Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride

Stender, Stefan; Šmagris, Ēriks; Lauridsen, Bo K; Kofoed, Klaus F.; Nordestgaard, Børge G.; Tybjærg‐Hansen, Anne; Pennacchio, Len A.; Dickel, Diane E.; Cohen, Jonathan C.; Hobbs, Helen H.

doi:10.1002/hep.29751

Cited by 54 publications

(61 citation statements)

References 42 publications

(90 reference statements)

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“…We combined two studies of the Danish general population, the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS), into one cohort, referred to here as the Copenhagen Cohort. (18,19) The CGPS and CCHS are prospective studies of the Danish general population initiated, respectively, in 2003-2015 and in 1976-1978, with follow-up examinations for CCHS in 1981-1983, 1991-1994, and 2001-2003. Individuals were selected based on the national Danish Civil Registration System to reflect the adult Danish population aged 20 to 100+.…”

Section: Patients and Methods Participantsmentioning

confidence: 99%

High Risk of Fatty Liver Disease Amplifies the Alanine Transaminase–Lowering Effect of a HSD17B13 Variant

et al. 2019

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A common loss‐of‐function variant in HSD17B13 (rs72613567:TA) was recently found to protect from chronic liver disease. Whether the variant confers protection from specific risk factors for liver disease is unclear. We tested the association of rs72613567 with plasma levels of alanine transaminase (ALT) and clinical liver disease and mortality in 111,612 individuals from the Danish general population, including 497 with cirrhosis and 113 with hepatocellular carcinoma. HSD17B13 rs72613567:TA was associated with stepwise lower levels of plasma ALT of up to 1.3 U/L in TA/TA homozygotes versus T/T homozygotes. For each TA‐allele, the risk of cirrhosis and hepatocellular carcinoma was reduced by 15% and 28%, respectively. In prospective analyses, the TA‐allele was associated with up to 33% lower rates of liver‐related mortality in the general population, and with up to 49% reduced liver‐related mortality in patients with cirrhosis. The ALT‐lowering effect of rs72613567:TA was amplified by increasing adiposity, alcohol consumption, and genetic risk of fatty liver disease. The TA‐allele was associated with only marginally lower ALT in lean nondrinkers with low genetic risk of hepatic steatosis. In contrast, compared with T/T homozygotes, TA/TA homozygotes had 12% to 18% lower plasma ALT among the most obese, in heavy drinkers, and in individuals carrying three or four steatogenic alleles in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) and transmembrane 6 superfamily 2 (TM6SF2). Conclusion: High risk of fatty liver disease amplifies the ALT‐lowering effect of HSD17B13 rs72613567:TA in the Danish general population.

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Section: Patients and Methods Participantsmentioning

confidence: 99%

High Risk of Fatty Liver Disease Amplifies the Alanine Transaminase–Lowering Effect of a HSD17B13 Variant

et al. 2019

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“…Generation of these mutants in mice endorses the functional involvement of PP1 in that particular mouse's phenotype (Tables 2 and 3). Importantly, other interactions within functional PP1 holoenzyme complexes such as the interaction of PIPs with subcellular structures can also be exploited as targets for therapeutically intervention as example by GM ΔC mutant ( [102,143]. Together with the recent expansion of structural biological methods and genome editing technologies, it is expected that structural reverse genetics will increase in popularity and lead to the identification of PP1 holoenzymes with a therapeutical potential.…”

Section: Mouse Models With Human Disease-associated Phenotypesmentioning

confidence: 99%

Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

Ferreira

Beullens

Eynde

2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Protein phosphatase 1 (PP1) catalyzes more than half of all phosphoserine/threonine dephosphorylation reactions in mammalian cells. In vivo PP1 does not exist as a free catalytic subunit but is always associated with at least one regulatory PP1-interacting protein (PIP) to generate a large set of distinct holoenzymes. Each PP1 complex controls the dephosphorylation of only a small subset of PP1 substrates. We screened the literature for genetically engineered mouse models and identified models for all PP1 isoforms and 104 PIPs. PP1 itself and at least 49 PIPs were connected to human disease-associated phenotypes. Additionally, phenotypes related to 17 PIPs were clearly linked to altered PP1 function, while such information was lacking for 32 other PIPs. We propose structural reverse genetics, which combines structural characterization of proteins with mouse genetics, to identify new PP1-related therapeutic targets. The available mouse models confirm the pleiotropic action of PP1 in health and diseases.

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“…Furthermore, we cannot rule out that other nongenetic factors might have modulated the accelerated course of the disease, including poor glucose control or the presence of morbid obesity. It is known that adiposity increases the genetic risk of NAFLD at multiple loci that predispose to the disease . Finally, it would have been particularly informative having information on the p.Arg227Ter mutation in family members of the proband; unfortunately, family members opted not to take part in the genetic testing.…”

Section: Discussionmentioning

confidence: 99%

“…It is known that adiposity increases the genetic risk of NAFLD at multiple loci that predispose to the disease. (26) Finally, it would have been particularly informative having information on the p.Arg227Ter mutation in family members of the proband; unfortunately, family members opted not to take part in the genetic testing. Therefore, phasing with other variants was not possible.…”

Section: Discussionmentioning

confidence: 99%

A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis

Pirola

Flichman

Dopazo

et al. 2018

Hepatology Communications

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We report on the presence of a rare nonsense mutation (rs149847328, p.Arg227Ter) in the glucokinase regulator (GCKR) gene in an adult patient with nonalcoholic fatty liver disease (NAFLD), morbid obesity, and type 2 diabetes; this patient developed a progressive histological form of the disease. Analysis of paired (5 years apart) liver biopsies (at baseline and follow‐up) showed progression of simple steatosis to severe nonalcoholic steatohepatitis and cirrhosis. Study design involved an initial exploration that consisted of deep sequencing of 14 chromosomal regions in 96 individuals (64 of whom were patients with NAFLD who were diagnosed by liver biopsy that showed the full spectrum of histological severity). We further performed a replication study to explore the presence of rs149847328 that included a sample of 517 unrelated individuals in a case‐control study (n = 390), including patients who were morbidly obese (n = 127). Exploration of sequence variation by next‐generation sequencing of exons, exon–intron boundaries, and 5′ and 3′ untranslated regions of 14 genomic loci that encode metabolic enzymes of the tricarboxylic acid cycle revealed the presence of heterozygosity for the p.Arg227Ter mutation, the frequency of which is 0.0003963 (4:10,000; Exome Aggregation Consortium database). GCKR protein expression was markedly decreased in the liver of the affected patient compared with patients with NAFLD who carry the wild‐type allele. Sequencing of the same 14 genomic loci in 95 individuals failed to reveal the rare mutation. The rarity of p.Arg227Ter was confirmed in a more extensive screening. Conclusion: While rare variants/mutations are difficult to detect in even reasonably large samples (frequency of the mutant allele of p.Arg227Ter was ~1:1,000 in our data set), the presence of this mutation should be suspected as potentially associated with NAFLD, particularly in young adults at the extreme of histological phenotypes. Hepatology Communications 2018;0:0‐0)

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Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride

Abstract: These observations are consistent with the notion that the minor allele of rs4841132 promotes a mild form of hepatic glycogenosis that is associated with hepatic injury. (Hepatology 2018;67:2182-2195).

Cited by 54 publications

References 42 publications

High Risk of Fatty Liver Disease Amplifies the Alanine Transaminase–Lowering Effect of a HSD17B13 Variant

High Risk of Fatty Liver Disease Amplifies the Alanine Transaminase–Lowering Effect of a HSD17B13 Variant

Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis

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