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

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.