TY - JOUR
T1 - 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
AU - Ji, Yingjie
AU - Yiorkas, Andrianos M.
AU - Frau, Francesca
AU - Mook-Kanamori, Dennis
AU - Staiger, Harald
AU - Thomas, E. Louise
AU - Atabaki-Pasdar, Naeimeh
AU - Campbell, Archie
AU - Tyrrell, Jessica
AU - Jones, Samuel E.
AU - Beaumont, Robin N.
AU - Wood, Andrew R.
AU - Tuke, Marcus A.
AU - Ruth, Katherine S.
AU - Mahajan, Anubha
AU - Murray, Anna
AU - Freathy, Rachel M.
AU - Weedon, Michael N.
AU - Hattersley, Andrew T.
AU - Hayward, Caroline
AU - Machann, Jürgen
AU - Häring, Hans-Ulrich
AU - Franks, Paul
AU - de Mutsert, Renée
AU - Pearson, Ewan
AU - Stefan, Norbert
AU - Frayling, Timothy M.
AU - Allebrandt, Karla V.
AU - Bell, Jimmy D.
AU - Blakemore, Alexandra I.
AU - Yaghootkar, Hanieh
N1 - HY is funded by Diabetes UK RD Lawrence fellowship (grant: 17/0005594). ARW and TMF are supported by the European Research Council (grant 323195:GLUCOSEGENES-FP7-IDEAS-ERC). RNB and RMF are funded by the Wellcome Trust and Royal Society grant 104150/Z/14/Z. JT is funded by the European Regional Development Fund (ERDF) and a Diabetes Research and Wellness Foundation fellowship. SEJ is funded by the Medical Research Council (grant MR/M005070/1). The TÜF study was supported in part by a grant (01GI0925) from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD) and by a grant from the German Research Foundation (DFG KFO114). IMI-DIRECT was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. The NEO study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area Vascular and Regenerative Medicine. Dennis Mook-Kanamori is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z).
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
KW - Adiposity/genetics
KW - Adult
KW - Aged
KW - Diabetes Mellitus, Type 2/diagnostic imaging
KW - Female
KW - Genome-Wide Association Study
KW - Heart Diseases/diagnostic imaging
KW - Humans
KW - Hypertension/diagnostic imaging
KW - Intra-Abdominal Fat/metabolism
KW - Magnetic Resonance Imaging/methods
KW - Male
KW - Middle Aged
KW - Obesity/diagnostic imaging
KW - Waist-Hip Ratio
UR - http://www.scopus.com/inward/record.url?scp=85058904141&partnerID=8YFLogxK
U2 - 10.2337/db18-0708
DO - 10.2337/db18-0708
M3 - Article
C2 - 30352878
SN - 0012-1797
VL - 68
SP - 207
EP - 219
JO - Diabetes
JF - Diabetes
IS - 1
ER -
