MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease

Petta, Salvatore; Valenti, Luca; Marra, Fabio; Grimaudo, Stefania; Tripodo, Claudio; Bugianesi, Elisabetta; Cammà, Calogero; Cappon, A.; Marco, V. Di; Maira, Giovanni Di; Dongiovanni, Paola; Rametta, Raffaela; Gulino, Alessandro; Mozzi, Enrico; Orlando, Elisabetta; Maggioni, Marco; Pipitone, Rosaria Maria; Fargion, Silvia; Craxı̀, Antonio

doi:10.1016/j.jhep.2015.10.016

Cited by 109 publications

(130 citation statements)

References 32 publications

Supporting

Mentioning

124

Contrasting

Order By: Relevance

“…Later, the MERTK SNP significantly added risk to accelerated fibrosis progression rate in the Swiss Hepatitis C Cohort Study [10]. Interestingly, a recent study also showed that the rs4374383 AA genotype was protective against F2-F4 fibrosis in patients with NAFLD [32]. One of the potential explanations for differences between the previously published data and our results could be linked to the sample size of our patient groups.…”

Section: Discussioncontrasting

confidence: 52%

PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population

Kupčinskas

Valantienė

Varkalaitė

et al. 2017

JGLD

View full text Add to dashboard Cite

Background & Aims: Genome-wide association studies have revealed an association between the risk of developing liver fibrosis or cirrhosis and the single nucleotide polymorphisms (SNPs) of the PNPLA3, RNF7, MERTK and PCSK7 genes. We aimed to validate these results in an Eastern European population.Methods: We evaluated the associations between the PNPLA3 (rs738409), RNF7 (rs16851720), MERTK (rs4374383) and PCSK7 (rs236918) variants and liver fibrosis and cirrhosis in a series of consecutive patients recruited at the Department of Gastroenterology, Lithuanian University of Health Sciences Hospital, during the period 2012-2015. The study included 317 individuals with liver cirrhosis, 154 individuals with liver fibrosis, and 498 controls. The studied SNPs were determined using RT-PCR TaqMan assays.Results: MERTK and PCSK7 SNPs were not associated with liver fibrosis or cirrhosis. The PNPLA3 SNP rs738409 was associated with a higher risk of developing liver fibrosis (aOR: 1.65, P=0.001) and cirrhosis (aOR: 1.92, P=5.57*10-7). PNPLA3 genotypes were also associated with higher risk of developing liver fibrosis and cirrhosis in dominant (aOR: 1.98, P=2.20*10-5; aOR: 1.67, P=0.008, respectively) and recessive (aOR: 3.94, P=5.16*10-5; aOR: 3.02, P=0.003, respectively) models. RNF7 rs16851720 was associated with liver cirrhosis comparing CC vs. AA + CA genotypes (aOR: 0.26, P=0.020).Conclusion: Our study showed that PNPLA3 rs738409 and RNF7 rs16851720 confer an increased risk of developing liver fibrosis and cirrhosis in this Eastern European population, while the MERTK and PCSK7 SNPs are not associated with these conditions.Abbreviations: GWAS: Genome-wide association studies; HBV: hepatitis B virus; HCV: hepatitis C virus; HH: hereditary hemochromatosis; MERTK: proto-oncogene tyrosine-protein kinase MER; NAFLD: non-alcoholic fatty liver disease; PCSK7: proprotein convertase 7; PNPLA3: patatin-like phospholipase domain containing 3; RNF7: SAG sensitive to apoptosis gene; SNP: single nucleotide polymorphism.

show abstract

Section: Discussioncontrasting

confidence: 52%

PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population

Kupčinskas

Valantienė

Varkalaitė

et al. 2017

JGLD

View full text Add to dashboard Cite

show abstract

“…In a very recent study on more than 600 biopsied patients with suspected NASH, the presence of clinically significant fibrosis (F2-F4) was also associated with the absence of MERTK AA genotype, after correction for confounders and for both PNPLA3 and TM6SF2 gene variants [56] . MERTK is a receptor of the tumor-associated macrophage family, involved in efferocytosis (the process by which apoptotic cells are filtered out by phagocytes).…”

Section: Role Of Genesmentioning

confidence: 96%

Pathophysiology of Nonalcoholic Fatty Liver Disease: Lifestyle-Gut-Gene Interaction

Mazzotti

Caletti

Sasdelli

et al. 2016

Dig Dis

View full text Add to dashboard Cite

Background: The accumulation of fat droplets in the hepatic parenchyma is driven by several factors, synergistically acting to increase triglyceride flow to the liver (diet and metabolic factors, endotoxemia from gut microbiota, genetic factors). Key Messages: In the presence of unhealthy lifestyles and behavioral factors, leading to enlarged adipose tissue and insulin resistance (IR), both lipolysis and de novo lipogenesis are expected to increase the risk of hepatic lipid depots, in association with high calorie (either high-fat or high-carbohydrate) diets. The gut microbiota may also be involved via obesity, IR and hepatic inflammation generated by gut-derived toxic factors. Finally, several data also support a primary role of genetic factors. A few gene polymorphisms have also been associated with the risk of nonalcoholic fatty liver disease development and nonalcoholic steatohepatitis progression to more fibrosis and advanced liver disease. In a few cases (e.g., patatin-like phospholipase domain-containing 3/adiponutrin), steatosis carries a high risk of both liver disease and cardiovascular morbidity/mortality; in other cases (e.g., transmembrane 6 superfamily 2 human gene), dissociation has been observed between the increased risk of liver disease versus cardiovascular disease. Conclusions: A variable interplay between the genetic background and the metabolic milieu is the likely physiopathologic mechanism involved in individual cases, which must be considered for implementing effective treatment strategies.

show abstract

“…Several genome‐wide association studies (GWAS) have been carried out in HCV‐infected patient cohorts finding, for example, variants associated to the immune response in the clearance of the virus like the interleukin‐28B cluster . More recently, the SNP rs4374383 has been found associated with significantly reduced risk of developing HCV‐induced liver fibrosis and linked to fibrosis progression in patients with NAFLD …”

Section: Introductionmentioning

confidence: 99%

Genetic prevention of hepatitis C virus‐induced liver fibrosis by allele‐specific downregulation of MERTK

Cavalli

Pan

Nord

et al. 2016

Hepatology Research

View full text Add to dashboard Cite

Treatment of hepatitis C with interferon-α results in increased IRF1 levels and our data suggest that this leads to an allele-specific downregulation of MERTK mediated by an allelic effect on the regulatory element containing the functional rs6726639. This variant also shows the hallmarks for being the driver of the genome-wide association studies for reduced risk of liver fibrosis and non-alcoholic fatty liver disease at MERTK.

show abstract

MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease

Abstract: The rs4374383 AA genotype, associated with lower intrahepatic expression of MERTK, is protective against F2-F4 fibrosis in patients with NAFLD. The mechanism may involve modulation of HSC activation.

Cited by 109 publications

References 32 publications

PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population

PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population

Pathophysiology of Nonalcoholic Fatty Liver Disease: Lifestyle-Gut-Gene Interaction

Genetic prevention of hepatitis C virus‐induced liver fibrosis by allele‐specific downregulation of MERTK

Contact Info

Product

Resources

About