipoprotein cholesterol is unaffected by the change in body position.