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Additive Effects of Genetic Interleukin-6 Signaling Downregulation and Low-Density Lipoprotein Cholesterol Lowering on Cardiovascular Disease: A 2×2 Factorial Mendelian Randomization Analysis.

ABSTRACT: Background Although trials suggest that anti-inflammatory approaches targeting interleukin (IL)-6 signaling can reduce cardiovascular risk, it remains unknown whether targeting IL-6 signaling could reduce risk additively to low-density lipoprotein cholesterol (LDL-C) lowering. Here, we assess interactions in associations of genetic downregulation of IL-6 signaling and LDL-C lowering with lifetime cardiovascular disease risk. Methods and Results Genetic scores for IL-6 signaling downregulation and LDL-C lowering were used to divide 408 225 White British individuals in UK Biobank into groups of lifelong exposure to downregulated IL-6 signaling, lower LDL-C, or both. Associations with risk of cardiovascular disease (coronary artery disease, ischemic stroke, peripheral artery disease, aortic aneurysm, vascular death) were explored in factorial Mendelian randomization. Compared with individuals with genetic IL-6 and LDL-C scores above the median, individuals with LDL-C scores lower than the median but IL-6 scores above the median had an odds ratio (OR) of 0.96 (95% CI, 0.93-0.98) for cardiovascular disease. A similar OR (0.96; 95% CI, 0.93-0.98) was estimated for individuals with genetic IL-6 scores below the median but LDL-C scores above the median. Individuals with both genetic scores lower than the median were at lower odds of cardiovascular disease (OR, 0.92; 95% CI, 0.90-0.95). There was no interaction between the 2 scores (relative excess risk attributed to interaction index, 0; synergy index, 1; P for multiplicative interaction=0.51). Genetic IL-6 score below the median was associated with lower cardiovascular disease risk across measured LDL-C strata (<100 or ≥100 mg/dL). Conclusions Genetically downregulated IL-6 signaling and genetically lowered LDL-C are associated with additively lower lifetime risk of cardiovascular disease. Future trials should explore combined IL-6 inhibition and LDL-C lowering treatments for cardiovascular prevention.

SUBMITTER: Georgakis MK

PROVIDER: S-EPMC9075213 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Additive Effects of Genetic Interleukin-6 Signaling Downregulation and Low-Density Lipoprotein Cholesterol Lowering on Cardiovascular Disease: A 2×2 Factorial Mendelian Randomization Analysis.

Georgakis Marios K MK Malik Rainer R Burgess Stephen S Dichgans Martin M

Journal of the American Heart Association 20211220 1

Background Although trials suggest that anti-inflammatory approaches targeting interleukin (IL)-6 signaling can reduce cardiovascular risk, it remains unknown whether targeting IL-6 signaling could reduce risk additively to low-density lipoprotein cholesterol (LDL-C) lowering. Here, we assess interactions in associations of genetic downregulation of IL-6 signaling and LDL-C lowering with lifetime cardiovascular disease risk. Methods and Results Genetic scores for IL-6 signaling downregulation an ...[more]

PMID: 34927447

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Project description:PurposeThe aim of this study was to investigate the causal relationship between low-density lipoprotein cholesterol (LDL-C) and five cancers (breast, cervical, thyroid, prostate and colorectal) using the Mendelian Randomization (MR) method, with a view to revealing the potential role of LDL-C in the development of these cancers.MethodsWe used gene variant data and disease data from the Genome-Wide Association Study (GWAS) database to assess the causal relationship between LDL-C and each cancer by Mendelian randomisation analysis methods such as inverse variance weighting and MR-Egger. Specifically, we selected Proprotein convertase subtilisin/kexin type 9 (PCSK9) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), genes associated with LDL-C levels, as instrumental variables, extracted the corresponding single nucleotide polymorphism (SNP) data and analysed the associations of these SNPs with five cancers.In addition, sensitivity analyses and heterogeneity tests were performed to ensure the reliability of the results.ResultsThe analyses showed that when using HMGCR gene, LDL-C were significantly and positively associated with breast (OR:1.200, 95% CI:1.082-1.329, p = 0.001), prostate (OR:1.198, 95% CI:1.050-1.366, p = 0.007), and thyroid cancers (OR:8.291, 95% CI:3.189- 21.555, p = 0.00001) were significantly positively correlated, whereas they were significantly negatively correlated with colorectal cancer (OR:0.641, 95% CI:0.442-0.928, p = 0.019); the results for cervical cancer were not significant (p = 0.050). When using the PCSK9 gene, LDL-C levels were significantly and positively associated with breast (OR:1.107, 95%:CI 1.031-1.187, p = 0.005) and prostate (OR:1.219, 95%:CI 1.101-1.349, p = 0.0001) cancers, but not with cervical (p = 0.294), thyroid cancer (p = 0.759) and colorectal cancer ( p = 0.572).ConclusionAnalyses using both the HMGCR and PCSK9 genes have shown that LDL-C may be a potential risk factor for breast and prostate cancer, while analyses of the HMGCR gene have also suggested that LDL-C may increase the risk of thyroid cancer and decrease the risk of colorectal cancer.

Project description:BackgroundHigh circulating low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerosis and age-associated cardiovascular events. Long-term dyslipidaemia could contribute to the development of frailty in older individuals through its role in determining cardiovascular health and potentially other physiological pathways.MethodsWe conducted Mendelian randomization (MR) analyses using genetic variants to estimate the effects of long-term LDL-C modification on frailty in UK Biobank (n = 378,161). Frailty was derived from health questionnaire and interview responses at baseline when participants were aged 40 to 69 years, and calculated using an accumulation-of-deficits approach, i.e. the frailty index (FI). Several aggregated instrumental variables (IVs) using 50 and 274 genetic variants were constructed from independent single-nucleotide polymorphisms (SNPs) to instrument circulating LDL-C concentrations. Specific sets of variants in or near genes that encode six lipid-lowering drug targets (HMGCR, PCSK9, NPC1L1, APOB, APOC3, and LDLR) were used to index effects of exposure to related drug classes on frailty. SNP-LDL-C effects were available from previously published studies. SNP-FI effects were obtained using adjusted linear regression models. Two-sample MR analyses were performed with the IVs as instruments using inverse-variance weighted, MR-Egger, weighted median, and weighted mode methods. To address the stability of the findings, MR analyses were also performed using i) a modified FI excluding the cardiometabolic deficit items and ii) data from comparatively older individuals (aged ≥60 years) only. Several sensitivity analyses were also conducted.FindingsOn average 0.14% to 0.23% and 0.16% to 0.31% decrements in frailty were observed per standard deviation reduction in LDL-C exposure, instrumented by the general IVs consisting of 50 and 274 variants, respectively. Consistent, though less precise, associations were observed in the HMGCR-, APOC3-, NPC1L1-, and LDLR-specific IV analyses. In contrast, results for PCSK9 were in the same direction but more modest, and null for APOB. All sensitivity analyses produced similar findings.InterpretationA genetically-predicted life-long lowering of LDL-C is associated with decreased frailty in midlife and older age, representing supportive evidence for LDL-C's role in multiple health- and age-related pathways. The use of lipid-lowering therapeutics with varying mechanisms of action may differ by the extent to which they provide overall health benefits.

Project description:BackgroundA previous study demonstrated that low-density lipoprotein cholesterol (LDL-C) is associated with hepatocellular carcinoma (HCC); however, the causality between them has not been proven due to conflicting research results and the interference of confounders. This study utilized Mendelian randomization (MR) to investigate the causal relationship between LDL-C and HCC and identify the mediating factors.MethodsLDL-C, HCC, and coronary artery disease (CAD) genome-wide association study (GWAS) data were obtained from a public database. To investigate causality, inverse variance weighting (IVW) was the main analysis approach. MR‒Egger, simple mode, weighted median (WM), and weighted mode were employed as supplementary analytic methods. In addition, horizontal pleiotropy and heterogeneity were tested. To evaluate the stability of the MR results, a "leave-one-out" approach was used. Multivariate MR (MVMR) was utilized to correct the confounders that might affect causality, and mediation analysis was used to investigate the potential mediating effects. Finally, we used HCC risk to infer the reverse causality with LDL-C level.ResultsRandom effects IVW results were (LDL-C-HCC: odds ratio (OR) = 0.703, 95% confidence interval (CI) = [0.508, 0.973], P = 0.034; CAD-HCC: OR = 0.722, 95% CI = [0.645, 0.808], P = 1.50 × 10-8; LDL-C-CAD: OR = 2.103, 95% CI = [1.862, 2.376], P = 5.65 × 10-33), demonstrating a causal link between LDL-C levels and a lower risk of HCC. Through MVMR, after mutual correction, the causal effect of LDL-C and CAD on HCC remained significant (P < 0.05). Through mediation analysis, it was proven that CAD mediated the causative connection between LDL-C and HCC, and the proportion of mediating effect on HCC was 58.52%. Reverse MR showed that HCC could affect LDL-C levels with a negative correlation (ORIVW = 0.979, 95% CI = [0.961, 0.997], P = 0.025).ConclusionThis MR study confirmed the causal effect between LDL-C levels and HCC risk, with CAD playing a mediating role. It may provide a new view on HCC occurrence and development mechanisms, as well as new metabolic intervention targets for treatment.

Project description:PurposeUndertake a systematic investigation into associations between genetic predictors of lipid fractions and age-related macular degeneration (AMD) risk.DesignTwo-sample Mendelian randomization investigation using published data.ParticipantsA total of 33 526 individuals (16 144 cases, 17 832 controls) predominantly of European ancestry from the International Age-related Macular Degeneration Genomics Consortium.MethodsWe consider 185 variants previously demonstrated to be associated with at least 1 of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides at a genome-wide level of significance, and test their associations with AMD. We particularly focus on variants in gene regions that are proxies for specific pharmacologic agents for lipid therapy. We then conduct a 2-sample Mendelian randomization investigation to assess the causal roles of LDL-cholesterol, HDL-cholesterol, and triglycerides on AMD risk. We also conduct parallel investigations for coronary artery disease (CAD) (viewed as a positive control) and Alzheimer's disease (a negative control) for comparison.Main outcome measuresDiagnosis of AMD.ResultsWe find evidence that HDL-cholesterol is a causal risk factor for AMD, with an odds ratio (OR) estimate of 1.22 (95% confidence interval [CI], 1.03-1.44) per 1 standard deviation increase in HDL-cholesterol. No causal effect of LDL-cholesterol or triglycerides was found. Variants in the CETP gene region associated with increased circulating HDL-cholesterol also associate with increased AMD risk, although variants in the LIPC gene region that increase circulating HDL-cholesterol have the opposite direction of association with AMD risk. Parallel analyses suggest that lipids have a greater role for AMD compared with Alzheimer's disease, but a lesser role than for CAD.ConclusionsSome genetic evidence suggests that HDL-cholesterol is a causal risk factor for AMD risk and that increasing HDL-cholesterol (particularly via CETP inhibition) will increase AMD risk.

Dataset Information

Additive Effects of Genetic Interleukin-6 Signaling Downregulation and Low-Density Lipoprotein Cholesterol Lowering on Cardiovascular Disease: A 2×2 Factorial Mendelian Randomization Analysis.

Publications

Additive Effects of Genetic Interleukin-6 Signaling Downregulation and Low-Density Lipoprotein Cholesterol Lowering on Cardiovascular Disease: A 2×2 Factorial Mendelian Randomization Analysis.

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