scholarly journals Metabolic Traits and Stroke Risk in Individuals of African Ancestry: Mendelian Randomization Analysis

Stroke ◽  
2021 ◽  
Author(s):  
Segun Fatumo ◽  
Ville Karhunen ◽  
Tinashe Chikowore ◽  
Toure Sounkou ◽  
Brenda Udosen ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Genetic Association ◽  
Mendelian Randomization ◽  
African Ancestry ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
European Ancestry ◽  
Minority Population ◽  
Genome Wide Association Studies ◽  
Metabolic Traits

Background and Purpose: Metabolic traits affect ischemic stroke (IS) risk, but the degree to which this varies across different ethnic ancestries is not known. Our aim was to apply Mendelian randomization to investigate the causal effects of type 2 diabetes (T2D) liability and lipid traits on IS risk in African ancestry individuals, and to compare them to estimates obtained in European ancestry individuals. Methods: For African ancestry individuals, genetic proxies for T2D liability and circulating lipids were obtained from a meta-analysis of the African Partnership for Chronic Disease Research study, the UK Biobank, and the Million Veteran Program (total N=77 061). Genetic association estimates for IS risk were obtained from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (3734 cases and 18 317 controls). For European ancestry individuals, genetic proxies for the same metabolic traits were obtained from Million Veteran Program (lipids N=297 626, T2D N=148 726 cases, and 965 732 controls), and genetic association estimates for IS risk were obtained from the MEGASTROKE study (34 217 cases and 406 111 controls). Random-effects inverse-variance weighted Mendelian randomization was used as the main method, complemented with sensitivity analyses more robust to pleiotropy. Results: Higher genetically proxied T2D liability, LDL-C (low-density lipoprotein cholesterol), total cholesterol and lower genetically proxied HDL-C (high-density lipoprotein cholesterol) were associated with increased risk of IS in African ancestry individuals (odds ratio per doubling the odds of T2D liability [95% CI], 1.09 [1.07–1.11]; per standard-deviation increase in LDL-C, 1.12 [1.04–1.21]; total cholesterol: 1.23 [1.06–1.43]; HDL-C, 0.93 [0.89–0.99]). There was no evidence for differences in these estimates when performing analyses in European ancestry individuals. Conclusions: Our analyses support a causal effect of T2D liability and lipid traits on IS risk in African ancestry individuals, with Mendelian randomization estimates similar to those obtained in European ancestry individuals.

scholarly journals Causal Associations Between Blood Lipids and COVID-19 Risk: A Two-Sample Mendelian Randomization Study

2021 ◽  
Author(s):  
Kun Zhang ◽  
Shan-Shan Dong ◽  
Yan Guo ◽  
Shi-Hao Tang ◽  
Hao Wu ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Blood Lipids ◽  
Mendelian Randomization ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Outcome Data ◽  
Causal Effects ◽  
Lipoprotein Cholesterol ◽  
Global Pandemic ◽  
The Uk

Objective: Coronavirus disease 2019 (COVID-19) is a global pandemic caused by the severe acute respiratory syndrome coronavirus 2. It has been reported that dyslipidemia is correlated with COVID-19, and blood lipids levels, including total cholesterol, HDL-C (high-density lipoprotein cholesterol), and LDL-C (low-density lipoprotein cholesterol) levels, were significantly associated with disease severity. However, the causalities of blood lipids on COVID-19 are not clear. Approach and Results: We performed 2-sample Mendelian randomization (MR) analyses to explore the causal effects of blood lipids on COVID-19 susceptibility and severity. Using the outcome data from the UK Biobank (1221 cases and 4117 controls), we observed potential positive causal effects of dyslipidemia (odds ratio [OR], 1.27 [95% CI, 1.08–1.49], P =3.18×10 −3 ), total cholesterol (OR, 1.19 [95% CI, 1.07–1.32], P =8.54×10 −4 ), and ApoB (apolipoprotein B; OR, 1.18 [95% CI, 1.07–1.29], P =1.01×10 −3 ) on COVID-19 susceptibility after Bonferroni correction. In addition, the effects of total cholesterol (OR, 1.01 [95% CI, 1.00–1.02], P =2.29×10 −2 ) and ApoB (OR, 1.01 [95% CI, 1.00–1.02], P =2.22×10 −2 ) on COVID-19 susceptibility were also identified using outcome data from the host genetics initiative (14 134 cases and 1 284 876 controls). Conclusions: In conclusion, we found that higher total cholesterol and ApoB levels might increase the risk of COVID-19 infection.

scholarly journals Using a two-sample Mendelian randomization design to investigate a possible causal effect of maternal lipid concentrations on offspring birth weight

2019 ◽  
Vol 48 (5) ◽  
pp. 1457-1467 ◽  
Author(s):  
Liang-Dar Hwang ◽  
Deborah A Lawlor ◽  
Rachel M Freathy ◽  
David M Evans ◽  
Nicole M Warrington
Keyword(s):  
Birth Weight ◽  
Standard Deviation ◽  
Structural Equation ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
European Ancestry ◽  
The Impact

Abstract Background The intrauterine environment is critical for fetal growth and development. However, observational associations between maternal gestational lipid concentrations and offspring birth weight (BW) have been inconsistent and ascertaining causality is challenging. Methods We used a novel two-sample Mendelian randomization (MR) approach to estimate the causal effect of maternal gestational high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride concentrations on offspring BW. Single nucleotide polymorphisms (SNPs) associated with serum HDL-C, LDL-C and triglyceride concentrations identified in the Global Lipids Genetics Consortium genome-wide association study meta-analysis (n = 188 577 European-ancestry individuals; sample 1) were selected as instrumental variables. The effects of these SNPs on offspring BW were estimated using a structural equation model in the UK Biobank and Early Growth Genetics consortium (n = 230 069 European-ancestry individuals; sample 2) that enabled partitioning of the genetic associations into maternal- (intrauterine) and fetal-specific effects. Results We found no evidence for a causal effect of maternal gestational HDL-C, LDL-C or triglyceride concentrations on offspring BW [standard deviation change in BW per standard deviation higher in HDL-C = −0.005 (95% confidence interval: −0.039, 0.029), LDL-C = 0.014 (−0.017, 0.045), and triglycerides = 0.014 (−0.025, 0.052)]. Conclusions Our findings suggest that maternal gestational HDL-C, LDL-C and triglyceride concentrations play a limited role in determining offspring BW. However, we cannot comment on the impact of these and other lipid fractions on fetal development more generally. Our study illustrates the power and flexibility of two-sample MR in assessing the causal effect of maternal environmental exposures on offspring outcomes.

Mendelian randomization highlights the causal role of normal thyroid function on blood lipid profiles

Endocrinology ◽  
2021 ◽  
Author(s):  
Yanjun Wang ◽  
Ping Guo ◽  
Lu Liu ◽  
Yanan Zhang ◽  
Ping Zeng ◽  
...  
Keyword(s):  
Correlation Analysis ◽  
Genetic Correlation ◽  
Thyroid Function ◽  
Observational Studies ◽  
Blood Lipids ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies

Abstract The association between thyroid function and dyslipidemia has been well documented in observational studies. However, observational studies are prone to confounding, making it difficult to conduct causal inference. We performed a two-sample bi-directional Mendelian randomization (MR) using summary statistics from large-scale genome-wide association studies (GWASs) of thyroid stimulating hormone (TSH), free thyroxine (FT4) and blood lipids. We chose inverse variance weighted (IVW) method as main analysis, and consolidated results through various sensitivity analyses involving six different MR methods under different model specifications. We further conducted genetic correlation analysis and colocalization analysis to deeply reflect the causality. The IVW method showed per one standard deviation (SD) increase in normal TSH was significantly associated with a 0.048 SD increase in total cholesterol (TC; P < 0.001) and a 0.032 SD increase in low-density lipoprotein cholesterol (LDL; P = 0.021). Per one SD increase in normal FT4 was significantly associated with a 0.056 SD decrease in TC (P = 0.014) and a 0.072 SD decrease in LDL (P = 0.009). Neither TSH nor FT4 showed causal associations with high-density lipoprotein cholesterol (HDL) and triglycerides (TG). No significant causal effect of blood lipids on normal TSH or FT4 can be detected. All results were largely consistent when using several alternative MR methods, and were re-confirmed by both genetic correlation analysis and colocalization analysis. Our study suggested that even within reference range, higher TSH or lower FT4 are causally associated with increased TC and LDL, while no reverse causal association can be found.

scholarly journals Evaluating lipid-lowering drug targets for Parkinson disease prevention with Mendelian randomization

2020 ◽  
Author(s):  
Dylan M. Williams ◽  
Sara Bandres-Ciga ◽  
Karl Heilbron ◽  
David Hinds ◽  
Alastair J Noyce ◽  
...  
Keyword(s):  
Protective Effect ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Genome Wide Association Studies ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol

AbstractObjectiveTo examine whether long-term exposure to statins and other lipid-lowering drugs may affect PD risk – either beneficially or adversely – using Mendelian randomization (MR).MethodsMR analyses were based on variants in genes encoding the targets of several approved or emerging drug classes that reduce circulating low-density lipoprotein cholesterol (LDL-C) or triglycerides. Variants were weighted by their associations with differences in circulating LDL-C, triglycerides or apolipoprotein B (ApoB) using data from genome-wide association studies of lipids (N = 14,004 to 295,826). MR models indexing the effects of modulating each drug target on PD risk were then estimated from genetic associations with PD case-control status (N = 37,688 cases and 981,372 controls).ResultsEstimates for statin exposure were incompatible with drug use increasing PD risk, but were not precise enough to confirm a protective effect: odds ratio for PD per standard deviation (SD) reduction in low-density lipoprotein cholesterol = 0.83; 95% confidence interval (CI): 0.65, 1.07. Findings for other LDL-lowering targets were also close to the null. Among triglyceride-lowering targets, variants indexing Apolipoprotein-A5 / Apolipoprotein-C3 modulation suggested a protective effect (OR per SD lower triglycerides = 0.84; 95% CI = 0.80, 0.89), whereas others were null.InterpretationThis genetic evidence does not support findings from large observational studies which suggest that statin exposure could alter risk of PD. Our overall pattern of results suggest peripheral lipid transport may not influence PD etiology, but this does not necessarily exclude effects of statins or the modulation of apolipoproteins A5/C3 via other mechanisms.

scholarly journals Mendelian randomization of dyslipidemia on cognitive impairment among older Americans

2020 ◽  
Author(s):  
Mingzhou Fu ◽  
Kelly M. Bakulski ◽  
Cesar Higgins ◽  
Erin B. Ware
Keyword(s):  
Risk Factor ◽  
Cognitive Impairment ◽  
Total Cholesterol ◽  
Instrumental Variable ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Cognitive Status ◽  
European Ancestry ◽  
High Total Cholesterol ◽  
Low Hdl

AbstractBackgroundAltered lipid metabolism may be a risk factor for dementia, and blood cholesterol level has a strong genetic component. We tested the hypothesis that dyslipidemia (either low levels of high-density lipoprotein cholesterol (HDL-C) or high total cholesterol) is associated with cognitive status and domains, and assessed inferred causality using genetic predisposition to dyslipidemia as an instrumental variable.MethodsUsing data from European and African genetic ancestry participants in the Health and Retirement Study, we selected observations at the first non-missing biomarker assessment (waves 2006 to 2012). Cognition domains were assessed using episodic memory, mental status, and vocabulary tests. Overall cognitive status was categorized in three levels (normal, cognitive impairment non-dementia, dementia). Based on 2018 clinical guidelines, we compared low HDL-C or high total cholesterol to normal levels. Polygenic scores for dyslipidemia were used as instrumental variables in a Mendelian randomization framework. Multivariable logistic regressions and Wald-type ratio estimators were used to examine associations.ResultsAmong European ancestry participants (n = 8781), at risk HDL-C levels were associated with higher odds of cognitive impairment (OR = 1.20, 95%CI: 1.03, 1.40) and worse episodic memory, specifically. Using cumulative genetic risk for HDL-C levels as a valid instrumental variable, a significant causal estimate was observed between at risk low HDL-C levels and higher odds of dementia (OR = 2.15, 95%CI: 1.16, 3.99). No significant associations were observed between total cholesterol levels and cognitive status. No significant associations were observed in the African ancestry sample (n = 2101).ConclusionOur study demonstrates low blood HDL-C is a potential causal risk factor for impaired cognition during aging in non-Hispanic whites of European ancestry. Dyslipidemia can be modified by changing diets, health behaviors, and therapeutic strategies, which can improve cognitive aging. Studies on low density lipoprotein cholesterol, the timing of cholesterol effects on cognition, and larger studies in non-European ancestries are needed.

scholarly journals Casual Effect of Serum Lipid Biomarkers On Early Age-Related Macular Degeneration Using Mendelian Randomization

2021 ◽  
Author(s):  
Fen-Fen Li ◽  
Yuqin Wang ◽  
Qi Chen ◽  
Lue Xiang ◽  
Feng-Qin Rao ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Serum Lipid ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Lipid Biomarkers ◽  
Age Related Macular Degeneration ◽  
Lipoprotein Cholesterol ◽  
European Ancestry ◽  
Age Related ◽  
Increased Risk

Abstract Background Age-related macular degeneration (AMD) is one of the major causes of vision loss. Early AMD needs to be taken seriously, whereas lipid biomarkers’ casual effects on early AMD remain unclear. Methods In this study, a two-sample Mendelian randomization (MR) analysis was performed to systematically assess the causal relationships between seven serum lipid biomarkers, consisting of apolipoprotein A (ApoA), apolipoprotein B (ApoB), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), direct low-density lipoprotein cholesterol (LDL-C), lipoprotein A [Lp(a)], and triglycerides (TG), and the risk of early AMD. Totally, 14,034 cases and 91,214 controls of European ancestry were included in the analysis (Number of SNPs = 11,304,110). Results MR estimates showed that a higher HDL-C level was strongly associated with increased risk of early AMD (OR = 1.25, 95% CI: 1.15-1.35, P = 2.61 × 10−8). In addition, the level of ApoA was also positively associated with the risk of early AMD (OR = 2.04, 95% CI: 1.50-2.77, P = 6.27 × 10−6). Conversely, higher LDL-C levels significantly decreased the risk of early AMD (OR = 0.90, 95% CI: 0.85-0.96, P = 2.03 × 10−3). In addition to LDL-C, higher levels of ApoB and TG were found to be positively associated with early AMD risk. Sensitivity analyses further supported these associations. Moreover, multivariable MR analyses, adjusting for the effects of correlated lipid biomarkers yielded similar results. Conclusion This study addresses the question of causality relationships that elevated circulating HDL-C/ApoA levels and increased risk of early AMD, whereas LDL-C, ApoB, and TG specifically reduce the risk of early AMD. These findings contribute to our better understanding of the role of lipid metabolism in drusen formation, particularly in early AMD development.

scholarly journals Investigating causal relationships between exposome and human longevity: a Mendelian randomization analysis

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shu-Yi Huang ◽  
Yu-Xiang Yang ◽  
Shi-Dong Chen ◽  
Hong-Qi Li ◽  
Xue-Qing Zhang ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Body Fat ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Environmental Exposures ◽  
Lipoprotein Cholesterol ◽  
European Ancestry ◽  
Human Longevity ◽  
Lower Odds ◽  
Age Related

Abstract Background Environmental 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. Methods A 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. Results Out 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. Conclusions The 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.

scholarly journals Mendelian Randomization of Dyslipidemia on Cognitive Impairment Among Older Americans

2021 ◽  
Vol 12 ◽  
Author(s):  
Mingzhou Fu ◽  
Kelly M. Bakulski ◽  
Cesar Higgins ◽  
Erin B. Ware
Keyword(s):  
Risk Factor ◽  
Cognitive Impairment ◽  
Total Cholesterol ◽  
Instrumental Variable ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Cognitive Status ◽  
European Ancestry ◽  
High Total Cholesterol ◽  
Low Hdl

Background: Altered lipid metabolism may be a risk factor for dementia, and blood cholesterol level has a strong genetic component. We tested the hypothesis that dyslipidemia (either low levels of high-density lipoprotein cholesterol (HDL-C) or high total cholesterol) is associated with cognitive status and domains, and assessed causality using genetic predisposition to dyslipidemia as an instrumental variable.Methods: Using data from European and African genetic ancestry participants in the Health and Retirement Study, we selected observations at the first non-missing biomarker assessment (waves 2006–2012). Cognition domains were assessed using episodic memory, mental status, and vocabulary tests. Overall cognitive status was categorized in three levels (normal, cognitive impairment non-dementia, dementia). Based on 2018 clinical guidelines, we compared low HDL-C or high total cholesterol to normal levels. Polygenic scores for dyslipidemia were used as instrumental variables in a Mendelian randomization framework. Multivariable logistic regressions and Wald-type ratio estimators were used to examine associations.Results: Among European ancestry participants (n = 8,781), at risk HDL-C levels were associated with higher odds of cognitive impairment (OR = 1.20, 95% CI: 1.03, 1.40) and worse episodic memory, specifically. Using cumulative genetic risk for HDL-C levels as a valid instrumental variable, a significant causal estimate was observed between at risk low HDL-C levels and higher odds of dementia (OR = 2.15, 95% CI: 1.16, 3.99). No significant associations were observed between total cholesterol levels and cognitive status. No significant associations were observed in the African ancestry sample (n = 2,101).Conclusion: Our study demonstrates low blood HDL-C is a potential causal risk factor for impaired cognition during aging in non-Hispanic whites of European ancestry. Dyslipidemia can be modified by changing diets, health behaviors, and therapeutic strategies, which can improve cognitive aging. Studies on low density lipoprotein cholesterol, the timing of cholesterol effects on cognition, and larger studies in non-European ancestries are needed.

scholarly journals Type 2 Diabetes and Adiposity Induce Different Lipid Profile Disorders: A Mendelian Randomization Analysis

2018 ◽  
Vol 103 (5) ◽  
pp. 2016-2025 ◽  
Author(s):  
Ningjian Wang ◽  
Jing Cheng ◽  
Zhiyuan Ning ◽  
Yi Chen ◽  
Bing Han ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Lipid Profile ◽  
Total Cholesterol ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Regression Coefficients ◽  
Causal Relationships ◽  
Genetically Determined

Abstract Context Type 2 diabetes and obesity often coexist, so it is difficult to judge whether diabetes or obesity induce certain types of hyperlipidemia due to mutual confounds and reverse causation. We used Mendelian randomization analyses to explore the causal relationships of diabetes and adiposity with lipid profiles. Design, Setting, and Main Outcome Measures From 23 sites in East China, 9798 participants were enrolled during 2014 to 2016. We calculated two weighted genetic risk scores as instrumental variables for type 2 diabetes and body mass index (BMI). These scores were used to measure the causal relationships of diabetes and BMI with lipid profiles that included total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TGs). Results The causal regression coefficients (βIV) of genetically determined diabetes for the total cholesterol, LDL-C, and log10TG were 0.130 [95% confidence interval (CI): 0.020, 0.240; P = 0.014], 0.125 (96% CI: 0.041, 0.209; P = 0.001), and 0.019 (95% CI: –0.001, 0.039; P = 0.055), respectively. The βIV for HDL-C was –0.008 (95% CI: –0.032. 0.016), which was not significant (P = 0.699). The causal regression coefficients of a genetically determined 10 kg/m2 increase in BMI for HDL-C and log10TG were –0.409 (96% CI: –0.698, –0.120; P = 0.004) and 0.227 (95% CI: 0.039, 0.415; P = 0.026), respectively. The βIVs for TGs and LDL-C were not significant. Conclusions This study has provided evidence for the biologically plausible causal effects of diabetes and adiposity by BMI on different elements of the lipid profile using Mendelian randomization analyses.

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