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

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

Research output: Contribution to journalArticle

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Abstract

Genetic variation at rs4240624 on chromosome 8 is associated with an attenuated signal on hepatic computerized tomography, which has been attributed to changes in hepatic fat. The closest coding gene to rs4240624, PPP1R3B, encodes a protein that promotes hepatic glycogen synthesis. Here, we performed studies to determine whether the x-ray attenuation associated with rs4240624 is due to differences in hepatic glycogen or hepatic triglyceride content (HTGC). A sequence variant in complete linkage disequilibrium with rs4240624, rs4841132, was genotyped in the Dallas Heart Study (DHS), the Dallas Liver Study, and the Copenhagen Cohort (n = 112,428) of whom 1,539 had nonviral liver disease. The minor A-allele of rs4841132 was associated with increased hepatic x-ray attenuation (n = 1,572; P = 4 × 10–5), but not with HTGC (n = 2,674; P = 0.58). Rs4841132-A was associated with modest, but significant, elevations in serum alanine aminotransferase (ALT) in the Copenhagen Cohort (P = 3 × 10–4) and the DHS (P = 0.004), and with odds ratios for liver disease of 1.13 (95% CI, 0.97-1.31) and 1.23 (1.01-1.51), respectively. Mice lacking protein phosphatase 1 regulatory subunit 3B (PPP1R3B) were deficient in hepatic glycogen, whereas HTGC was unchanged. Hepatic overexpression of PPP1R3B caused accumulation of hepatic glycogen and elevated plasma levels of ALT, but did not change HTGC. Conclusion: 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).

Original languageEnglish (US)
Pages (from-to)2182-2195
Number of pages14
JournalHepatology
Volume67
Issue number6
DOIs
StatePublished - Jun 1 2018

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Protein Phosphatase 1
Liver Glycogen
Triglycerides
Liver
Alanine Transaminase
Liver Diseases
Alleles
X-Rays
Glycogen Storage Disease
Chromosomes, Human, Pair 8
Linkage Disequilibrium
Gastroenterology
Cohort Studies
Fats
Odds Ratio
Tomography

ASJC Scopus subject areas

  • Hepatology

Cite this

Stender, S., Smagris, E., Lauridsen, B. K., Kofoed, K. F., Nordestgaard, B. G., Tybjærg-Hansen, A., ... Hobbs, H. H. (2018). Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride. Hepatology, 67(6), 2182-2195. https://doi.org/10.1002/hep.29751

Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride. / Stender, Stefan; Smagris, Eriks; Lauridsen, Bo K.; Kofoed, Klaus F.; Nordestgaard, Børge G.; Tybjærg-Hansen, Anne; Pennacchio, Len A.; Dickel, Diane E.; Cohen, Jonathan C.; Hobbs, Helen H.

In: Hepatology, Vol. 67, No. 6, 01.06.2018, p. 2182-2195.

Research output: Contribution to journalArticle

Stender, S, Smagris, E, Lauridsen, BK, Kofoed, KF, Nordestgaard, BG, Tybjærg-Hansen, A, Pennacchio, LA, Dickel, DE, Cohen, JC & Hobbs, HH 2018, 'Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride', Hepatology, vol. 67, no. 6, pp. 2182-2195. https://doi.org/10.1002/hep.29751
Stender S, Smagris E, Lauridsen BK, Kofoed KF, Nordestgaard BG, Tybjærg-Hansen A et al. Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride. Hepatology. 2018 Jun 1;67(6):2182-2195. https://doi.org/10.1002/hep.29751
Stender, Stefan ; Smagris, Eriks ; Lauridsen, Bo K. ; Kofoed, Klaus F. ; Nordestgaard, Børge G. ; Tybjærg-Hansen, Anne ; Pennacchio, Len A. ; Dickel, Diane E. ; Cohen, Jonathan C. ; Hobbs, Helen H. / Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride. In: Hepatology. 2018 ; Vol. 67, No. 6. pp. 2182-2195.
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abstract = "Genetic variation at rs4240624 on chromosome 8 is associated with an attenuated signal on hepatic computerized tomography, which has been attributed to changes in hepatic fat. The closest coding gene to rs4240624, PPP1R3B, encodes a protein that promotes hepatic glycogen synthesis. Here, we performed studies to determine whether the x-ray attenuation associated with rs4240624 is due to differences in hepatic glycogen or hepatic triglyceride content (HTGC). A sequence variant in complete linkage disequilibrium with rs4240624, rs4841132, was genotyped in the Dallas Heart Study (DHS), the Dallas Liver Study, and the Copenhagen Cohort (n = 112,428) of whom 1,539 had nonviral liver disease. The minor A-allele of rs4841132 was associated with increased hepatic x-ray attenuation (n = 1,572; P = 4 × 10–5), but not with HTGC (n = 2,674; P = 0.58). Rs4841132-A was associated with modest, but significant, elevations in serum alanine aminotransferase (ALT) in the Copenhagen Cohort (P = 3 × 10–4) and the DHS (P = 0.004), and with odds ratios for liver disease of 1.13 (95{\%} CI, 0.97-1.31) and 1.23 (1.01-1.51), respectively. Mice lacking protein phosphatase 1 regulatory subunit 3B (PPP1R3B) were deficient in hepatic glycogen, whereas HTGC was unchanged. Hepatic overexpression of PPP1R3B caused accumulation of hepatic glycogen and elevated plasma levels of ALT, but did not change HTGC. Conclusion: 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).",
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AU - Tybjærg-Hansen, Anne

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AB - Genetic variation at rs4240624 on chromosome 8 is associated with an attenuated signal on hepatic computerized tomography, which has been attributed to changes in hepatic fat. The closest coding gene to rs4240624, PPP1R3B, encodes a protein that promotes hepatic glycogen synthesis. Here, we performed studies to determine whether the x-ray attenuation associated with rs4240624 is due to differences in hepatic glycogen or hepatic triglyceride content (HTGC). A sequence variant in complete linkage disequilibrium with rs4240624, rs4841132, was genotyped in the Dallas Heart Study (DHS), the Dallas Liver Study, and the Copenhagen Cohort (n = 112,428) of whom 1,539 had nonviral liver disease. The minor A-allele of rs4841132 was associated with increased hepatic x-ray attenuation (n = 1,572; P = 4 × 10–5), but not with HTGC (n = 2,674; P = 0.58). Rs4841132-A was associated with modest, but significant, elevations in serum alanine aminotransferase (ALT) in the Copenhagen Cohort (P = 3 × 10–4) and the DHS (P = 0.004), and with odds ratios for liver disease of 1.13 (95% CI, 0.97-1.31) and 1.23 (1.01-1.51), respectively. Mice lacking protein phosphatase 1 regulatory subunit 3B (PPP1R3B) were deficient in hepatic glycogen, whereas HTGC was unchanged. Hepatic overexpression of PPP1R3B caused accumulation of hepatic glycogen and elevated plasma levels of ALT, but did not change HTGC. Conclusion: 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).

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