scholarly journals Insights into genetic variants associated with NASH-fibrosis from metabolite profiling

2020 ◽  
Vol 29 (20) ◽  
pp. 3451-3463 ◽  
Author(s):  
Jake P Mann ◽  
Maik Pietzner ◽  
Laura B Wittemans ◽  
Emmanuela De Lucia Rolfe ◽  
Nicola D Kerrison ◽  
...  
Keyword(s):  
Metabolite Profile ◽  
Population Based ◽  
Liver Fat ◽  
Gene Variants ◽  
Single Nucleotide Variants ◽  
Metabolomics Data ◽  
Alcoholic Fatty Liver ◽  
Risk Alleles ◽  
Protective Variant ◽  
Molecular Patterns

Abstract Several genetic discoveries robustly implicate five single-nucleotide variants in the progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and fibrosis (NASH-fibrosis), including a recently identified variant in MTARC1. To better understand these variants as potential therapeutic targets, we aimed to characterize their impact on metabolism using comprehensive metabolomics data from two population-based studies. A total of 9135 participants from the Fenland study and 9902 participants from the EPIC-Norfolk cohort were included in the study. We identified individuals with risk alleles associated with NASH-fibrosis: rs738409C>G in PNPLA3, rs58542926C>T in TM6SF2, rs641738C>T near MBOAT7, rs72613567TA>T in HSD17B13 and rs2642438A>G in MTARC1. Circulating levels of 1449 metabolites were measured using targeted and untargeted metabolomics. Associations between NASH-fibrosis variants and metabolites were assessed using linear regression. The specificity of variant-metabolite associations were compared to metabolite associations with ultrasound-defined steatosis, gene variants linked to liver fat (in GCKR, PPP1R3B and LYPLAL1) and gene variants linked to cirrhosis (in HFE and SERPINA1). Each NASH-fibrosis variant demonstrated a specific metabolite profile with little overlap (8/97 metabolites) comprising diverse aspects of lipid metabolism. Risk alleles in PNPLA3 and HSD17B13 were both associated with higher 3-methylglutarylcarnitine and three variants were associated with lower lysophosphatidylcholine C14:0. The risk allele in MTARC1 was associated with higher levels of sphingomyelins. There was no overlap with metabolites that associated with HFE or SERPINA1 variants. Our results suggest a link between the NASH-protective variant in MTARC1 to the metabolism of sphingomyelins and identify distinct molecular patterns associated with each of the NASH-fibrosis variants under investigation.

A Replication Study of Gene Variants Associated with Venous Thrombosis. Results From a Population-Based Nested Case-Cohort Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3985-3985 ◽  
Author(s):  
Willem M Lijfering ◽  
Irene D Bezemer ◽  
Sverre C Christiansen ◽  
Inger-Anne Naess ◽  
Frits Rosendaal ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Venous Thrombosis ◽  
Population Based ◽  
Gene Variants ◽  
Odds Ratios ◽  
Population Based Study ◽  
Vein Thrombosis ◽  
Risk Alleles ◽  
Increased Risk ◽  
Deep Vein

Abstract Abstract 3985 Poster Board III-921 Background Venous thrombosis has genetic and acquired risk factors, and it has been proposed that several risk factors are needed for the occurrence of the disease. The identification of common gene variants associated with venous thrombosis may improve the ability to predict the risk and understanding of this disease. In a recent study, we aimed to identify genetic variants that are associated with deep vein thrombosis in individuals aged younger than 70 years (JAMA 2008; 299:1306-14). Of nearly 20000 single nucleotide polymorphisms (SNPs) that were genotyped, 7 SNPs were associated with deep vein thrombosis (range odds ratios, 1.1-1.3). However, studies of thousands of SNPs can lead to false-positive associations. Replication studies are therefore pivotal to account for false-positive associations. Objective To assess the risk of venous thrombosis of aforementioned SNPs in a large population based study. Methods From the residents of Nord-Trøndelag county in Norway aged 20 years and older (n = 94194), we identified all patients with an objectively verified diagnosis of venous thrombosis that occurred between 1995 and 2001. By this date we had registered 515 patients with a first venous thrombosis; an age- and sex-stratified random sample of 1476 controls without previous venous thrombosis was drawn from the original cohort. Patients and diagnosis characteristics were retrieved from medical records. Of the 7 SNPs that were associated with deep vein thrombosis in our previous study, 6 were analyzed in the present study, i.e. rs13146272 in CYP4V2; rs2227589 in SERPINC1; rs1613662 in GP6; rs670659 in RGS7; rs1523127 in NR1I2; and rs6048 in F9. DNA concentrations were standardized to 10 ng/μL using PicoGreen (Molecular Probes, Invitrogen Corp, Carlsbad, CA, USA) fluorescent dye. Genotyping of individual DNA samples were demonstrated by polymerase chain reactions using the TaqMan assay. The technicians were blinded to whether the samples came from patients or control subjects. Results The median age of both cases and controls at baseline was 70 years (range, 20-98). Almost half of patients and controls were men. Two thirds of the patients had deep vein thrombosis and one third had pulmonary embolism. Among the 515 events, 246 were idiopathic (48%). The prevalences of the 6 analyzed risk alleles were 17-96% in the patients and 16-96% in the control group. Only the F9 (rs6048) risk allele in men was consistently associated with an increased risk of venous thrombosis with odds ratios of 1.27 (95% CI, 0.83-1.93) for deep vein thrombosis, 1.62 (95% CI, 0.91-2.89) for pulmonary embolism, and 1.38 (95% CI, 0.97-1.97) for total venous thrombosis. For all other risk alleles we found odds ratios for venous thrombosis close to 1.0 compared to their reference allele. Odds ratios for provoked or idiopathic venous thrombosis again showed that only the F9 risk allele in men was consistently associated with an increased risk with an odds ratio of 1.30 (95% CI, 0.82-2.08) for provoked venous thrombosis and 1.47 (95% CI, 0.90-2.38) for idiopathic venous thrombosis, respectively, compared to men with the G allele. To make the current analysis more similar with our previous study, we restricted the analysis to those who were younger than 70 years. This resulted in slightly higher odds ratios for venous thrombosis in CYP4V2, SERPINC1 and GP6 variants (Table). Conclusion This population based study confirmed the previous finding that men with the A allele of rs6048 in F9 have an increased risk of venous thrombosis, while we could not replicate the association of gene variants in CYP4V2, SERPINC1, GP6, RGS7 and NR1I2 with venous thrombosis, possibly excepted for CYP4V2, SERPINC1 and GP6 gene variants in individuals aged younger than 70 years. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Associations between Free Sugar and Sugary Beverage Intake in Early Childhood and Adult NAFLD in a Population-Based UK Cohort

Children ◽  
2021 ◽  
Vol 8 (4) ◽  
pp. 290
Author(s):  
Ahlia Sekkarie ◽  
Jean A. Welsh ◽  
Kate Northstone ◽  
Aryeh D. Stein ◽  
Usha Ramakrishnan ◽  
...  
Keyword(s):  
Total Energy ◽  
Hepatic Steatosis ◽  
Population Based ◽  
Free Sugar ◽  
Alcoholic Fatty Liver ◽  
Free Sugars ◽  
Logistic Regression Models ◽  
Sugar Intake ◽  
Sugary Beverages ◽  
Alcoholic Fatty Liver Disease

(1) Background: High sugar intake is prevalent among children and is associated with non-alcoholic fatty liver disease (NAFLD). The purpose of this study is to determine if a high intake of free sugars and sugary beverages (SB) in childhood is associated with NAFLD in adulthood; (2) Methods: At 24 years, 3095 participants were assessed for severe hepatic steatosis (controlled attenuation parameter >280 dB/m) and had dietary data collected via a food frequency questionnaire at age three years. Multiple logistic regression models adjusted for total energy intake, potential confounders, and a mediator (offspring body mass index (BMI) at 24 years); (3) Results: Per quintile increase of free sugar intake association with severe hepatic steatosis at 24 years after adjusting for total energy was odds ratio (OR):1.07 (95% CL: 0.99–1.17). Comparing the lowest vs. the highest free sugar consumers, the association was OR:1.28 (95% CL: 0.88–1.85) and 1.14 (0.72, 1.82) after full adjustment. The OR for high SB consumption (>2/day) compared to <1/day was 1.23 (95% CL: 0.82–1.84) and OR: 0.98 (95% CL: 0.60–1.60) after full adjustment; (4) Conclusions: High free sugar and SB intake at three years were positively but weakly associated with severe hepatic steatosis at 24 years. These associations were completely attenuated after adjusting for confounders and 24-year BMI.

scholarly journals Relationship between Muscle Mass and Non-Alcoholic Fatty Liver Disease

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 122
Author(s):  
Jun-Hyuk Lee ◽  
Hye-Sun Lee ◽  
Byoung-Kwon Lee ◽  
Yu-Jin Kwon ◽  
Ji-Won Lee
Keyword(s):  
Skeletal Muscle ◽  
Risk Factor ◽  
Liver Disease ◽  
Fatty Liver ◽  
Muscle Mass ◽  
Fatty Liver Disease ◽  
Skeletal Muscle Mass ◽  
Liver Fat ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Although sarcopenia is known to be a risk factor for non-alcoholic fatty liver disease (NAFLD), whether NAFLD is a risk factor for the development of sarcopenia is not clear. We investigated relationships between NAFLD and low skeletal muscle mass index (LSMI) using three different datasets. Participants were classified into LSMI and normal groups. LSMI was defined as a body mass index (BMI)-adjusted appendicular skeletal muscle mass <0.789 in men and <0.512 in women or as the sex-specific lowest quintile of BMI-adjusted total skeletal muscle mass. NAFLD was determined according to NAFLD liver fat score or abdominal ultrasonography. The NAFLD groups showed a higher hazard ratios (HRs) with 95% confidence intervals (CIs) for LSMI than the normal groups (HRs = 1.21, 95% CIs = 1.05–1.40). The LSMI groups also showed a higher HRs with 95% CIs for NAFLD than normal groups (HRs = 1.56, 95% CIs = 1.38–1.78). Participants with NAFLD had consistently less skeletal muscle mass over 12 years of follow-up. In conclusion, LSMI and NAFLD showed a relationship. Maintaining muscle mass should be emphasized in the management of NAFLD.

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