Human genetics of metabolic dysfunction–associated steatotic liver disease: from variants to cause to precision treatment DOI Creative Commons
Vincent Chen, Annapurna Kuppa, Antonino Oliveri

et al.

Journal of Clinical Investigation, Journal Year: 2025, Volume and Issue: 135(7)

Published: March 31, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by increased hepatic steatosis with cardiometabolic and a leading cause of advanced disease. We review here the genetic basis MASLD. The variants most consistently associated implicate genes involved in lipoprotein input or output, glucose metabolism, adiposity/fat distribution, insulin resistance, mitochondrial/ER biology. distinct mechanisms which these promote result effects on that may be best suited to precision medicine. Recent work gene-environment interactions has shown risk not fixed exacerbated attenuated modifiable (diet, exercise, alcohol intake) nonmodifiable environmental factors. Some steatosis-associated variants, notably those patatin-like phospholipase domain-containing 3 (PNPLA3) transmembrane 6 superfamily member 2 (TM6SF2), are developing adverse liver-related outcomes provide information beyond clinical stratification tools, especially individuals at intermediate high for Future better characterize heterogeneity combining genetics factors holistically predict develop therapies based required.

Language: Английский

The role of hepatokines in NAFLD DOI Creative Commons
Norbert Stefan, Fritz Schick, Andreas L. Birkenfeld

et al.

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(2), P. 236 - 252

Published: Feb. 1, 2023

Language: Английский

Citations

150
Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease DOI
Yanhua Chen,

Xiaomeng Du,

Annapurna Kuppa

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(10), P. 1640 - 1650

Published: Sept. 14, 2023

Language: Английский

Citations

90
Therapeutic opportunities for the treatment of NASH with genetically validated targets DOI Open Access
Daniel Lindén, Stefano Romeo

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(4), P. 1056 - 1064

Published: May 17, 2023

Language: Английский

Citations

48
Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) on heart, muscle, and kidney related diseases DOI Creative Commons

Reddemma Sandireddy,

Suganya Sakthivel,

Priyanka Gupta

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: July 16, 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty (NAFLD), is the most common disorder worldwide, with an estimated global prevalence of more than 31%. steatohepatitis (MASH), formerly (NASH), a progressive form MASLD characterized by hepatic steatosis, inflammation, and fibrosis. This review aims to provide comprehensive analysis extrahepatic manifestations MASH, focusing on chronic diseases related cardiovascular, muscular, renal systems. A systematic published studies literature was conducted summarize findings systemic impacts MASH. The focused association MASH metabolic comorbidities, cardiovascular mortality, sarcopenia, kidney disease. Mechanistic insights into concept lipotoxic inflammatory "spill over" from MASH-affected were also explored. are highly associated (50%-80%) other comorbidities such impaired insulin response, type 2 diabetes, dyslipidemia, hypertriglyceridemia, hypertension. Furthermore, 90% obese patients diabetes have Data suggest that in middle-aged individuals (especially those aged 45-54), independent risk factor for plays crucial role mediating pathological effects observed. Understanding multifaceted impact heart, muscle, early detection stratification. knowledge timely implementing management strategies addressing multi-organ involvement pathogenesis.

Language: Английский

Citations

27
Opportunities and barriers in omics-based biomarker discovery for steatotic liver diseases DOI Creative Commons
Maja Thiele, Ida Falk Villesen, Lili Niu

et al.

Journal of Hepatology, Journal Year: 2024, Volume and Issue: 81(2), P. 345 - 359

Published: March 28, 2024

The rising prevalence of liver diseases related to obesity and excessive use alcohol is fuelling an increasing demand for accurate biomarkers aimed at community screening, diagnosis steatohepatitis significant fibrosis, monitoring, prognostication prediction treatment efficacy. Breakthroughs in omics methodologies the power bioinformatics have created excellent opportunity apply technological advances clinical needs, instance development precision personalised medicine. Via technologies, biological processes from genes circulating protein, as well microbiome - including bacteria, viruses fungi, can be investigated on axis. However, there are important barriers omics-based biomarker discovery validation, semi-quantitative measurements untargeted platforms, which may exhibit high analytical, inter- intra-individual variance. Standardising methods need validate them across diverse populations presents a challenge, partly due disease complexity dynamic nature expression different stages. Lack validity causes lost opportunities when studies fail provide knowledge needed regulatory approvals, all contributes delayed translation these discoveries into practice. While no matured implementation, extent data generated has enabled hypothesis-free plethora candidate that warrant further validation. To explore many hepatologists detailed commonalities differences between various layers, both advantages approaches.

Language: Английский

Citations

19
Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis DOI Creative Commons
Jonas Ghouse, Garðar Sveinbjörnsson, Marijana Vujković

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(5), P. 827 - 837

Published: April 17, 2024

Abstract We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals function tests validation cohort of 21,689 617,729 we identify validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One these, PNPLA3 p.Ile148Met, interacts alcohol intake, obesity diabetes the hepatocellular carcinoma (HCC). develop polygenic score that associates progression HCC. By focusing prioritized common variant analyses, find rare coding GPAM associate lower ALT, supporting as potential target therapeutic inhibition. In conclusion, this provides insights into genetic underpinnings

Language: Английский

Citations

19
Metabolic dysfunction-associated steatotic liver disease in adults DOI
Daniel Q. Huang, Vincent Wai–Sun Wong, Mary E. Rinella

et al.

Nature Reviews Disease Primers, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 6, 2025

Language: Английский

Citations

6
MAFLD: Exploring the Systemic Effects Beyond Liver. DOI Creative Commons
Utkarsh Dayal, Ujjwal Soni, Sourav Bansal

et al.

Journal of Community Hospital Internal Medicine Perspectives, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 4, 2025

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a growing global health concern which driven by the increasing prevalence of diabetes and obesity. MAFLD characterized excessive fat accumulation in liver, encompasses range conditions, from simple hepatic steatosis to more severe forms. This condition associated with various complications, including chronic kidney (CKD), Cardiovascular Disease (CVD), cirrhosis, even malignancy. Recent research has highlighted potential connection between gut dysbiosis MAFLD, particularly relation CKD. underscored significance gut-liver-kidney axis understanding MAFLD's pathogenesis. Inflammation triggered increases risk CVD through multiple mechanisms linked metabolic dysfunction. These include heightened oxidative stress, systemic insulin resistance, low-grade inflammation, endothelial Hepatic dysfunction are major diagnostic criteria for often coexisting other ailments. prospective review emphasizes intricate associations cardiovascular renal issues, diseases. Understanding underlying pathophysiological pathways crucial comprehending increased CKD, CVD, complications individuals MAFLD.

Language: Английский

Citations

4
The hepato-ovarian axis: genetic evidence for a causal association between non-alcoholic fatty liver disease and polycystic ovary syndrome DOI Creative Commons
Dong Liu, Xue Gao, Xiong‐Fei Pan

et al.

BMC Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Feb. 20, 2023

Recent studies found associations between non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS), but the causal nature of this association is still uncertain.We performed a bidirectional two-sample Mendelian randomization (MR) analysis to test for NAFLD PCOS using data from large-scale biopsy-confirmed genome-wide study (GWAS) (1483 cases 17,781 controls) GWAS (10,074 103,164 in European ancestries. Data glycemic-related traits (in up 200,622 individuals) sex hormones 189,473 women) UK Biobank (UKB) were used MR mediation assess potential mediating roles these molecules pathway PCOS. Replication was conducted two independent datasets GWASs UKB meta-analysis FinnGen Estonian Biobank, respectively. A linkage disequilibrium score regression genetic correlations NAFLD, PCOS, traits, full summary statistics.Individuals with higher liability more likely develop (OR per one-unit log odds increase NAFLD: 1.10, 95% CI: 1.02-1.18; P = 0.013). Indirect effects on via fasting insulin only (OR: 1.02, 1.01-1.03; 0.004) further suggestive indirect effect concert androgen levels revealed analyses. However, conditional F statistics less than 10, suggesting weak instrument bias MVMR analyses.Our suggests that genetically predicted associated risk developing evidence vice versa. Fasting might mediate link

Language: Английский

Citations

41
Genetics and epidemiology of mutational barcode-defined clonal hematopoiesis DOI Creative Commons
Simon Stacey,

Florian Zink,

Gísli H. Halldórsson

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(12), P. 2149 - 2159

Published: Nov. 6, 2023

Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from single hematopoietic stem cell lineage. Using whole-genome sequencing 45,510 Icelandic and 130,709 UK Biobank participants combined with mutational barcode method, we identified 16,306 people CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates dosage-dependent impact on risk CH associates several smoking-related diseases. Contrary to published claims, find no evidence that associated cardiovascular disease. We provide driven by genes are commonly mutated myeloid neoplasia implicate new driver genes. The presence nature mutation alters the profile for hematological disorders. Nevertheless, most cases have known mutations. A genome-wide association study 25 loci, including 19 not implicated previously Splicing, protein expression quantitative trait loci were CD164 TCL1A.

Language: Английский

Citations

41