scholarly journals Investigating genetically mimicked effects of statins via HMGCR inhibition on immune-related diseases in men and women using Mendelian randomization

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Guoyi Yang ◽  
C. Mary Schooling
Keyword(s):  
Lupus Erythematosus ◽  
Multiple Testing ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Allergic Diseases ◽  
Genome Wide Association Studies ◽  
East Asians ◽  
Genome Wide

AbstractStatins have been suggested as a potential treatment for immune-related diseases. Conversely, statins might trigger auto-immune conditions. To clarify the role of statins in allergic diseases and auto-immune diseases, we conducted a Mendelian randomization (MR) study. Using established genetic instruments to mimic statins via 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibition, we assessed the effects of statins on asthma, eczema, allergic rhinitis, rheumatoid arthritis (RA), psoriasis, type 1 diabetes, systemic lupus erythematosus (SLE), multiple sclerosis (MS), Crohn’s disease and ulcerative colitis in the largest available genome wide association studies (GWAS). Genetically mimicked effects of statins via HMGCR inhibition were not associated with any immune-related diseases in either study after correcting for multiple testing; however, they were positively associated with the risk of asthma in East Asians (odds ratio (OR) 2.05 per standard deviation (SD) decrease in low-density lipoprotein cholesterol (LDL-C), 95% confidence interval (CI) 1.20 to 3.52, p value 0.009). These associations did not differ by sex and were robust to sensitivity analysis. These findings suggested that genetically mimicked effects of statins via HMGCR inhibition have little effect on allergic diseases or auto-immune diseases. However, we cannot exclude the possibility that genetically mimicked effects of statins via HMGCR inhibition might increase the risk of asthma in East Asians.

scholarly journals Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Caroline J. Bull ◽  
Joshua A. Bell ◽  
Neil Murphy ◽  
Eleanor Sanderson ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Genome Wide Association Studies ◽  
Metabolic Alterations ◽  
Genome Wide ◽  
Inverse Variance ◽  
Colon Cancer Family Registry

Abstract Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

scholarly journals The association between depression and metabolic syndrome and its components: a bidirectional two-sample Mendelian randomization study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Min Zhang ◽  
Jing Chen ◽  
Zhiqun Yin ◽  
Lanbing Wang ◽  
Lihua Peng
Keyword(s):  
Metabolic Syndrome ◽  
Waist Circumference ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Fasting Blood Glucose ◽  
Density Lipoprotein ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Level Data ◽  
Inverse Variance

AbstractObservational studies suggested a bidirectional correlation between depression and metabolic syndrome (MetS) and its components. However, the causal associations between them remained unclear. We aimed to investigate whether genetically predicted depression is related to the risk of MetS and its components, and vice versa. We performed a bidirectional two-sample Mendelian randomization (MR) study using summary-level data from the most comprehensive genome-wide association studies (GWAS) of depression (n = 2,113,907), MetS (n = 291,107), waist circumference (n = 462,166), hypertension (n = 463,010) fasting blood glucose (FBG, n = 281,416), triglycerides (n = 441,016), high-density lipoprotein cholesterol (HDL-C, n = 403,943). The random-effects inverse-variance weighted (IVW) method was applied as the primary method. The results identified that genetically predicted depression was significantly positive associated with risk of MetS (OR: 1.224, 95% CI: 1.091–1.374, p = 5.58 × 10−4), waist circumference (OR: 1.083, 95% CI: 1.027–1.143, p = 0.003), hypertension (OR: 1.028, 95% CI: 1.016–1.039, p = 1.34 × 10−6) and triglycerides (OR: 1.111, 95% CI: 1.060–1.163, p = 9.35 × 10−6) while negative associated with HDL-C (OR: 0.932, 95% CI: 0.885–0.981, p = 0.007) but not FBG (OR: 1.010, 95% CI: 0.986–1.034, p = 1.34). No causal relationships were identified for MetS and its components on depression risk. The present MR analysis strength the evidence that depression is a risk factor for MetS and its components (waist circumference, hypertension, FBG, triglycerides, and HDL-C). Early diagnosis and prevention of depression are crucial in the management of MetS and its components.

scholarly journals Mendelian randomization rules out the causal relationship between serum lipids and cholecystitis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Hongqun Yang ◽  
Lanlan Chen ◽  
Kaiyu Liu ◽  
Chengnan Li ◽  
Haitao Li ◽  
...  
Keyword(s):  
Protective Effect ◽  
Serum Lipids ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Genome Wide Association Studies ◽  
Complementary Method

Abstract Background The relationship between serum lipids and cholecystitis is still under investigation. To examine the causal effect of serum lipids on cholecystitis using the Mendelian randomization method. Methods We conducted univariable Mendelian randomization (MR) analyses using summary statistics from two independent genome-wide association studies (GWAS) on serum lipids (n = 132,908) and cholecystitis (n = 361,194). Mainly, the inverse-variance weighted (IVW) method was utilized to combine each SNP’s causal estimation, and the MR-Egger was adopted as a complementary method, together with the weighted median. Cochrane’s Q value was employed to appraise heterogeneity. The MR-Egger intercept and MR-PRESSO were used to detect the horizontal pleiotropy. Results Our univariable results displayed a minor protective effect of serum low-density lipoprotein (LDL) cholesterol (OR [95% CI] = 0.9984483 [0.9984499, 0.9984468]; p = 0.008) on cholecystitis. No significant causal effect of total cholesterol (TC) (OR [95% CI] = 0.9994228 [0.9994222, 0.9994233]; p = 0.296), triglycerides (OR [95% CI] = 0.9990893 [0.9990882, 0.9990903]; p = 0.238) and high-density lipoprotein (HDL) cholesterol (OR [95% CI] = 0.9997020 [0.9997017, 0.9997023]; p = 0.565) was found on cholecystitis. Conclusion These findings suggest that LDL cholesterolhas a slight protective effect on cholecystitis, which can be easily affected by confounding factors. TC, triglycerides and HDL cholesterol don’t have causal effect on cholecystitis. The protective effect of serum lipids on cholecystitis, though possible, remain less certain.

scholarly journals High-Density Lipoproteins and the Immune System

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Hidesuke Kaji
Keyword(s):  
Immune System ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Density ◽  
Ldl Oxidation ◽  
High Density Lipoproteins ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Adaptive Immune Systems

High-density lipoprotein (HDL) plays a major role in vasodilation and in the reduction of low-density lipoprotein (LDL) oxidation, inflammation, apoptosis, thrombosis, and infection; however, HDL is now less functional in these roles under certain conditions. This paper focuses on HDL, its anti-inflammation behavior, and the mechanisms by which HDL interacts with components of the innate and adaptive immune systems. Genome-wide association studies (GWAS) and proteomic studies have elucidated important molecules involved in the interaction between HDL and the immune system. An understanding of these mechanisms is expected to be useful for the prevention and treatment of chronic inflammation due to metabolic syndrome, atherosclerosis, or various autoimmune diseases.

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 Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

2020 ◽  
Author(s):  
Caroline J. Bull ◽  
Joshua A. Bell ◽  
Neil Murphy ◽  
Eleanor Sanderson ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Genome Wide Association Studies ◽  
Lipoprotein Subclass ◽  
Site Specific ◽  
Metabolic Alterations ◽  
Inverse Variance

AbstractImportanceEvidence on adiposity altering colorectal cancer (CRC) risk differently among men and women, and on metabolic alterations mediating effects of adiposity on CRC, is unclear.ObjectiveTo examine sex- and site-specific associations of adiposity with CRC risk, and whether adiposity-associated metabolites explain associations of adiposity with CRC.DesignTwo-sample Mendelian randomization (MR) study.SettingGenetic variants from expanded genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N=806,810), and 123 metabolites (mostly lipoprotein subclass-specific lipids) from targeted nuclear magnetic resonance metabolomics (N=24,925), were used as instruments. Sex-combined and sex-specific MR was conducted for BMI and WHR with CRC risk; sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes.Participants58,221 cases and 67,694 controls (Genetics and Epidemiology of Colorectal Cancer Consortium; Colorectal Cancer Transdisciplinary Study; Colon Cancer Family Registry).Main outcome measuresIncident CRC (overall and site-specific).ResultsAmong men, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95%-confidence interval (CI)=1.08, 1.38) times higher CRC odds (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95%-CI=0.97, 1.22) times higher CRC odds. Higher WHR was more strongly associated with CRC risk among women (IVW-OR=1.25, 95%-CI=1.08, 1.43 per 0.07-ratio) than men (IVW-OR=1.05, 95%-CI=0.81, 1.36 per 0.07-ratio). BMI or WHR was associated with 104 metabolites (false-discovery-rate-corrected P≤0.05) including low-density lipoprotein (LDL) cholesterol, but these metabolites were generally unassociated with CRC in directions consistent with mediation of adiposity-CRC relations. In multivariable MR, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes – e.g. the univariable IVW-OR of BMI for CRC was 1.12 (95%-CI=1.00, 1.26), and 1.11 (95%-CI=0.99, 1.26) adjusting for LDL lipids.Conclusions and relevanceOur results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women.Adiposity was associated with numerous metabolic alterations, but none of these alterations explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify mechanistic pathways.

scholarly journals A large-scale genome-wide enrichment analysis identifies new trait-associated genes, pathways and tissues across 31 human phenotypes*

2017 ◽  
Author(s):  
Xiang Zhu ◽  
Matthew Stephens
Keyword(s):  
Complex Traits ◽  
Large Scale ◽  
Late Onset ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Enrichment Analysis ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Artery Disease

Genome-wide association studies (GWAS) aim to identify genetic factors that are associated with complex traits. Standard analyses test individual genetic variants, one at a time, for association with a trait. However, variant-level associations are hard to identify (because of small effects) and can be difficult to interpret biologically. “Enrichment analyses” help address both these problems by focusing on sets of biologically-related variants. Here we introduce a new model-based enrichment analysis method that requires only GWAS summary statistics, and has several advantages over existing methods. Applying this method to interrogate 3,913 biological pathways and 113 tissue-based gene sets in 31 human phenotypes identifies many previously-unreported enrichments. These include enrichments of the endochondral ossification pathway for adult height, the NFAT-dependent transcription pathway for rheumatoid arthritis, brain-related genes for coronary artery disease, and liver-related genes for late-onset Alzheimer’s disease. A key feature of our method is that inferred enrichments automatically help identify new trait-associated genes. For example, accounting for enrichment in lipid transport genes yields strong evidence for association between MTTP and low-density lipoprotein levels, whereas conventional analyses of the same data found no significant variants near this gene.

scholarly journals Mendelian randomization analysis identified genes pleiotropically associated with the risk and prognosis of COVID-19

2020 ◽  
Author(s):  
Di Liu ◽  
Jingyun Yang ◽  
Bowen Feng ◽  
Wenjin Lu ◽  
Chuntao Zhao ◽  
...  
Keyword(s):  
Multiple Testing ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Global Pandemic ◽  
Genome Wide ◽  
Biological Interpretation ◽  
Disease Behavior ◽  
Randomization Analysis ◽  
Summary Data

Objectives: COVID-19 has caused a large global pandemic. Patients with COVID-19 exhibited considerable variation in disease behavior. Pervious genome-wide association studies have identified potential genetic variants involved in the risk and prognosis of COVID-19, but the underlying biological interpretation remains largely unclear. Methods: We applied the summary data-based Mendelian randomization (SMR) method to identify genes that were pleiotropically associated with the risk and various outcomes of COVID-19, including severe respiratory confirmed COVID-19 and hospitalized COVID-19. Results: In blood, we identified 2 probes, ILMN_1765146 and ILMN_1791057 tagging IFNAR2, that showed pleiotropic association with hospitalized COVID-19 (Beta; [SE]=0.42 [0.09], P=4.75E-06 and Beta; [SE]=-0.48 [0.11], P=6.76E-06, respectively). Although no other probes were significant after correction for multiple testing in both blood and lung, multiple genes as tagged by the top 5 probes were involved in inflammation or antiviral immunity, and several other tagged genes, such as PON2 and HPS5, were involved in blood coagulation. Conclusions: We identified IFNAR2 and other potential genes that could be involved in the susceptibility or prognosis of COVID-19. These findings provide important leads to a better understanding of the mechanisms of cytokine storm and venous thromboembolism in COVID-19 and potential therapeutic targets for the effective treatment of COVID-19.

scholarly journals Genetic Contribution of Endometriosis to the Risk of Developing Hormone-Related Cancers

2021 ◽  
Vol 22 (11) ◽  
pp. 6083
Author(s):  
Aintzane Rueda-Martínez ◽  
Aiara Garitazelaia ◽  
Ariadna Cilleros-Portet ◽  
Sergi Marí ◽  
Rebeca Arauzo ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Clear Cell ◽  
Association Studies ◽  
Epidemiological Data ◽  
Epidemiological Studies ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Genomic Analyses ◽  
Gynecological Disorder ◽  
Robust Evidence

Endometriosis is a common gynecological disorder that has been associated with endometrial, breast and epithelial ovarian cancers in epidemiological studies. Since complex diseases are a result of multiple environmental and genetic factors, we hypothesized that the biological mechanism underlying their comorbidity might be explained, at least in part, by shared genetics. To assess their potential genetic relationship, we performed a two-sample mendelian randomization (2SMR) analysis on results from public genome-wide association studies (GWAS). This analysis confirmed previously reported genetic pleiotropy between endometriosis and endometrial cancer. We present robust evidence supporting a causal genetic association between endometriosis and ovarian cancer, particularly with the clear cell and endometrioid subtypes. Our study also identified genetic variants that could explain those associations, opening the door to further functional experiments. Overall, this work demonstrates the value of genomic analyses to support epidemiological data, and to identify targets of relevance in multiple disorders.

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