The type 2 diabetes risk allele of TMEM154-rs6813195 associates with decreased beta cell function in a study of 6,486 Danes

PLoS One. 2015 Mar 23;10(3):e0120890. doi: 10.1371/journal.pone.0120890. eCollection 2015.

Abstract

Objectives: A trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified seven novel susceptibility variants in or near TMEM154, SSR1/RREB1, FAF1, POU5F1/TCF19, LPP, ARL15 and ABCB9/MPHOSPH9. The aim of our study was to investigate associations between these novel risk variants and type 2 diabetes and pre-diabetic traits in a Danish population-based study with measurements of plasma glucose and serum insulin after an oral glucose tolerance test in order to elaborate on the physiological impact of the variants.

Methods: Case-control analyses were performed in up to 5,777 patients with type 2 diabetes and 7,956 individuals with normal fasting glucose levels. Quantitative trait analyses were performed in up to 5,744 Inter99 participants naïve to glucose-lowering medication. Significant associations between TMEM154-rs6813195 and the beta cell measures insulinogenic index and disposition index and between FAF1-rs17106184 and 2-hour serum insulin levels were selected for further investigation in additional Danish studies and results were combined in meta-analyses including up to 6,486 Danes.

Results: We confirmed associations with type 2 diabetes for five of the seven SNPs (TMEM154-rs6813195, FAF1-rs17106184, POU5F1/TCF19-rs3130501, ARL15-rs702634 and ABCB9/MPHOSPH9-rs4275659). The type 2 diabetes risk C-allele of TMEM154-rs6813195 associated with decreased disposition index (n=5,181, β=-0.042, p=0.012) and insulinogenic index (n=5,181, β=-0.032, p=0.043) in Inter99 and these associations remained significant in meta-analyses including four additional Danish studies (disposition index n=6,486, β=-0.042, p=0.0044; and insulinogenic index n=6,486, β=-0.037, p=0.0094). The type 2 diabetes risk G-allele of FAF1-rs17106184 associated with increased levels of 2-hour serum insulin (n=5,547, β=0.055, p=0.017) in Inter99 and also when combining effects with three additional Danish studies (n=6,260, β=0.062, p=0.0040).

Conclusion: Studies of type 2 diabetes intermediary traits suggest the diabetogenic impact of the C-allele of TMEM154-rs6813195 is mediated through reduced beta cell function. The impact of the diabetes risk G-allele of FAF1-rs17106184 on increased 2-hour insulin levels is however unexplained.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Blood Glucose
  • Case-Control Studies
  • Denmark
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Fasting
  • Genetic Association Studies*
  • Humans
  • Insulin-Secreting Cells / metabolism*
  • Membrane Proteins / genetics*
  • Meta-Analysis as Topic
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Quantitative Trait, Heritable

Substances

  • Blood Glucose
  • Membrane Proteins
  • TMEM154 protein, human

Grants and funding

This work was supported by research grants from The Novo Nordisk Foundation Center for Basic Metabolic Research, an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation, the PhD School of Molecular Metabolism University of Southern Denmark, the Copenhagen Graduate School of Health and Medical Sciences, the Danish Council for Independent Research and the Gene Diet Interactions in Obesity (GENDINOB, www.gendinob.dk) project. The study is a part of the LuCamp initiative (www.lucamp.org) and is sponsored by the Lundbeck Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.