Genome‐wide Association Study and Meta‐analysis on Alcohol‐Associated Liver Cirrhosis Identifies Genetic Risk Factors

Schwantes‐An, Tae‐Hwi; Darlay, Rebecca; Maury, Philippe; Masson, Steven; Liangpunsakul, Suthat; Mueller, Sebastian; Aithal, Guruprasad P.; Eyer, Florian; Gleeson, Dermot; Thompson, Andrew; Muellhaupt, Beat; Stickel, Felix; Soyka, Michael; Goldman, David; Liang, Tiebing; Lumeng, Lawrence; Pirmohamed, Munir; Nalpas, Bertrand; Jacquet, Jean‐Marc; Moirand, Romain; Nahon, Pierre; Naveau, Sylvie; Perney, Pascal; Botwin, Greg; Haber, Paul S.; Seitz, Helmut K.; Day, Christopher P.; Foroud, Tatiana; Daly, Ann K.; Cordell, Heather J.; Whitfield, John B.; Morgan, Timothy R.; Seth, Devanshi

doi:10.1002/hep.31535

Cited by 70 publications

(76 citation statements)

References 53 publications

(95 reference statements)

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“…3 Recently, a common coding variant (MTARC1 p.Ala165Thr) was reported to be associated with protection against NAFLD and its progression, [4][5][6] as well as protection from alcohol-related and all-cause cirrhosis. 7,8 Other reports indicated that NAFLD severity was reduced in MTARC1 p.Ala165Thr carriers. 9,10 MTARC1, the mitochondrial amidoxime-reducing component 1 gene, encodes the mitochondrial amidoxime-reducing component, which is involved in metabolic processes in the liver (e.g., activating N-hydroxylated prodrugs or reducing nitrite to produce nitric oxide).…”

Section: Context and Significancementioning

confidence: 99%

A genome-first approach to mortality and metabolic phenotypes in MTARC1 p.Ala165Thr (rs2642438) heterozygotes and homozygotes

Schneider

Conlon

et al. 2021

Med

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Section: Context and Significancementioning

confidence: 99%

A genome-first approach to mortality and metabolic phenotypes in MTARC1 p.Ala165Thr (rs2642438) heterozygotes and homozygotes

Schneider

Conlon

et al. 2021

Med

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“…The protective role of UBXN3B in these disease conditions in mice may be potentially applicable to those in humans considering that the UBXN3B protein is highly conserved in mammals (98% identity between human and rodent protein). Importantly, an rs374702773 (delta T allele in intron) in UBXN3B is associated with protection against alcoholic liver cirrhosis, a chronic inflammatory condition in humans 51 .…”

Section: Discussionmentioning

confidence: 99%

An Essential Role of UBXN3B in B Lymphopoiesis

Geng

Yang

Lin

et al. 2021

Preprint

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Hematopoiesis is finely regulated to enable timely production of the right number and type of mature immune cells to maintain tissue homeostasis. Dysregulated hematopoiesis may compromise antiviral immunity and/or exacerbate immunopathogenesis. Herein, we report an essential and new role of ubiquitin X domain containing gene 3B (UBXN3B) in balancing myelopoiesis and lymphopoiesis. Ubxn3b deficiency (Ubxn3b−/−) results in a remarkable increase in myeloid cells and neutrophil-to-lymphocyte ratio, along with a reduction in lymphocytes in steady-state mice. This dysregulation is exacerbated during viral infection and renders mice highly vulnerable to severe lung pathology induced by severe acute respiratory syndrome coronavirus 2 and arthritis by arthritogenic alphaviruses. Ubxn3b−/− mice present normal type I IFNs, higher viral loads and inflammatory mediators, lower virus-specific immunoglobulin G and slower resolution of disease, when compared to Ubxn3b+/+ littermates. Mechanistically, Ubxn3b−/− mice have fewer multipotent progenitors and common lymphoid progenitors, but more common myeloid progenitors. In particular, the precursor and immature B cell numbers are dramatically decreased in the bone marrow of Ubxn3b−/− mice. These data demonstrate that UBXN3B signaling is essential for restricting viral infection and immunopathogenesis by maintaining hematopoietic homeostasis.

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“…The occurrence of single nucleotide variants rs738409 in PNPLA and rs58542926 in transmembrane 6 superfamily member 2 (TM6SF2) associate with the risk of hepatocellular carcinoma, whereas variant rs4607179 of hydroxysteroid 17-beta dehydrogenase (HSD17B13) reduces the risk [213]. In a genome-wide association study, variants rs738409 of PNPLA and rs4607179 of HSD17B13 show significant association with the appearance of alcohol-associated liver cirrhosis, and rs374702773 of Fas-associated factor family member 2 (FASF2) shows a protective association [206].…”

Section: Gene Variantsmentioning

confidence: 99%

Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers.

Rodríguez

Coveñas

2021

Preprint

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The World Health Organization identifies alcohol as a cause in several neoplasias of the oro-pharynx cavity, esophagus, gastrointestinal tract, larynx, liver, or female breast. This study re-views ethanol's nonoxidative and oxidative metabolism and one-carbon metabolism that en-compasses both redox and transfer reactions that influence crucial cell proliferation machinery. Ethanol favors the uncontrolled production and action of free radicals that interfere with the maintenance of essential cellular functions. We focus on the generation of protein, DNA, and lipid adducts that interfere with the cellular processes related to growth and differentiation. Ethanol's effects on stem cells responsible for building and repairing tissues are reviewed. Cancer stem cells suffer disturbances related to the expression of cell surface markers, enzymes, and transcription factors after ethanol exposure with consequent dysregulation of mechanisms related to cancer metastasis or resistance to treatments. Our analysis aims to underlie and discuss potential targets that show more sensitivity to ethanol's action and identify specific metabolic routes and metabolic realms that may be corrected to recover metabolic homeostasis after pharmacological interven-tion. Specifically, research should pay attention to reestablish metabolic fluxes by fine-tuning the functioning of specific pathways related to one-carbon metabolism and antioxidant processes.

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Genome‐wide Association Study and Meta‐analysis on Alcohol‐Associated Liver Cirrhosis Identifies Genetic Risk Factors

Abstract: 25,26,28 **, for the GenomALC ConsortiumBaCKgRoUND aND aIMS: Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC.

Cited by 70 publications

References 53 publications

A genome-first approach to mortality and metabolic phenotypes in MTARC1 p.Ala165Thr (rs2642438) heterozygotes and homozygotes

A genome-first approach to mortality and metabolic phenotypes in MTARC1 p.Ala165Thr (rs2642438) heterozygotes and homozygotes

An Essential Role of UBXN3B in B Lymphopoiesis

Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers.

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