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The Type 2 Diabetes Risk Allele of TMEM154-rs6813195 Associates with Decreased Beta Cell Function in a Study of 6,486 Danes

Author

Listed:
  • Marie Neergaard Harder
  • Emil Vincent Rosenbaum Appel
  • Niels Grarup
  • Anette Prior Gjesing
  • Tarunveer S Ahluwalia
  • Torben Jørgensen
  • Cramer Christensen
  • Ivan Brandslund
  • Allan Linneberg
  • Thorkild I A Sørensen
  • Oluf Pedersen
  • Torben Hansen

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.

Suggested Citation

  • Marie Neergaard Harder & Emil Vincent Rosenbaum Appel & Niels Grarup & Anette Prior Gjesing & Tarunveer S Ahluwalia & Torben Jørgensen & Cramer Christensen & Ivan Brandslund & Allan Linneberg & Thorki, 2015. "The Type 2 Diabetes Risk Allele of TMEM154-rs6813195 Associates with Decreased Beta Cell Function in a Study of 6,486 Danes," PLOS ONE, Public Library of Science, vol. 10(3), pages 1-13, March.
    • Handle: RePEc:plo:pone00:0120890
    DOI: 10.1371/journal.pone.0120890
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    1. Lavinia Paternoster & David M Evans & Ellen Aagaard Nohr & Claus Holst & Valerie Gaborieau & Paul Brennan & Anette Prior Gjesing & Niels Grarup & Daniel R Witte & Torben Jørgensen & Allan Linneberg & , 2011. "Genome-Wide Population-Based Association Study of Extremely Overweight Young Adults – The GOYA Study," PLOS ONE, Public Library of Science, vol. 6(9), pages 1-9, September.
    2. Kim, Jaehoon & Kim, Sangsin, 2015. "2012년 국회법 개정의 효과 연구 [A Study on the Effect of the 2012 National Assembly Act Amendment]," KDI Research Monographs, Korea Development Institute (KDI), volume 127, number v:2015-03(k):y:2015:p:1-1.
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    1. Ping Rao & Yong Zhou & Si-Qi Ge & An-Xin Wang & Xin-Wei Yu & Mohamed Ali Alzain & Andrea Katherine Veronica & Jing Qiu & Man-Shu Song & Jie Zhang & Hao Wang & Hong-Hong Fang & Qing Gao & You-Xin Wang , 2016. "Validation of Type 2 Diabetes Risk Variants Identified by Genome-Wide Association Studies in Northern Han Chinese," IJERPH, MDPI, vol. 13(9), pages 1-10, August.

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