Liver Enzymes and Risk of Ischemic Heart Disease and Type 2 Diabetes Mellitus: A Mendelian Randomization Study

Liu, Junxi; Yeung, Shiu Lun Au; Lin, Shi Lin; Leung, Gabriel M.; Schooling, CM

doi:10.1038/srep38813

Cited by 50 publications

(41 citation statements)

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“…In addition to the suggested genetic correlations in Europeans (type 2 diabetes and BMI; triglycerides, blood sugar, and hemoglobin A1c; coronary artery disease and BMI; and high-density-lipoprotein cholesterol and triglycerides) 15 , we empirically corroborated novel genetic correlations that have been implicated in Mendelian randomization analyses (e.g., type 2 diabetes and alanine aminotransferase 31 ; atrial fibrillation and height 32 ; asthma and eosinophil count 9 ; and colorectal cancer and height 33 ) and epidemiological studies (e.g., ischemic stroke and uric acid 34 ; myocardial infarction and albumin/globulin ratio 35 ; peripheral artery disease and total Tables 1 and 2. bilirubin 36 ; and urolithiasis and blood pressure 37 ) (Supplementary Table 8). Thus, we further investigated causal relationships between the significant pairs of quantitative traits and diseases by using a Mendelian randomization approach (Methods).…”

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confidence: 65%

Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases

et al. 2018

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Clinical measurements can be viewed as useful intermediate phenotypes to promote understanding of complex human diseases. To acquire comprehensive insights into the underlying genetics, here we conducted a genome-wide association study (GWAS) of 58 quantitative traits in 162,255 Japanese individuals. Overall, we identified 1,407 trait-associated loci (P < 5.0 × 10), 679 of which were novel. By incorporating 32 additional GWAS results for complex diseases and traits in Japanese individuals, we further highlighted pleiotropy, genetic correlations, and cell-type specificity across quantitative traits and diseases, which substantially expands the current understanding of the associated genetics and biology. This study identified both shared polygenic effects and cell-type specificity, represented by the genetic links among clinical measurements, complex diseases, and relevant cell types. Our findings demonstrate that even without prior biological knowledge of cross-phenotype relationships, genetics corresponding to clinical measurements successfully recapture those measurements' relevance to diseases, and thus can contribute to the elucidation of unknown etiology and pathogenesis.

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Section: And Supplementarysupporting

confidence: 65%

Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases

et al. 2018

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“…[1] Mendelian randomization (MR) studies, taking advantage of the random allocation of genetic endowment at conception to obtain un-confounded estimates, [2] have clarified the role of liver function in T2DM. Specifically, these studies suggest that higher alanine aminotransferase (ALT) [3,4] or aspartate aminotransferase (AST) [4] rather than other measures of liver function, such as glutamyltransferase (GGT), [3,4] could play a role in T2DM. However, modifiable targets on the pathway from poor liver function to T2DM are unclear and worthy of exploration.…”

Section: Introductionmentioning

confidence: 99%

The effect of liver enzymes on body composition: A Mendelian randomization study

et al. 2020

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BackgroundHigher alanine transaminase (ALT), indicating poor liver function, is positively associated with diabetes but inversely associated with body mass index (BMI) in Mendelian randomization (MR) studies, suggesting liver function affects muscle mass. To clarify, we assessed the associations of liver enzymes with muscle and fat mass observationally with two-sample MR as a validation. MethodsIn the population-representative "Children of 1997" birth cohort (n = 3,455), we used multivariable linear regression to assess the adjusted associations of ALT and alkaline phosphatase (ALP) at~17.5 years with muscle mass and body fat percentage observationally. Genetic variants predicting ALT, ALP and gamma glutamyltransferase (GGT) were applied to fat-free and fat mass in the UK Biobank (n =~331,000) to obtain unconfounded MR estimates. ResultsObservationally, ALT was positively associated with muscle mass (0.11 kg per IU/L, 95% confidence interval (CI) 0.10 to 0.12) and fat percentage (0.15% per IU/L, 95% CI 0.13 to 0.17). ALP was inversely associated with muscle mass (-0.03 kg per IU/L, 95% CI -0.04 to -0.02) and fat percentage (-0.02% per IU/L, 95% CI -0.03 to -0.01). Using MR, ALT was inversely associated with fat-free mass (-0.41 kg per 100% in concentration, 95% CI -0.64 to -0.19) and fat mass (-0.58 kg per 100% in concentration, 95% CI -0.85 to -0.30). ALP and GGT were unclearly associated with fat-free mass or fat mass. GM, et al. (2020) The effect of liver enzymes on body composition: A Mendelian randomization study. PLoS ONE 15(2): e0228737. ConclusionALT reducing fat-free mass provides a possible pathway for the positive association of ALT with diabetes and suggests a potential target of intervention.Liver enzymes on body composition PLOS ONE | https://doi.org/10.

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“…Abnormal serum ALT levels are found in a variety of liver diseases such as viral hepatitis, alcoholic liver disease, or nonalcoholic fatty liver disease (NAFLD). The risk of cardiovascular disease such as ischemic heart disease or type 2 diabetes mellitus also increases in the case of elevated ALT levels [4,5]. Furthermore, the risk of MS increases in participants with elevated ALT levels [6,7].…”

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confidence: 99%

Risk of metabolic syndrome in participants within the normal range of alanine aminotransferase: A population-based nationwide study

2020

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This study aimed to investigate the risk of metabolic syndrome (MS) in participants whose alanine aminotransferase (ALT) levels were within the normal range in the general population. A cross-sectional study was conducted using nationally representative samples from the Korea National Health and Nutrition Examination Survey 2007-2015. A total of 43,402 adults (men, 17,535; women, 25,867) with ALT �40 U/L without a history of hepatitis B and C, liver cirrhosis, or liver cancer were analyzed. The risk of MS was evaluated according to the ALT level. The prevalence of MS significantly increased as the ALT levels increased. The proportions of MS in men were 12.6%, 25.2%, and 39.7% in the ALT levels of <15, 15~30, and 30~40 U/L, respectively (p < 0.001), and those of women were 7.2%, 23.3%, and 44.7% in the ALT levels of <10, 10~20, and 20~40 U/L, respectively (p < 0.001). There was an ALT-dependent relationship in the risk of MS in participants with normal ALT level after adjustment for age, alcohol intake, and body mass index. The adjusted odds ratio (aOR) of MS in men was 2.48 (95% confidence interval [CI], 2.16-2.85) in an ALT level of 30~40 U/L compared with that in ALT <15 U/L (p < 0.001), and the aOR of MS in women was 2.67 (95% CI, 2.26-3.15) in an ALT level of 20~40 U/L compared with that in ALT <10 U/L (p < 0.001). Although within the normal range of ALT, the risk of MS increases as the ALT levels increase. The ALT level in the general population without a history of chronic liver disease may be a useful marker to evaluate for MS. OPEN ACCESS Citation: Cho J-Y, Jeong JY, Sohn W (2020) Risk of metabolic syndrome in participants within the normal range of alanine aminotransferase: A population-based nationwide study. PLoS ONE 15 (4): e0231485. https://doi.org/10.Metabolic syndrome with the normal range of ALT PLOS ONE | https://doi.org/10.1371/journal.pone.

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Liver Enzymes and Risk of Ischemic Heart Disease and Type 2 Diabetes Mellitus: A Mendelian Randomization Study

Cited by 50 publications

References 50 publications

Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases

Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases

The effect of liver enzymes on body composition: A Mendelian randomization study

Risk of metabolic syndrome in participants within the normal range of alanine aminotransferase: A population-based nationwide study

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