Variation in the FFAR1 gene modifies BMI, body composition and beta-cell function in overweight subjects: an exploratory analysis

Abstract

Background: FFAR1 receptor is a long chain fatty acid G-protein coupled receptor which is expressed widely, but found in high density in the pancreas and central nervous system. It has been suggested that FFAR1 may play a role in insulin sensitivity, lipotoxicity and is associated with type 2 diabetes. Here we investigate the effect of three common SNPs of FFAR1 (rs2301151; rs16970264; rs1573611) on pancreatic function, BMI, body composition and plasma lipids.

Methodology/principal findings: For this enquiry we used the baseline RISCK data, which provides a cohort of overweight subjects at increased cardiometabolic risk with detailed phenotyping. The key findings were SNPs of the FFAR1 gene region were associated with differences in body composition and lipids, and the effects of the 3 SNPs combined were cumulative on BMI, body composition and total cholesterol. The effects on BMI and body fat were predominantly mediated by rs1573611 (1.06 kg/m(2) higher (P = 0.009) BMI and 1.53% higher (P = 0.002) body fat per C allele). Differences in plasma lipids were also associated with the BMI-increasing allele of rs2301151 including higher total cholesterol (0.2 mmol/L per G allele, P = 0.01) and with the variant A allele of rs16970264 associated with lower total (0.3 mmol/L, P = 0.02) and LDL (0.2 mmol/L, P<0.05) cholesterol, but also with lower HDL-cholesterol (0.09 mmol/L, P<0.05) although the difference was not apparent when controlling for multiple testing. There were no statistically significant effects of the three SNPs on insulin sensitivity or beta cell function. However accumulated risk allele showed a lower beta cell function on increasing plasma fatty acids with a carbon chain greater than six.

Conclusions/significance: Differences in body composition and lipids associated with common SNPs in the FFAR1 gene were apparently not mediated by changes in insulin sensitivity or beta-cell function.

Figure 1. The cumulative effect of carrying risk alleles in three SNPs of FFAR1 on BMI and body fat.

Data presented are mean ± SEM of BMI (Panel a) and body fat (Panel b) for individuals according to the number of SNPs for which risk alleles were present. Each SNP (rs2301151; rs1573611; rs16970264) was scored 0 or 1 based on the presence of risk alleles (dominant model). The presence of risk alleles for each SNP was summed. All individuals had at least 1 SNP with risk alleles present. There was a cumulative effect on BMI of 1.04±0.41 kg/m2 per SNP, P = 0.01 and of body fat (%) of 1.75±0.6% per SNP, P = 0.001 assessed by linear regression analysis with age and gender as covariates. The effects were statistically significant when accounting for multiple comparisons by the Benjamini and Hochberg False Discovery Rate procedure with q* = 0.05.

Figure 2. The cumulative effect of carrying risk alleles in three SNPs of FFAR1 on total cholesterol.

Data presented are mean ± SEM of total cholesterol for individuals according to the number of SNPs for which risk alleles were present. Each SNP in the FFAR1 region which was examined (rs2301151; rs1573611; rs16970264) was scored 0 or 1 based on the presence of risk alleles (dominant model). The number of SNPs with risk alleles was summed. All individuals had at least 1 SNP with risk alleles present. There was a cumulative effect on total cholesterol of 0.18±0.08 mmol/L per SNP, P = 0.03 assessed by linear regression analysis with age, gender and BMI. This was not statistically significant when accounting for multiple comparisons by the Benjamini and Hochberg False Discovery Rate procedure with q* = 0.05.