Associations of triglyceride levels with longevity and frailty: A Mendelian randomization analysis.
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ABSTRACT:
SUBMITTER: Liu Z
PROVIDER: S-EPMC5278549 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
Publications
Associations of triglyceride levels with longevity and frailty: A Mendelian randomization analysis.
Liu Zuyun Z Burgess Stephen S Wang Zhengdong Z Deng Wan W Chu Xuefeng X Cai Jian J Zhu Yinsheng Y Shi Jianming J Xie Xuejuan X Wang Yong Y Jin Li L Wang Xiaofeng X
Scientific reports 20170130
Observational studies suggest associations of triglyceride levels with longevity and frailty. This study aimed to test whether the associations are causal. We used data from the Rugao Longevity and Ageing Study, a population-based cohort study performed in Rugao, China. A variant in the APOA5 gene region (rs662799) was used as the genetic instrument. Mendelian randomization (MR) analyses were performed to examine the associations of genetically predicted triglycerides with two ageing phenotypes ...[more]
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Project description:ObjectiveThis study examined the association between blood triglyceride (TG) levels (TLIB) and age spots (AS).MethodsWe acquired data from the Mendelian randomization (MR) Base database and evaluated the causal association between TLIB and AS.ResultsFrom genome-wide association studies, we selected 33 single nucleotide polymorphisms (SNPs) that were significantly associated with TLIB and AS. The inverse variance-weighted (IVW) and weighted median estimation methods showed that TLIB had a protective effect on AS (IVW: β=-0.214, P=0.019, odds ratio [OR]=0.807, 95% confidence interval [CI]=0.674-0.966; weighted median: β=-0.277, P=0.032, OR=0.758, 95% CI=0.589-0.977). However, the MR-Egger analysis suggested no causal association (β=-0.234, P=0.085, OR=0.792, 95% CI=0.612-1.024). The greater precision of the weighted median estimation and IVW suggests that our results support a potential causal association between TLIB and AS.ConclusionThe MR analysis proved that TLIB has a protective effect against AS and that triglycerides have potential preventive and therapeutic effects against AS. However, the specific dose-effect relationship requires further study.
| S-EPMC10625373 | biostudies-literature
Project description:BackgroundCausality between plasma triglyceride (TG) levels and atherosclerotic cardiovascular disease (ASCVD) risk remains controversial despite more than four decades of study and two recent landmark trials, STRENGTH, and REDUCE-IT. Further unclear is the association between TG levels and non-atherosclerotic diseases across organ systems.MethodsHere, we conducted a phenome-wide, two-sample Mendelian randomization (MR) analysis using inverse-variance weighted (IVW) regression to systematically infer the causal effects of plasma TG levels on 2600 disease traits in the European ancestry population of UK Biobank. For replication, we externally tested 221 nominally significant associations (p<0.05) in an independent cohort from FinnGen. To account for potential horizontal pleiotropy and the influence of invalid instrumental variables, we performed sensitivity analyses using MR-Egger regression, weighted median estimator, and MR-PRESSO. Finally, we used multivariable MR (MVMR) controlling for correlated lipid fractions to distinguish the independent effect of plasma TG levels.ResultsOur results identified seven disease traits reaching Bonferroni-corrected significance in both the discovery (p<1.92 × 10-5) and replication analyses (p<2.26 × 10-4), suggesting a causal relationship between plasma TG levels and ASCVDs, including coronary artery disease (OR 1.33, 95% CI 1.24-1.43, p=2.47 × 10-13). We also identified 12 disease traits that were Bonferroni-significant in the discovery or replication analysis and at least nominally significant in the other analysis (p<0.05), identifying plasma TG levels as a novel potential risk factor for nine non-ASCVD diseases, including uterine leiomyoma (OR 1.19, 95% CI 1.10-1.29, p=1.17 × 10-5).ConclusionsTaking a phenome-wide, two-sample MR approach, we identified causal associations between plasma TG levels and 19 disease traits across organ systems. Our findings suggest unrealized drug repurposing opportunities or adverse effects related to approved and emerging TG-lowering agents, as well as mechanistic insights for future studies.FundingRD is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) (R35-GM124836) and the National Heart, Lung, and Blood Institute of the NIH (R01-HL139865 and R01-HL155915).
| S-EPMC10079290 | biostudies-literature
Project description:BackgroundAlthough altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD.Methods and findingsWe included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n=10,578). We constructed weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at p<5×10-8 and trait specific scores using SNPs associated exclusively with each trait at p<5 × 10-8 were developed. We used logistic regression to investigate whether the GRSs were associated with LOAD in each study and results were combined together by meta-analysis. We found no association between any of the full GRSs and LOAD (meta-analysis results: odds ratio [OR]=1.005, 95% CI 0.82-1.24, p?=?0.962 per 1 unit increase in HDL-c; OR=0.901, 95% CI 0.65-1.25, p=0.530 per 1 unit increase in LDL-c; OR=1.104, 95% CI 0.89-1.37, p=0.362 per 1 unit increase in triglycerides; and OR=0.954, 95% CI 0.76-1.21, p=0.688 per 1 unit increase in total cholesterol). Results for the trait specific scores were similar; however, the trait specific scores explained much smaller phenotypic variance.ConclusionsGenetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. The observed epidemiological associations between abnormal lipid levels and LOAD risk could therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD. Limitations of this study include the small proportion of lipid variance explained by the GRS, biases in case-control ascertainment, and the limitations implicit to Mendelian randomization studies. Future studies should focus on larger LOAD datasets with longitudinal sampled peripheral lipid measures and other markers of lipid metabolism, which have been shown to be altered in LOAD. Please see later in the article for the Editors' Summary.
| S-EPMC4165594 | biostudies-literature
Project description:BackgroundEnvironmental factors are associated with human longevity, but their specificity and causality remain mostly unclear. By integrating the innovative "exposome" concept developed in the field of environmental epidemiology, this study aims to determine the components of exposome causally linked to longevity using Mendelian randomization (MR) approach.MethodsA total of 4587 environmental exposures extracting from 361,194 individuals from the UK biobank, in exogenous and endogenous domains of exposome were assessed. We examined the relationship between each environmental factor and two longevity outcomes (i.e., surviving to the 90th or 99th percentile age) from various cohorts of European ancestry. Significant results after false discovery rates correction underwent validation using an independent exposure dataset.ResultsOut of all the environmental exposures, eight age-related diseases and pathological conditions were causally associated with lower odds of longevity, including coronary atherosclerosis (odds ratio = 0.77, 95% confidence interval [0.70, 0.84], P = 4.2 × 10-8), ischemic heart disease (0.66, [0.51, 0.87], P = 0.0029), angina (0.73, [0.65, 0.83], P = 5.4 × 10-7), Alzheimer's disease (0.80, [0.72, 0.89], P = 3.0 × 10-5), hypertension (0.70, [0.64, 0.77], P = 4.5 × 10-14), type 2 diabetes (0.88 [0.80, 0.96], P = 0.004), high cholesterol (0.81, [0.72, 0.91], P = 0.0003), and venous thromboembolism (0.92, [0.87, 0.97], P = 0.0028). After adjusting for genetic correlation between different types of blood lipids, higher levels of low-density lipoprotein cholesterol (0.72 [0.64, 0.80], P = 2.3 × 10-9) was associated with lower odds of longevity, while high-density lipoprotein cholesterol (1.36 [1.13, 1.62], P = 0.001) showed the opposite. Genetically predicted sitting/standing height was unrelated to longevity, while higher comparative height size at 10 was negatively associated with longevity. Greater body fat, especially the trunk fat mass, and never eat sugar or foods/drinks containing sugar were adversely associated with longevity, while education attainment showed the opposite.ConclusionsThe present study supports that some age-related diseases as well as education are causally related to longevity and highlights several new targets for achieving longevity, including management of venous thromboembolism, appropriate intake of sugar, and control of body fat. Our results warrant further studies to elucidate the underlying mechanisms of these reported causal associations.
| S-EPMC8290559 | biostudies-literature
Project description:Previous observational studies supported a positive association of glycated hemoglobin A1c (HbA1c) level with serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). However, the causal relationship between HbA1c and either one of them was unclear in the East Asians. We performed a Mendelian Randomization (MR) analysis in a community-based study sample in Shanghai, China (n = 11,935). To clarify the cause-and-effect relationships of HbA1c with the four interested lipids, an Expanded HbA1c genetic risk score (GRS) with 17 HbA1c-related common variants and a Conservative score by excluding 11 variants were built and adopted as the Instrumental Variables (IVs), respectively. The Expanded HbA1c-GRS was associated with 0.19 unit increment in log-TG (P = 0.009), 0.42 mmol/L TC (P = 0.01), and 0.33 mmol/L LDL-C (P = 0.01); while the Conservative HbA1c-GRS was associated with 0.22 unit in log-TG (P = 0.03), 0.60 mmol/L TC (P = 0.01), and 0.51 mmol/L LDL-C (P = 0.007). No causal relationship was detected for HDL-C. Sensitivity analysis supported the above findings. In conclusions, MR analysis supports a causal role of increased HbA1c level in increment of circulating TG, TC, and LDL-C in a Chinese population.
| S-EPMC6445078 | biostudies-literature
Project description:BackgroundTriglycerides and their lipoprotein transport molecules are risk factors for heart disease. Observational studies have associated elevated levels of serum urate (SU) with triglycerides and risk of heart disease. However, owing to unmeasured confounding, observational studies do not provide insight into the causal relationship between SU and triglyceride. The aim of this study was to test for a causal role of SU in increasing triglyceride using Mendelian randomization that accounts for unmeasured confounding.Methods and resultsSubjects were of European ancestry from the atherosclerosis risk in communities (n=5237) and Framingham heart (n=2971) studies. Mendelian randomization by the 2-stage least squares regression method was done with SU as the exposure, a uric acid transporter genetic risk score as instrumental variable, and triglyceride as the outcome. In ordinary linear regression, SU was significantly associated with triglyceride levels (β=2.69 mmol/L change in triglyceride per mmol/L increase in SU). However, Mendelian randomization-based estimation showed no evidence for a direct causal association of SU with triglyceride concentration-there was a nonsignificant 1.01 mmol/L decrease in triglyceride per mmol/L increase in SU attributable to the genetic risk score (P=0.21). The reverse analysis using a triglyceride genetic risk score provided evidence of a causal role for triglyceride in raising urate in men (P(Corrected)=0.018).ConclusionsThese data provide no evidence for a causal role for SU in raising triglyceride levels, consistent with a previous Mendelian randomization report of no association between SU and ischemic heart disease.
| S-EPMC4270849 | biostudies-literature
Project description:ObjectiveThe VITAL trial of vitamin D supplementation suggested a possible protective effect for autoimmune diseases but uncertainties remain. We investigated potential causal effects of vitamin D on composite and individual autoimmune diseases using Mendelian randomization.MethodsWe used data from 332,984 participants of the UK Biobank of whom 23,089 had at least one autoimmune disease defined using ICD code and/or self-report. Diseases were further considered in mechanistic subgroups driven by "autoimmunity" (n = 12,774) or "autoinflammation" (n = 11,164), then individually. We selected variants within gene regions implicated in vitamin D biology to generate a weighted genetic score. We performed population-wide analysis using the ratio method, then examined non-linear effects across five quantiles based on 25-hydroxycholecalciferol levels.ResultsGenetically-predicted vitamin D was associated with lower risk of diseases in the autoinflammation group (OR 0.95 per 10 ng/ml increase in 25-hydroxycholecalciferol; 95%CI 0.91-0.99; p = 0.03) but not the autoimmunity group (OR 0.99; 95%CI 0.95-1.03; p = 0.64) or combined. When considering individual diseases, genetically-predicted vitamin D was associated with lower risk of psoriasis (OR 0.91; 95%CI 0.85-0.97; p = 0.005), the most common disease in the autoinflammation group, and suggestively with systemic lupus erythematosus (OR 0.84; 95%CI 0.69-1.02; p = 0.08); results were replicated using data from independent studies. We found no evidence for a plausible non-linear relationship between vitamin D and any outcome.ConclusionsWe found genetic evidence to support a causal link between 25-hydroxycholecalciferol concentrations and psoriasis and systemic lupus erythematosus. These results have implications for potential disease prevention strategies, and the interpretation and design of vitamin D supplementation trials.
| S-EPMC7614794 | biostudies-literature
Project description:BackgroundObservational studies have suggested that better protein nutritional status may contribute to prevention of frailty.ObjectiveWe sought to examine this hypothesis using a Mendelian randomization (MR) analysis.MethodsWe conducted a two-sample MR study using GWAS summary statistics data of the UK Biobank. We applied genetically predicted serum albumin as a primary exposure measure and serum total protein as a secondary exposure measure. The outcome measure was the Rockwood frailty index (FI) based on 49 deficits from 356,432 individuals (53.3% of them were women, with a mean ± SD age of 56.7 ± 8.0 y. The association between serum protein measures and FI was mainly analyzed by use of the inverse variance weighted method.ResultsA genetically predicted serum albumin concentration was not statistically significantly associated with FI in the full sample. However, in women, we observed a preventive association between genetically predicted serum albumin and FI (β = -0.172 per g/L; 95% CI: -0.336, -0.007; P = 0.041). In the full sample, genetically predicted serum total protein was inversely associated with FI (β: -0.153 per g/L; 95% CI: -0.251, -0.056; P = 0.002). In both women and men, higher serum total protein was significantly inversely associated with FI; regression coefficients were -0.148 per g/L (95% CI: -0.287, -0.009; P = 0.037) for women, -0.154 per g/L (95% CI: -0.290, -0.018; P = 0.027) for men.ConclusionsThe present MR study implies that better protein nutritional status modestly contributes to reducing the risk of frailty.
| S-EPMC8754580 | biostudies-literature
Project description:Background: Tobacco smoking and alcohol consumption have been associated with frailty in observational studies. We sought to examine whether these associations reflect causality using the two-sample Mendelian randomization (MR) design. Methods: We used summary genome-wide association statistics for smoking initiation (N = 2,669,029), alcohol consumption (N = 2,428,851), and the frailty index (FI, N = 175,226) in participants of European ancestry. Both univariable and multivariable MR were performed to comprehensively evaluate the independent effects of smoking and alcohol consumption on the FI, accompanied by multiple sensitivity analyses. Results were verified using lifetime smoking and alcohol use disorder. Reverse direction MR was undertaken to assess the potential for reverse causation. Results: Genetic predisposition to smoking initiation was significantly associated with increased FI (univariable MR: β = 0.345; 95% confidence interval [CI] = 0.316 to 0.374; p = 1.36E-113; multivariable MR: β = 0.219; 95% CI = 0.197 to 0.241; p = 2.44E-83). Genetically predicted alcohol consumption showed a suggestive association with the FI (univariable MR: β = −0.090; 95% CI = −0.151 to −0.029; p = 0.003; multivariable MR β = −0.153; 95% CI = −0.212 to −0.094; p = 2.03E-07), with inconsistent results in sensitivity analyses. In complementary analysis, genetic predicted lifetime smoking, but not alcohol use disorder was associated with the FI. There is no convincing evidence for reverse causation. Conclusion: The present MR study supported smoking as a causal risk factor of frailty. Further research is warranted to investigate whether alcohol consumption has a causal role in frailty.
| S-EPMC9935614 | biostudies-literature
Project description:Background: The association between immune imbalances and adverse pregnancy outcomes has been extensive investigated by observational studies, but remain unclear. Thus, this study aimed to establish the causality of the circulation levels of cytokines on adverse pregnancy outcomes, such as offspring's birthweight (BW), preterm birth (PTB), spontaneous miscarriage (SM), and stillbirth (SB). Methods: Two-sample Mendelian randomization (MR) analysis was employed to investigate potential causal relations between 41 cytokines and pregnancy outcomes on the basis of previously published GWAS datasets. Multivariable MR (MVMR) analysis was implemented to investigate the effect of the composition of cytokine networks on the pregnancy outcomes. Potential risk factors were further estimated to explore the potential mediators. Results: Genetic correlation analysis based on large GWAS data sources revealed that genetically predicted MIP1b (β = -0.027, S.E. = 0.010, p = 0.009) and MCSF (β = -0.024, S.E. = 0.011, p = 0.029) were associated with reduced offspring's BW, MCP1 (OR: 0.90, 95% CI: 0.83-0.97, p = 0.007) was associated with reduced SM risk, SCF (β = -0.014, S.E. = 0.005, p = 0.012) associated with decreased number of SB in MVMR. The univariable MR showed that GROa (OR: 0.92, 95% CI: 0.87-0.97, p = 0.004) was associated with decreased PTB risk. Except for the MCSF-BW association, all above associations surpassed the Bonferroni corrected threshold. The MVMR results revealed that MIF, SDF1a, MIP1b, MCSF and IP10 composed cytokine networks, associated with offspring's BW. Risk factors analysis indicated that the above causal associations might be mediated by smoking behaviors. Conclusion: These findings suggest the causal associations of several cytokines with adverse pregnancy outcomes, which were potentially mediated by smoking and obesity. Some of the results did not been corrected through multiple tests and larger samples verification is required in further studies.
| S-EPMC9986262 | biostudies-literature