Mendelian randomization analysis reveals causal effects of blood lipidome on gestational diabetes mellitus.
Observational studies have revealed associations between maternal lipid metabolites and gestational diabetes mellitus (GDM). However, whether these associations are causal remain uncertain.
To evaluate the causal relationship between lipid metabolites and GDM.
A two-sample Mendelian randomization (MR) analysis was performed based on summary statistics. Sensitivity analyses, validation analyses and reverse MR analyses were conducted to assess the robustness of the MR results. Additionally, a phenome-wide MR (Phe-MR) analysis was performed to evaluate potential side effects of the targeted lipid metabolites.
A total of 295 lipid metabolites were included in this study, 29 of them had three or more instrumental variables (IVs) suitable for sensitivity analyses. The ratio of triglycerides to phosphoglycerides (TG_by_PG) was identified as a potential causal biomarker for GDM (inverse variance weighted (IVW) estimate: odds ratio (OR) = 2.147, 95% confidential interval (95% CI) 1.415-3.257, P = 3.26e-4), which was confirmed by validation and reverse MR results. Two other lipid metabolites, palmitoyl sphingomyelin (d18:1/16:0) (PSM(d18:1/16:0)) (IVW estimate: OR = 0.747, 95% CI 0.583-0.956, P = 0.021) and triglycerides in very small very low-density lipoprotein (XS_VLDL_TG) (IVW estimate: OR = 2.948, 95% CI 1.197-5.215, P = 0.015), were identified as suggestive potential biomarkers for GDM using a conventional cut-off P-value of 0.05. Phe-MR results indicated that lowering TG_by_PG had detrimental effects on two diseases but advantageous effects on the other 13 diseases.
Genetically predicted elevated TG_by_PG are causally associated with an increased risk of GDM. Side-effect profiles indicate that TG_by_PG might be a target for GDM prevention, though caution is advised due to potential adverse effects on other conditions.
Dong Y
，Hu AQ
，Han BX
，Cao MT
，Liu HY
，Li ZG
，Li Q
，Zheng YJ
... -
《Cardiovascular Diabetology》
Causal Relationships Between Blood Lipid Levels and Chronic Obstructive Pulmonary Disease: A Mendelian Randomization Analysis.
In preliminary research and literature review, we identified a potential link between chronic obstructive pulmonary disease (COPD) and lipid metabolism. Therefore, this study employed Mendelian randomization (MR) analysis to investigate the potential causal connection between blood lipids and COPD.
A genome-wide association study (GWAS) on COPD was conducted, encompassing a total of 112,583 European participants from the MRC-IEU. Additionally, extensive UK Biobank data pertaining to blood lipid profiles within European cohorts included measurements for low-density lipoprotein cholesterol (LDL-C) with 440,546 individuals, high-density lipoprotein cholesterol (HDL-C) with 403,943 individuals, triglycerides (TG) with 441,016 individuals, total cholesterol (TC) with 187,365 individuals, apolipoprotein A-I (apoA-I) with 393,193 individuals, and apolipoprotein B (apoB) with 439,214 individuals. Then, MR analyses were performed for lipids and COPD, respectively. The primary analytical technique employed was the inverse-variance weighted (IVW) approach, which included a 95% confidence interval (CI) to calculate the odds ratio (OR). Additionally, a sensitivity analysis was conducted to assess the dependability of the MR analysis outcomes.
MR analysis was primarily based on IVW, unveiled a causal link between COPD and LDL-C (OR=0.994, 95% CI (0.989, 0.999), P=0.019), TG (OR=1.005, 95% CI (1.002, 1.009), P=0.006), and apoA-I (OR=0.995, 95% CI (0.992, 0.999), P=0.008), in addition, no causal link was found with HDL-C, TC, apoB. Sensitivity analysis demonstrated the robustness of these causal relationships. However, through multivariate MR(MVMR) and multiple testing correction, LDL-C and TG had no causal effect on the outcome. ApoA-I remained a protective factor for the risk of COPD (OR=0.994, 95% CI (0.990-0.999), P=0.008).
Through MR analysis, this study offers evidence of a causal link between apoA-I with COPD. This further substantiates the potential role of lipid metabolism in COPD, and has significant clinical implications for the prevention and management of COPD.
Huang P
，Zhao Y
，Wei H
，Wu W
，Guo Z
，Ma S
，Xu M
，Wang Q
，Jia C
，Xiang T
，Li H
... -
《International Journal of Chronic Obstructive Pulmonary Disease》
Gestational diabetes and future cardiovascular diseases: associations by sex-specific genetic data.
Observational studies have highlighted that gestational diabetes mellitus is associated with a higher risk of cardiovascular diseases, but the causality remains unclear. Herein, the causality between genetic predisposition to gestational diabetes mellitus and the risk of cardiovascular diseases was investigated using sex-specific Mendelian randomization analysis.
Linkage disequilibrium score regression analysis and two-sample Mendelian randomization analysis were applied to infer the genetic correlation and causality, respectively. Mediation analysis was conducted using a two-step Mendelian randomization approach. Sensitivity analyses were performed to differentiate causality from pleiotropy. The genome-wide association study summary statistics for gestational diabetes mellitus were obtained from FinnGen consortium, while for cardiovascular diseases were generated based on individual-level genetic data from the UK Biobank.
Linkage disequilibrium score regression analyses revealed that gestational diabetes mellitus had a significant genetic correlation with coronary artery disease and myocardial infarction after Benjamini-Hochberg correction in ever-pregnant women. In Mendelian randomization analyses, odds ratios (95% confidence interval) for coronary artery disease and myocardial infarction were 1.09 (1.01-1.17) and 1.12 (.96-1.31) per unit increase in the log-odds of genetic predisposition to gestational diabetes mellitus in ever-pregnant women, respectively. Further, Type 2 diabetes and hypertension were identified as mediators for the causality of genetic predisposition to gestational diabetes mellitus on coronary artery disease. In sensitivity analyses, the direction of odds ratio for the association between instrumental variables with gestational diabetes mellitus-predominant effects and the risk of coronary artery disease was consistent with the primary results in ever-pregnant women, although not statistically significant.
This study demonstrated a suggestive causal relationship between genetic predisposition to gestational diabetes mellitus and the risk of coronary artery disease, which was mainly mediated by Type 2 diabetes and hypertension. These findings highlight targeting modifiable cardiometabolic risk factors may reduce the risk of coronary artery disease in women with a history of gestational diabetes mellitus.
Zhang Y
，Yu S
，Chen Z
，Liu H
，Li H
，Long X
，Ye F
，Luo W
，Dai Y
，Tu S
，Chen W
，Kong S
，He Y
，Xue L
，Tan N
，Liang H
，Zhang Z
，He P
，Duan C
，Liu Y
... -
《-》
ResearchGate
(全网免费下载)
钛学术
(全网免费下载)
