Genome-Wide and Abdominal MRI-Imaging Data Provides Evidence that a Genetically Determined Favourable Adiposity Phenotype is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease and Hypertension

Yingjie Ji, Andrianos M. Yiorkas, Francesca Frau, Dennis Mook-Kanamori, Harald Staiger, E. Louise Thomas, Naeimeh Atabaki-Pasdar, Archie Campbell, Jessica Tyrrell, Samuel E. Jones, Robin N. Beaumont, Andrew R. Wood, Marcus A. Tuke, Katherine S. Ruth, Anubha Mahajan, Anna Murray, Rachel M. Freathy, Michael N. Weedon, Andrew T. Hattersley, Caroline HaywardJürgen Machann, Hans-Ulrich Häring, Paul Franks, Renée de Mutsert, Ewan Pearson, Norbert Stefan, Timothy M. Frayling, Karla V. Allebrandt, Jimmy D. Bell, Alexandra I. Blakemore, Hanieh Yaghootkar

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Abstract

Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14, and IRS1, whereas the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots.

Original languageEnglish
Pages (from-to)207-219
Number of pages13
JournalDiabetes
Volume68
Issue number1
Early online date23 Oct 2018
DOIs
Publication statusPublished - 1 Jan 2019

Keywords

  • Adiposity/genetics
  • Adult
  • Aged
  • Diabetes Mellitus, Type 2/diagnostic imaging
  • Female
  • Genome-Wide Association Study
  • Heart Diseases/diagnostic imaging
  • Humans
  • Hypertension/diagnostic imaging
  • Intra-Abdominal Fat/metabolism
  • Magnetic Resonance Imaging/methods
  • Male
  • Middle Aged
  • Obesity/diagnostic imaging
  • Waist-Hip Ratio

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    Ji, Y., Yiorkas, A. M., Frau, F., Mook-Kanamori, D., Staiger, H., Thomas, E. L., Atabaki-Pasdar, N., Campbell, A., Tyrrell, J., Jones, S. E., Beaumont, R. N., Wood, A. R., Tuke, M. A., Ruth, K. S., Mahajan, A., Murray, A., Freathy, R. M., Weedon, M. N., Hattersley, A. T., ... Yaghootkar, H. (2019). Genome-Wide and Abdominal MRI-Imaging Data Provides Evidence that a Genetically Determined Favourable Adiposity Phenotype is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease and Hypertension. Diabetes, 68(1), 207-219. https://doi.org/10.2337/db18-0708