Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study

Smith, Madeleine L; Bull, Caroline J.; Holmes, Michael V.; Smith, George Davey; Sanderson, Eleanor; Anderson, E. S.; Bell, Joshua A.

doi:10.1016/j.ebiom.2023.104503

Cited by 8 publications

(3 citation statements)

References 74 publications

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“…Studies have established a causal relationship of T2D on lipid traits using Mendelian randomization, where T2D genes were used as instrumental variables. 36 , 37 Genes with pleiotropy effects on glycemic and lipid traits were also identified. 38 These genes with either indirect or pleiotropy effects may not have been identified by GWAS for lipid traits.…”

Section: Discussionmentioning

confidence: 99%

Evaluating polygenic risk scores for predicting cardiometabolic traits and disease risks in the Taiwan Biobank

Chung,

Chuang,

Zhuang

et al. 2024

Human Genetics and Genomics Advances

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Section: Discussionmentioning

confidence: 99%

Evaluating polygenic risk scores for predicting cardiometabolic traits and disease risks in the Taiwan Biobank

Chung,

Chuang,

Zhuang

et al. 2024

Human Genetics and Genomics Advances

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“…The above results are presented through leave-one-out analysis, scatter plots, and funnel plots. Reverse MR was used to estimate the effect of outcome on exposure to demonstrate the reverse causality between them [34].…”

Section: Mendelian Randomization Analysesmentioning

confidence: 99%

Causal Relationship between Immune Cells and Gynecological Cancers through Bidirectional and Multivariable Mendelian Randomization Analyses

Zhang,

Lu,

Wang

et al. 2024

J. Cancer

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Background: Evidence suggests potential associations between gynecological malignancies and various immune cell chemicals and systems. However, establishing a causal relationship remains uncertain. Methods: This work employed Wald ratio for one single-nucleotide polymorphism (SNP) or the inverse-variance weighted method (IVW) for multiple SNPs to conduct bidirectional two-sample Mendelian randomization (MR) analysis by utilizing genome-wide association study (GWAS) data. We employed supplementary methods, including MR-Egger and weighted median methods, to detect and correct for the influence of horizontal pleiotropy. In addition, we also use colocalization analysis for further validation. Results: In IVW analysis, increases in relative count of circulating CD11c + HLA-DR ++ conventional dendritic cells (cDC) were associated with an elevated risk of breast cancer (OR [95% CI], 1.1295 [1.0632-1.2000], P = 8.044 × 10 -5 ), while elevated levels of HLA-DR on plasmacytoid dendritic cells (DC) and HLA-DR on DC were protective against breast cancer. In addition, actual count of CD39 + resting Treg AC was also shown to be causally associated with the development of ovarian cancer, whereas a high relative count of CD28 + CD45RA -CD8 + T cells reduced the risk of cervical cancer. Sensitivity analysis revealed almost no evidence of bias in the current study. Multivariable MR (MVMR) analyses further confirmed a direct impact of the CD11c + HLA-DR ++ cDC immune phenotype on breast cancer. Colocalization analysis showed the lead SNP, rs780094, suggesting HLA-DR GWAS shared a common genetic mechanism with breast cancer. Conclusions: The MR study identified significant causal relationships between multiple immunophenotypes and breast cancer, aiming to provide clinicians with some reference for cancer prediction and explore further potential associations between immune phenotypes and gynecologic tumors.

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“…The causal relationships between T2D, VLDL, and coronary atherosclerosis have each been independently established through 2-sample analyses ( 26 – 28 ). However, substantial research gaps persist in elucidating the intricate pathways that connect T2D to coronary atherosclerosis, highlighting the imperative for further investigation.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the role of VLDL in the relationship between type 2 diabetes and coronary atherosclerosis: a Mendelian randomization analysis

Feng,

Guo,

Liu

et al. 2023

Front. Cardiovasc. Med.

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BackgroundThe causal link between Type 2 diabetes (T2D) and coronary atherosclerosis has been established through wet lab experiments; however, its analysis with Genome-wide association studies (GWAS) data remains unexplored. This study aims to validate this relationship using Mendelian randomization analysis and explore the potential mediation of VLDL in this mechanism.MethodsEmploying Mendelian randomization analysis, we investigated the causal connection between T2D and coronary atherosclerosis. We utilized GWAS summary statistics from European ancestry cohorts, comprising 23,363 coronary atherosclerosis patients and 195,429 controls, along with 32,469 T2D patients and 183,185 controls. VLDL levels, linked to SNPs, were considered as a potential mediating causal factor that might contribute to coronary atherosclerosis in the presence of T2D. We employed the inverse variance weighted (IVW), Egger regression (MR-Egger), weighted median, and weighted model methods for causal effect estimation. A leave-one-out sensitivity analysis was conducted to ensure robustness.ResultsOur Mendelian randomization analysis demonstrated a genetic association between T2D and an increased coronary atherosclerosis risk, with the IVW estimate at 1.13 [95% confidence interval (CI): 1.07–1.20]. Additionally, we observed a suggestive causal link between T2D and VLDL levels, as evidenced by the IVW estimate of 1.02 (95% CI: 0.98–1.07). Further supporting lipid involvement in coronary atherosclerosis pathogenesis, the IVW-Egger estimate was 1.30 (95% CI: 1.06–1.58).ConclusionIn conclusion, this study highlights the autonomous contributions of T2D and VLDL levels to coronary atherosclerosis development. T2D is linked to a 13.35% elevated risk of coronary atherosclerosis, and within T2D patients, VLDL concentration rises by 2.49%. Notably, each standard deviation increase in VLDL raises the likelihood of heart disease by 29.6%. This underscores the significant role of lipid regulation, particularly VLDL, as a mediating pathway in coronary atherosclerosis progression.

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Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study

Cited by 8 publications

References 74 publications

Evaluating polygenic risk scores for predicting cardiometabolic traits and disease risks in the Taiwan Biobank

Evaluating polygenic risk scores for predicting cardiometabolic traits and disease risks in the Taiwan Biobank

Causal Relationship between Immune Cells and Gynecological Cancers through Bidirectional and Multivariable Mendelian Randomization Analyses

Unraveling the role of VLDL in the relationship between type 2 diabetes and coronary atherosclerosis: a Mendelian randomization analysis

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