Contribution of the low-frequency, loss-of-function p.R270H mutation in FFAR4 (GPR120) to increased fasting plasma glucose levels. Issue 9 (29th May 2015)

• Record Type: Journal Article
• Authors: Bonnefond, Amélie; Lamri, Amel; Leloire, Audrey; Vaillant, Emmanuel; Roussel, Ronan; Lévy-Marchal, Claire; Weill, Jacques; Galan, Pilar; Hercberg, Serge; Ragot, Stéphanie; Hadjadj, Samy; Charpentier, Guillaume; Balkau, Beverley; Marre, Michel; Fumeron, Frédéric; Froguel, Philippe
• Is Part Of: Journal of medical genetics. Volume 52:Issue 9(2015)
• Page Start: 595
• Page End: 598
• Publication Date: 2015-05-29
• Subjects: Diabetes -- Genetics -- Obesity; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2015-103065
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : 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.