Dissecting causal relationships between nonalcoholic fatty liver disease proxied by chronically elevated alanine transaminase levels and 34 extrahepatic diseases

Liu, Zhenqiu; Suo, Chen; Hong, Fan; Zhang, Tiejun; Li, Jin; Chen, Xingdong

doi:10.1016/j.metabol.2022.155270

Cited by 25 publications

(22 citation statements)

References 64 publications

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“…A two-sample MR analysis was carried out to assess the causal relationship between the risk of CVD and genetic susceptibility to RA, and SNPs were used as instrumental variables (IVs) (23). The three principal hypotheses of a classical MR study were met for the overall process: exposure was directly influenced by IVs; IVs and confounders were not associated; through exposure, the risk of outcomes was directly influenced by IVs.…”

Section: Data Sources and Study Designmentioning

confidence: 99%

“…The variance R 2 was calculated for the screened SNPs, and the strength of IVs was evaluated using F-statistics. This avoided weak-tool bias (23). Additionally, a meticulous calculation method (F = R 2 (N-K-1)/[K(1-R 2 )] was adopted, where R 2 indicates cumulative explained variance of the selected SNPs during exposure, N refers to the number of samples for the selected GWAS, and K refers to the number of SNPs for the final analysis.…”

Section: Ivsmentioning

confidence: 99%

“…Different outcomes, such as arrhythmia, AF, and IHD were adjusted. In the MR analysis, the primary analytical method used in accordance with heterogeneity was the IVW method as described previously (23). Simultaneously, to explore and deduce causality comprehensively, maximum-likelihood, MR-pleiotropy residual sum and outlier (MR-PRESSO), MR-Egger, median weighting, and MR-robust adjusted profile score (MR-RAPS) were also utilized (25).…”

Section: Ivsmentioning

confidence: 99%

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Relationship between rheumatoid arthritis and cardiovascular comorbidity, causation or co-occurrence: A Mendelian randomization study

Min

Chao

Mei

et al. 2023

Front. Cardiovasc. Med.

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BackgroundIn recent years, the incidence rates of rheumatoid arthritis (RA) and heart disease (HD) have noticeably increased worldwide. Previous studies have found that patients with RA are more likely to develop HD, while the cause and effect have still remained elusive. In this study, Mendelian randomization (MR) analysis was used to indicate whether there was a potential association between RA and HD.MethodsData of RA, ischemic heart disease (IHD), myocardial infarction (MI), atrial fibrillation (AF), and arrhythmia were based on the genome-wide association study (GWAS) dataset. No disease group was intersected. Inverse-variance weighted (IVW) method was used to calculate MR estimates, and sensitivity analysis was performed.ResultsThe primary MR analysis showed that genetic susceptibility to RA was significantly associated with the risk of IHD and MI, rather than with AF and arrhythmia. Besides, there was no heterogeneity and horizontal pleiotropy between the primary and replicated analyses. There was a significant correlation between RA and the risk of IHD (odds ratio (OR), 1.0006; 95% confidence interval (CI), 1.000244–1.00104; P = 0.001552), meanwhile, there was a significant correlation between RA and the risk of MI (OR, 1.0458; 95% CI, 1.07061–1.05379; P = 0.001636). The results were similar to those of sensitivity analysis, and the sensitivity analysis also verified the conclusion. Furthermore, sensitivity and reverse MR analyses suggested that no heterogeneity, horizontal pleiotropy or reverse causality was found between RA and cardiovascular comorbidity.ConclusionRA was noted to be causally associated with IHD and MI, rather than with AF and arrhythmia. This MR study might provide a new genetic basis for the causal relationship between RA and the risk of CVD. The findings suggested that the control of RA activity might reduce the risk of cardiovascular disease.

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Section: Data Sources and Study Designmentioning

confidence: 99%

Section: Ivsmentioning

confidence: 99%

Section: Ivsmentioning

confidence: 99%

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Relationship between rheumatoid arthritis and cardiovascular comorbidity, causation or co-occurrence: A Mendelian randomization study

Min

Chao

Mei

et al. 2023

Front. Cardiovasc. Med.

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“…Nonetheless, the numbers of IVs for NAFLD are substantially smaller than the IVs for BMI/WC/WHR/WHRadjBMI/FI. In addition, one study implemented the chronically elevated alanine transaminase level as the proxy of NAFLD to select more IVs, and the results demonstrated a robust causal relationship between NAFLD and T2D [42].…”

Section: Discussionmentioning

confidence: 99%

Shared genetic etiology and causal relationships among NAFLD, obesity and glycemic traits: A large-scale genome-wide cross-trait analysis.

Wang

Song

Wang

et al. 2023

Preprint

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Background: The shared genetic etiology among nonalcoholic fatty liver disease (NAFLD), overweight/obesity and type 2 diabetes (T2D), three closely related diseases, has not yet been thoroughly investigated. We aimed to explore the shared genetic etiology and causal relationships between the 3 diseases. Methods: Using public large-scale genome-wide association study (GWAS) data, the shared genetics between NAFLD (case=8,434, control=770,180) and 5 obesity traits (n= 224,459~700,000)/5 glycemic traits (n=281,416~659,316) were conducted with linkage disequilibrium score regression and cross-phenotype association (CPASSOC). The causal associations were explored with Mendelian Randomization (MR). Results: We revealed 20 shared loci between NAFLD and obesity traits and 10 loci between NAFLD and glycemic traits (P<5×10-8). Among them, 10 loci were not reported previously in any association with NAFLD/obesity/glycemic traits. Ten out of 11 reported variants [after removing the high LD (r2≥0.8)] were missense variants. Most shared loci with known function were involved in the metabolism of lipids. Positive causal effects of obesity traits (particularly abdominal obesity) on NAFLD were detected, while NAFLD negatively impacted general obesity (BMI) and positively impacted abdominal obesity. Intriguingly, only fast insulin had a positive causal association with NAFLD and vice versa. Conclusions: Our study suggests that NAFLD, obesity and glycemic traits have shared genetic etiologies, particularly in the metabolism of lipids. The present work advances our understanding of the genetic basis of these 3 closely related diseases and sheds light on a new method for drug design.

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“…24 In recent MR studies, the positive associations were identified between non-alcoholic fatty liver disease and the risk of CHD and myocardial infarction using genetic instruments for non-alcoholic fatty liver disease defined by increased alanine aminotransferase levels, imaging, or biopsy information. 25,26 All these findings may imply liver disease as a causal risk factor for the development of CVD, in particular CHD. This link may be mediated by multiple traditional cardiovascular risk factors, such as obesity, diabetes, metabolic syndrome, hyperlipidaemia, and hypertension.…”

Section: Discussionmentioning

confidence: 99%

Risk of incident cardiovascular disease among patients with gastrointestinal disorder: prospective cohort study of 340,862 individuals

Chen

Sun

et al. 2023

Preprint

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Background and Aims The associations between gastrointestinal diseases (GIs) and cardiovascular disease (CVD) were unclear. We conducted a prospective cohort study to explore their associations. Methods This study included 340,862 individuals without baseline CVD from the UK Biobank cohort. Individuals with and without GIs were followed up until the ascertainment of incident CVDs, including coronary heart disease (CHD), cerebrovascular disease (CeVD), and peripheral artery disease (PAD). The diagnosis of diseases was confirmed with combination of the nationwide inpatient data, primary care data, and cancer registries. A multivariable Cox proportional hazard regression model was used to estimate the associations between GIs and the risk of incident CVD. Results During a median follow-up of 12.4 years, 28,787 incident CVD cases were diagnosed. Individuals with GIs had an elevated risk of CVD (hazard ratio 1.38; 95% confidence interval 1.35-1.42, P<0.001). Eleven out of fifteen GIs were associated with an increased risk of CVD after Bonferroni-correction, including cirrhosis, non-alcoholic fatty liver disease, gastritis and duodenitis, irritable bowel syndrome, gastroesophageal reflux disease, peptic ulcer, celiac disease, pancreatitis, diverticular disease, biliary disease, and appendicitis. The associations were stronger among women, individuals aged ≤ 60 years, and those with body mass index ≥ 25 kg/m2. Conclusions This large-scale prospective cohort study revealed the associations of GIs with an increased risk of incident CVD, in particular CHD and PAD. These findings support the reinforced secondary CVD prevention among patients with gastrointestinal disorders.

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Dissecting causal relationships between nonalcoholic fatty liver disease proxied by chronically elevated alanine transaminase levels and 34 extrahepatic diseases

Cited by 25 publications

References 64 publications

Relationship between rheumatoid arthritis and cardiovascular comorbidity, causation or co-occurrence: A Mendelian randomization study

Relationship between rheumatoid arthritis and cardiovascular comorbidity, causation or co-occurrence: A Mendelian randomization study

Shared genetic etiology and causal relationships among NAFLD, obesity and glycemic traits: A large-scale genome-wide cross-trait analysis.

Risk of incident cardiovascular disease among patients with gastrointestinal disorder: prospective cohort study of 340,862 individuals

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