Causally Associations of Blood Lipids Levels with COVID-19 Risk: Mendelian Randomization Study

Abstract BackgroundCoronavirus disease 2019 (COVID-19) is a global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). It has been found that coronary artery disease (CAD) is a comorbid condition for COVID-19. As the risk factors of CAD, whether blood lipids levels are causally related to increasing susceptibility and severity of COVID-19 is still unknown.ObjectiveWe aim to measure the causal effects between blood lipids and COVID-19 using two-sample Mendelian Randomization (MR) methods.MethodsWe performed two-sample MR analyses to explore whether dyslipidemia, low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), triglyceride (TG) and total cholesterol (TC) were causally related to COVID-19 risk and severity. The GWAS summary data of blood lipids involving in 312571 individuals and dyslipidemia in a total of 53991 individuals were used as exposures, respectively. Two COVID-19 GWASs including 1221 infected patients and 1610 severe patients defined as respiratory failure were employed as outcomes. ResultsThe MR results showed that dyslipidemia was casually associated with the susceptibility of COVID-19 and induced 27% higher odds for COVID-19 infection (MR-IVW OR = 1.27, 95% CI: 1.08 to 1.49, p-value = 3·18 × 10-3). For blood lipids, the increasing level of TC will raise 18 % higher odds for the susceptibility of COVID-19 (MR-IVW OR = 1.18, 95% CI: 1.06 to 1.31, p-value = 3.08 × 10-3). Based on MR estimates, we further carried out gene-based analysis and found that ABO gene was associated with TC.Conclusions Dyslipidemia is casually associated with the susceptibility of COVID-19 and the blood TC level is a risk factor for the susceptibility of COVID-19. In addition, the different susceptibility of COVID-19 in specific blood group may be partly explained by the TC concentration in diverse ABO blood groups.

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Causally Associations of Blood Lipids Levels with COVID-19 Risk: Mendelian Randomization Study

10.1101/2020.07.07.20147926 ◽

2020 ◽

Author(s):

Kun Zhang ◽

Yan Guo ◽

Zhuo-Xin Wang ◽

Jing-Miao Ding ◽

Shi Yao ◽

...

Keyword(s):

Blood Lipids ◽

Mendelian Randomization ◽

Causal Effect ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Gene Set Analysis ◽

P Value ◽

Comorbid Condition ◽

Gene Set

AbstractBackgroundCoronavirus disease 2019 (COVID-19) is a global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). It has been found that coronary artery disease (CAD) is a comorbid condition for COVID-19. As the risk factors of CAD, whether blood lipids levels are causally related to increasing susceptibility and severity of COVID-19 is still unknown.DesignWe performed two-sample Mendelian Randomization (MR) analyses to explore whether dyslipidemia, low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), triglyceride (TG) and total cholesterol (TC) were causally related to COVID-19 risk and severity. The GWAS summary data of blood lipids involving in 188,578 individuals and dyslipidemia in a total of 53,991 individuals were used as exposures, respectively. Two COVID-19 GWASs including 1,221 infected patients and 1,610 severe patients defined as respiratory failure were employed as outcomes. Based on the MR estimates, we further carried out gene-based and gene-set analysis to explain the potential mechanism for causal effect.ResultsThe MR results showed that dyslipidemia was casually associated with the susceptibility of COVID-19 and induced 27% higher odds for COVID-19 infection (MR-IVW OR = 1.27, 95% CI: 1.08 to 1.49, p-value = 3.18 × 10−3). Moreover, the increasing level of blood TC will raise 14 % higher odds for the susceptibility of COVID-19 (MR-IVW OR = 1.14, 95% CI: 1.04 to 1.25, p-value = 5.07 × 10−3). Gene-based analysis identified that ABO gene was associated with TC and the gene-set analysis found that immune processes were involved in the risk effect of TC.ConclusionsWe obtained three conclusions: 1) Dyslipidemia is casually associated with the susceptibility of COVID-19; 2) TC is a risk factor for the susceptibility of COVID-19; 3) The different susceptibility of COVID-19 in specific blood group may be partly explained by the TC concentration in diverse ABO blood groups.

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.121.316324 ◽

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.

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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

Journal of the American Heart Association ◽

10.1161/jaha.121.023277 ◽

2021 ◽

Author(s):

Marios K. Georgakis ◽

Rainer Malik ◽

Stephen Burgess ◽

Martin Dichgans

Keyword(s):

Cardiovascular Disease ◽

Mendelian Randomization ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Low Density ◽

Low Density Lipoprotein Cholesterol ◽

Artery Disease

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.

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Low-Density Lipoprotein Cholesterol 4: The Notable Risk Factor of Coronary Artery Disease Development

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.619386 ◽

2021 ◽

Vol 8 ◽

Author(s):

Dongmei Wu ◽

Qiuju Yang ◽

Baohua Su ◽

Jia Hao ◽

Huirong Ma ◽

...

Keyword(s):

Risk Factors ◽

Coronary Artery Disease ◽

Blood Lipids ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Low Density ◽

Low Density Lipoprotein Cholesterol ◽

Artery Disease ◽

Cad Risk

Background: Coronary artery disease (CAD) is the leading cause of death worldwide, which has a long asymptomatic period of atherosclerosis. Thus, it is crucial to develop efficient strategies or biomarkers to assess the risk of CAD in asymptomatic individuals.Methods: A total of 356 consecutive CAD patients and 164 non-CAD controls diagnosed using coronary angiography were recruited. Blood lipids, other baseline characteristics, and clinical information were investigated in this study. In addition, low-density lipoprotein cholesterol (LDL-C) subfractions were classified and quantified using the Lipoprint system. Based on these data, we performed comprehensive analyses to investigate the risk factors for CAD development and to predict CAD risk.Results: Triglyceride, LDLC-3, LDLC-4, LDLC-5, LDLC-6, and total small and dense LDL-C were significantly higher in the CAD patients than those in the controls, whereas LDLC-1 and high-density lipoprotein cholesterol (HDL-C) had significantly lower levels in the CAD patients. Logistic regression analysis identified male [odds ratio (OR) = 2.875, P < 0.001], older age (OR = 1.018, P = 0.025), BMI (OR = 1.157, P < 0.001), smoking (OR = 4.554, P < 0.001), drinking (OR = 2.128, P < 0.016), hypertension (OR = 4.453, P < 0.001), and diabetes mellitus (OR = 8.776, P < 0.001) as clinical risk factors for CAD development. Among blood lipids, LDLC-3 (OR = 1.565, P < 0.001), LDLC-4 (OR = 3.566, P < 0.001), and LDLC-5 (OR = 6.866, P < 0.001) were identified as risk factors. To predict CAD risk, six machine learning models were constructed. The XGboost model showed the highest AUC score (0.945121), which could distinguish CAD patients from the controls with a high accuracy. LDLC-4 played the most important role in model construction.Conclusions: The established models showed good performance for CAD risk prediction, which can help screen high-risk CAD patients in asymptomatic population, so that further examination and prevention treatment might be taken before any sudden or serious event.

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P1635Impact of serum low-density lipoprotein cholesterol level after endovascular therapy for symptomatic peripheral artery disease

European Heart Journal ◽

10.1093/eurheartj/ehy565.p1635 ◽

2018 ◽

Vol 39 (suppl_1) ◽

Author(s):

Y Tomoi ◽

K Yamaji ◽

Y Soga ◽

S Hiramori ◽

K Ando

Keyword(s):

Cholesterol Level ◽

Peripheral Artery Disease ◽

Endovascular Therapy ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Low Density ◽

Low Density Lipoprotein Cholesterol ◽

Peripheral Artery ◽

Artery Disease

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Should We Adjust Low-Density Lipoprotein Cholesterol Management to the Severity of Coronary Artery Disease?

JACC Cardiovascular Imaging ◽

10.1016/j.jcmg.2020.04.007 ◽

2020 ◽

Vol 13 (9) ◽

pp. 1973-1975

Author(s):

William S. Weintraub ◽

Armin Arbab-Zadeh

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Low Density ◽

Low Density Lipoprotein Cholesterol ◽

Artery Disease ◽

Cholesterol Management

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Impact of different statins on low-density lipoprotein cholesterol levels in patients with peripheral artery disease

Atherosclerosis ◽

10.1016/j.atherosclerosis.2021.06.886 ◽

2021 ◽

Vol 331 ◽

pp. e288

Author(s):

K. Gebauer ◽

N. Malyar

Keyword(s):

Peripheral Artery Disease ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Low Density ◽

Low Density Lipoprotein Cholesterol ◽

Peripheral Artery ◽

Cholesterol Levels ◽

Artery Disease

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Association between genetically determined leptin and blood lipids considering alcohol consumption: a Mendelian randomisation study

BMJ Open ◽

10.1136/bmjopen-2018-026860 ◽

2019 ◽

Vol 9 (11) ◽

pp. e026860 ◽

Cited By ~ 1

Author(s):

Luqi Shen ◽

José F Cordero ◽

Jia-Sheng Wang ◽

Ye Shen ◽

Shengxu Li ◽

...

Keyword(s):

Alcohol Consumption ◽

Alcohol Drinking ◽

Blood Lipids ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Risk Scores ◽

Mendelian Randomisation ◽

Lipid Levels ◽

Genetically Determined

ObjectivesThe objective of this study was to evaluate the association of genetically determined leptin with lipids.DesignWe conducted a Mendelian randomisation study to assess a potential causal relationship between serum leptin and lipid levels. We also evaluated whether alcohol drinking modified the associations of genetically determined leptin with blood lipids.Setting and participants3860 participants of the Framingham Heart Study third generation cohort.ResultsBoth genetic risk scores (GRSs), the GRS generated using leptin loci independent of body mass index (BMI) and GRS generated using leptin loci dependent of BMI, were positively associated with log-transformed leptin (log-leptin). The BMI-independent leptin GRS was associated with log-transformed triglycerides (log-TG, β=−0.66, p=0.01), but not low-density lipoprotein cholesterol (LDL-C, p=0.99), high-density lipoprotein cholesterol (HDL-C, p=0.44) or total cholesterol (TC, p=0.49). Instrumental variable estimation showed that per unit increase in genetically determined log-leptin was associated with 0.55 (95% CI: 0.05 to 1.00) units decrease in log-TG. Besides significant association with log-TG (β=−0.59, p=0.009), the BMI-dependent GRS was nominally associated with HDL-C (β=−10.67, p=0.09) and TC (β=−28.05, p=0.08). When stratified by drinking status, the BMI-dependent GRS was associated with reduced levels of LDL-C (p=0.03), log-TG (p=0.004) and TC (p=0.003) among non-current drinkers only. Significant interactions between the BMI-dependent GRS and alcohol drinking were identified for LDL-C (p=0.03), log-TG (p=0.03) and TC (p=0.02).ConclusionThese findings together indicated that genetically determined leptin was negatively associated with lipid levels and the association may be modified by alcohol consumption.

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Baseline Low-Density-Lipoprotein Cholesterol Modifies the Risk of All-Cause Death Associated With Elevated Lipoprotein(a) in Coronary Artery Disease Patients

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.817442 ◽

2022 ◽

Vol 8 ◽

Author(s):

Younan Yao ◽

Jin Liu ◽

Bo Wang ◽

Ziyou Zhou ◽

Xiaozhao Lu ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Low Density ◽

Low Density Lipoprotein Cholesterol ◽

Penalized Spline ◽

All Cause Mortality ◽

Artery Disease

Background: The prognostic value of elevated lipoprotein(a) [Lp(a)] in coronary artery disease (CAD) patients is inconsistent in previous studies, and whether such value changes at different low-density-lipoprotein cholesterol (LDL-C) levels is unclear.Methods and Findings: CAD patients treated with statin therapy from January 2007 to December 2018 in the Guangdong Provincial People's Hospital (NCT04407936) were consecutively enrolled. Individuals were categorized according to the baseline LDL-C at cut-off of 70 and 100 mg/dL. The primary outcome was 5-year all-cause death. Multivariate Cox proportional models and penalized spline analyses were used to evaluate the association between Lp(a) and all-cause mortality. Among 30,908 patients, the mean age was 63.1 ± 10.7 years, and 76.7% were men. A total of 2,383 (7.7%) patients died at 5-year follow-up. Compared with Lp(a) <50 mg/dL, Lp(a) ≥ 50 mg/dL predicted higher all-cause mortality (multivariable adjusted HR = 1.19, 95% CI 1.07–1.31) in the total cohort. However, when analyzed within each LDL-C category, there was no significant association between Lp(a) ≥ 50 mg/dL and higher all-cause mortality unless the baseline LDL-C was ≥ 100 mg/dL (HR = 1.19, 95% CI 1.04–1.36). The results from penalized spline analyses were robust.Conclusions: In statin-treated CAD patients, elevated Lp(a) was associated with increased risks of all-cause death, and such an association was modified by the baseline LDL-C levels. Patients with Lp(a) ≥ 50 mg/dL had higher long-term risks of all-cause death compared with those with Lp(a) <50 mg/dL only when their baseline LDL-C was ≥ 100 mg/dL.

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