A <scp>STAT</scp>4 variant increases liver fibrosis risk in Caucasian patients with chronic hepatitis B

Sharkawy, Rasha El; Thabet, Khaled; Lampertico, Pietro; Petta, Salvatore; Mangia, Alessandra; Berg, Thomas; Metwally, Mostafa; Bayoumi, Ali; Boonstra, André; Brouwer, Willem Pieter; Smedile, A.; Abate, Maria Lorena; Loglio, Alessandro; Douglas, Mark W.; Khan, A.; Santoro, Rosanna; Fischer, Janett; Leeming, Diana Julie; Liddle, Christopher; George, Jacob; Eslam, Mohammed

doi:10.1111/apt.14866

Cited by 20 publications

(31 citation statements)

References 39 publications

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“…Whether the above findings can be replicated in Caucasian patients infected with hepatitis B or with the early stages of histologically characterised disease, and the underlying mechanisms for the effect are largely unknown. We demonstrated in a large cohort (n = 830), that STAT4 rs7574865 is associated with liver inflammation and fibrosis . Consistent with other reports, STAT4 rs7574865 regulated STAT4 expression in peripheral blood mononuclear cells (PBMC), natural killer (NK) cells and liver.…”

supporting

confidence: 90%

Editorial: STAT‐4 polymorphism ‐ a tool to personalise clinical practice in chronic HBV infection. Authors’ reply

Sharkawy

George

Eslam

2018

Aliment Pharmacol Ther

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supporting

confidence: 90%

Editorial: STAT‐4 polymorphism ‐ a tool to personalise clinical practice in chronic HBV infection. Authors’ reply

Sharkawy

George

Eslam

2018

Aliment Pharmacol Ther

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“…In addition, several studies investigating polymorphisms in HCC patients have identified a specific STAT4 polymorphism (rs7574865) which increases the risk of HBV-related HCC in several cohorts, including Chinese, Thai, Korean, Vietnamese and Caucasian. This specific rs7574865 STAT4 variant also showed a corresponding reduction in STAT4 mRNA expression levels [72][73][74][75][76]. However, there are still no conclusive studies detailing the exact role of the variant.…”

Section: The Role Of Other Stats In Hccmentioning

confidence: 94%

JAK/STAT signaling in hepatocellular carcinoma

et al. 2020

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Liver cancer is the second most lethal cancer in the world with limited treatment options. Hepatocellular carcinoma (HCC), which accounts for more than 80% of all liver cancers, has had increasing global incidence over the past few years. There is an urgent need for novel and better therapeutic intervention for HCC patients. The JAK/STAT signaling pathway plays a multitude of important biological functions in both normal and malignant cells. In a subset of HCC, JAK/STAT signaling is aberrantly activated, leading to dysregulation of downstream target genes that controls survival, angiogenesis, stemness, immune surveillance, invasion and metastasis. In this review, we will focus on the role of JAK/STAT signaling in HCC and discuss the current clinical status of several JAK/STAT inhibitors.

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“…Stage 3 analysis included replicating SNPs as well as SNPs that have been previously reported to associate with cirrhosis in subpopulations, as described in the introduction (Table ) . As above, we included only SNPs with minor allele count >6 in the European populations of UKBB and MGI, which corresponded to minor allele frequency >0.006.…”

Section: Methodsmentioning

confidence: 99%

Genetic variants that associate with cirrhosis have pleiotropic effects on human traits

Chen

et al. 2020

Liver International

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Background and Aims Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver‐related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. Methods We carried out a genome‐wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top‐associating loci for replication with cirrhosis in a hospital‐based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. Results Unbiased genome‐wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase‐to‐platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. Conclusions We identified eight loci that reproducibly associate with population‐based cirrhosis and define their diverse effects on human diseases and traits.

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A STAT4 variant increases liver fibrosis risk in Caucasian patients with chronic hepatitis B

Abstract: Genetic susceptibility to HBV persistence, hepatic inflammation and fibrosis in Caucasians associates with STAT4 rs7574865 variant. Downstream effects on NK cell function through STAT4 phosphorylation-dependent IFN-γ production likely contribute to these effects.

Cited by 20 publications

References 39 publications

Editorial: STAT‐4 polymorphism ‐ a tool to personalise clinical practice in chronic HBV infection. Authors’ reply

Editorial: STAT‐4 polymorphism ‐ a tool to personalise clinical practice in chronic HBV infection. Authors’ reply

JAK/STAT signaling in hepatocellular carcinoma

Genetic variants that associate with cirrhosis have pleiotropic effects on human traits

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