Increased frequency of rare missense PPP1R3B variants among Danish patients with type 2 diabetes

PLoS One. 2019 Jan 10;14(1):e0210114. doi: 10.1371/journal.pone.0210114. eCollection 2019.

Abstract

Background: PPP1R3B has been suggested as a candidate gene for monogenic forms of diabetes as well as type 2 diabetes (T2D) due to its association with glycaemic trait and its biological role in glycogen synthesis.

Objectives: To study if rare missense variants in PPP1R3B increase the risk of maturity onset diabetes of the young (MODY), T2D or affect measures of glucose metabolism.

Method: Targeted resequencing of PPP1R3B was performed in 8,710 samples; MODY patients with unknown etiology (n = 54), newly diagnosed patients with T2D (n = 2,930) and population-based control individuals (n = 5,726, of whom n = 4,569 had normal glucose tolerance). All population-based sampled individuals were examined using an oral glucose tolerance test.

Results: Among n = 396 carriers, we identified twenty-three PPP1R3B missense mutations, none of which segregated with MODY. The burden of likely deleterious PPP1R3B variants was significantly increased with a total of 17 carriers among patients with T2D (0.58% (95% CI: 0.36-0.93)) compared to 18 carriers among non-diabetic individuals (0.31% (95% CI: 0.20-0.49)), resulting in an increased risk of T2D (OR (95% CI) = 2.57 (1.14-5.79), p = 0.02 (age and sex adjusted)). Furthermore, carriers with diabetes had less abdominal fat and a higher serum concentration of LDL-cholesterol compared to patients with T2D without rare missense PPP1R3B variants. In addition, non-diabetic carriers had a higher birth weight compared to non-carriers.

Conclusion: Rare missense PPP1R3B variants may predispose to T2D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Blood Glucose / genetics
  • Denmark
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Glucose Tolerance Test
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense
  • Protein Phosphatase 1 / genetics*

Substances

  • Blood Glucose
  • PPP1R3B protein, human
  • Protein Phosphatase 1

Supplementary concepts

  • Maturity-Onset Diabetes of the Young, Type 2

Grants and funding

This project received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 667191 (authors awarded: APG, NG and TH). In addition, the study was supported from the Steno Diabetes Center, the Danish Diabetes Academy, the Danish Medical Research Council, the European Foundation for the Study of Diabetes (EFSD), the Novo Nordisk Foundation (Immunometabolism, NNF15CC0018486) and the Danish Diabetes Association. The DD2 cohort was funded by the Danish Agency for Science (grant no. 09-067009 and 09-075724) (authors awarded: JSN and JR). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). The BGI provided support in the form of salaries for author [JS], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. No other funders had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.