Dataset Information

Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis.

ABSTRACT: Importance:Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk. Objective:To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design, Setting, and Participants:A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20?793 individuals with CHD and 27?540 controls with individual participant data, whereas summarized data included 62?240 patients with CHD and 127?299 controls. Data were analyzed from November 2016 to March 2018. Exposures:Genetic LPA score and plasma Lp(a) mass concentration. Main Outcomes and Measures:Coronary heart disease. Results:Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P?=?3?×?10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P?=?2?×?10-12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. Conclusions and Relevance:The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).

SUBMITTER: Burgess S

PROVIDER: S-EPMC6481553 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis.

Burgess Stephen S Ference Brian A BA Staley James R JR Freitag Daniel F DF Mason Amy M AM Nielsen Sune F SF Willeit Peter P Young Robin R Surendran Praveen P Karthikeyan Savita S Bolton Thomas R TR Peters James E JE Kamstrup Pia R PR Tybjærg-Hansen Anne A Benn Marianne M Langsted Anne A Schnohr Peter P Vedel-Krogh Signe S Kobylecki Camilla J CJ Ford Ian I Packard Chris C Trompet Stella S Jukema J Wouter JW Sattar Naveed N Di Angelantonio Emanuele E Saleheen Danish D Howson Joanna M M JMM Nordestgaard Børge G BG Butterworth Adam S AS Danesh John J

JAMA cardiology 20180701 7

<h4>Importance</h4>Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk.<h4>Objective</h4>To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) chang ...[more]

PMID: 29926099

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Project description:BackgroundThere is a well-documented empirical relationship between lipoprotein (a) [Lp(a)] and cardiovascular disease (CVD); however, causal evidence, especially from the Chinese population, is lacking. Therefore, this study aims to estimate the causal association between variants in genes affecting Lp(a) concentrations and CVD in people of Han Chinese ethnicity.MethodsTwo-sample Mendelian randomization analysis was used to assess the causal effect of Lp(a) concentrations on the risk of CVD. Summary statistics for Lp(a) variants were obtained from 1256 individuals in the Cohort Study on Chronic Disease of Communities Natural Population in Beijing, Tianjin and Hebei. Data on associations between single-nucleotide polymorphisms (SNPs) and CVD were obtained from recently published genome-wide association studies.ResultsThirteen SNPs associated with Lp(a) levels in the Han Chinese population were used as instrumental variables. Genetically elevated Lp(a) was inversely associated with the risk of atrial fibrillation [odds ratio (OR), 0.94; 95% confidence interval (95%CI), 0.901-0.987; P = 0.012)], the risk of arrhythmia (OR, 0.96; 95%CI, 0.941-0.990; P = 0.005), the left ventricular mass index (OR, 0.97; 95%CI, 0.949-1.000; P = 0.048), and the left ventricular internal dimension in diastole (OR, 0.97; 95%CI, 0.950-0.997; P = 0.028) according to the inverse-variance weighted method. No significant association was observed for congestive heart failure (OR, 0.99; 95% CI, 0.950-1.038; P = 0.766), ischemic stroke (OR, 1.01; 95%CI, 0.981-1.046; P = 0.422), and left ventricular internal dimension in systole (OR, 0.98; 95%CI, 0.960-1.009; P = 0.214).ConclusionsThis study provided evidence that genetically elevated Lp(a) was inversely associated with atrial fibrillation, arrhythmia, the left ventricular mass index and the left ventricular internal dimension in diastole, but not with congestive heart failure, ischemic stroke, and the left ventricular internal dimension in systole in the Han Chinese population. Further research is needed to identify the mechanism underlying these results and determine whether genetically elevated Lp(a) increases the risk of coronary heart disease or other CVD subtypes.

Project description:BackgroundSeveral 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.MethodsWe 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.ResultsThe 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.ConclusionOur 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.

Project description:ImportanceTriglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels.ObjectiveTo compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB.Design, setting, and participantsMendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017.ExposuresDifferences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores.Main outcomes and measuresOdds ratio (OR) for coronary heart disease (CHD)-defined as coronary death, myocardial infarction, or coronary revascularization-per 10-mg/dL lower concentration of ApoB-containing lipoproteins.ResultsA total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10-1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10-465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 × 10-38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 × 10-46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P = .19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P = .19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 × 10-20).Conclusions and relevanceTriglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.

Project description:BackgroundThe impact of lipid-lowering medications on sepsis is still not well defined. A Mendelian randomization (MR) study was carried out to probe the causal connections between genetically determined lipids, lipid-reducing drugs, and the risk of sepsis.Materials and methodsData on total serum cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), and triglycerides (TG) were retrieved from the MR-Base platform and the Global Lipids Genetics Consortium in 2021 (GLGC2021). Our study categorized sepsis into two groups: total sepsis and 28-day mortality of sepsis patients (sepsis28). The inverse-variance weighted (IVW) method was the primary method used in MR analysis. Cochran's Q test and the MR-Egger intercept method were used to assess the heterogeneity and pleiotropy.ResultsIn the MR analysis, we found that ApoA-I played a suggestively positive role in protecting against both total sepsis (OR, 0.863 per SD increase in ApoA-I; 95% CI, 0.780-0.955; P = 0.004) and sepsis28 (OR, 0.759; 95% CI, 0.598-0.963; P = 0.023). HDL-C levels were also found to suggestively reduce the incidence of total sepsis (OR, 0.891 per SD increase in HDL-C; 95% CI, 0.802-0.990; P = 0.031). Reverse-MR showed that sepsis28 led to a decrease in HDL-C level and an increase in TG level. In drug-target MR, we found that HMGCR inhibitors positively protected against total sepsis (1OR, 0.719 per SD reduction in LDL-C; 95% CI, 0.540-0.958; P = 0.024). LDL-C and HDL-C proxied CETP inhibitors were found to have a protective effect on total sepsis, with only LDL-C proxied CETP inhibitors showing a suggestively protective effect on sepsis28. In Mediated-MR, BMI exhibited a negative indirect effect in HMGCR inhibitors curing sepsis. The indirect impact of ApoA-I explained over 50% of the curative effects of CETP inhibitors in sepsis.ConclusionsOur MR study suggested that ApoA-I and HDL-C protected against sepsis, while HMGCR and CETP inhibitors showed therapeutic potential beyond lipid-lowering effects. ApoA-I explained the effects of CETP inhibitors. Our study illuminates how lipids affect sepsis patients and the effectiveness of new drugs, opening new avenues for sepsis treatment.

Dataset Information

Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis.

Publications

Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis.

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