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Contribution of the low-frequency, loss-of-function p.R270H mutation in FFAR4 (GPR120) to increased fasting plasma glucose levels
  1. Amélie Bonnefond1,2,3,
  2. Amel Lamri4,5,6,
  3. Audrey Leloire1,2,3,
  4. Emmanuel Vaillant1,2,3,
  5. Ronan Roussel4,5,7,
  6. Claire Lévy-Marchal8,
  7. Jacques Weill9,
  8. Pilar Galan10,
  9. Serge Hercberg10,
  10. Stéphanie Ragot11,12,13,
  11. Samy Hadjadj11,12,13,
  12. Guillaume Charpentier14,
  13. Beverley Balkau15,
  14. Michel Marre4,5,7,
  15. Frédéric Fumeron4,5,
  16. Philippe Froguel1,2,3,16
  1. 1CNRS-UMR8199, Lille Pasteur Institute, Lille, France
  2. 2Lille University, Lille, France
  3. 3European Genomic Institute for Diabetes (EGID), Lille, France
  4. 4Inserm U-1138, Centre de Recherche des Cordeliers, Paris, France
  5. 5Paris-Diderot University, Sorbonne Paris-Cité, Paris, France
  6. 6Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada
  7. 7Department of Endocrinology-Diabetology and Nutrition, DHU-FIRE, Bichat Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
  8. 8Inserm CIE 05—Department of Clinical Epidemiology, Robert Debré Hospital, Paris, France
  9. 9Pediatric Endocrine Unit, Lille University Hospital, Lille, France
  10. 10Nutritional Epidemiology Research Group, Sorbonne-Paris-Cité, UMR University of Paris 13/Inserm U-557/INRA U-1125/CNAM, Bobigny, France
  11. 11Inserm, CIC1402 and U-1082, Poitiers, France
  12. 12Department of Endocrinology-Diabetology, Centre for Clinical Investigation, CHU of Poitiers, Poitiers, France
  13. 13University of Poitiers, UFR Medicine Pharmacy, Poitiers, France
  14. 14Department of Diabetes and Endocrinology, Centre Hospitalier Sud-Francilien, Corbeil-Essonne, France
  15. 15Inserm U-1018, CESP, Team 5 (EpReC, Renal and cardiovascular Epidemiology), UVSQ-UPS, Villejuif, France
  16. 16Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK
  1. Correspondence to Dr Amélie Bonnefond or Prof Philippe Froguel, CNRS UMR8199, Lille Pasteur Institute, 1 rue du Prof Calmette, Lille Cedex 59019, France; amelie{at} or froguel{at}


Background We previously reported that the low-frequency, loss-of-function variant p.R270H in FFAR4 encoding the lipid sensor GPR120 was associated with obesity. Gpr120-deficient mice develop obesity and both impaired fasting glucose and glucose intolerance under a high-fat diet. We aimed to assess the contribution of p.R270H to type 2 diabetes (T2D) risk and the variation of glucose-related traits.

Methods We genotyped p.R270H in 8996 non-diabetic individuals (among whom 4523 had an oral glucose tolerance test (OGTT)) and in a T2D case–control study including 4725 cases and 4339 controls. The regression models were adjusted for age, sex and body mass index (BMI).

Results We found a significant association between p.R270H and increased fasting glucose levels (β=0.092±0.05 mmol/L; p=4.13×10−4). Furthermore, p.R270H nominally contributed to decreased homeostasis model of pancreatic β-cell function (HOMA-B; β=−0.090±0.06; p=6.01×10−3). Despite a high statistical power, we did not find any significant association between p.R270H and T2D risk or the variation of fasting insulin levels, the homeostasis model of insulin resistance or OGTT-derived indices.

Conclusions These results suggest that the low-frequency p.R270H variant which inhibits GPR120 activity might influence fasting glucose levels in a normal physiological range. This study does not exclude that other coding mutations in FFAR4 with stronger functional effect than p.R270H may be associated with T2D.

  • Diabetes
  • Genetics
  • Obesity

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