Variants in the FFAR1 Gene Are Associated with Beta Cell Function

Abstract

BackgroundThe FFAR1 receptor is expressed mainly in pancreatic beta cells and is activated by medium to long chain free fatty acids (FFAs), as well as by thiazolidinediones, resulting in elevated Ca2+ concentrations and promotion of insulin secretion. These properties suggest that FFAR1 could be a mediator of lipotoxicity and a potential candidate gene for Type 2 diabetes (T2D). We therefore investigated whether variations at the FFAR1 locus are associated with T2D and beta cell function.Methodology/Principal FindingsWe re-sequenced the FFAR1 region in 96 subjects (48 healthy and 48 T2D individuals) and found 13 single nucleotide polymorphisms (SNPs) 8 of which were not previously described. Two SNPs located in the upstream region of the FFAR1 gene (rs1978013 and rs1978014) were chosen and genotyped in 1929 patients with T2D and 1405 healthy control subjects. We observed an association of rs1978013 and rs1978014 with insulinogenic index in males (p = 0.024) and females (p = 0.032), respectively. After Bonferroni corrections, no association with T2D was found in the case-control material, however a haplotype consisting of the T-G alleles conferred protection against T2D (p = 0.0010).Conclusions/SignificanceVariation in the FFAR1 gene may contribute to impaired beta cell function in T2D.

Reevaluation of Fatty Acid Receptor 1 as a Drug Target for the Stimulation of Insulin Secretion in Humans

“…Previously, a study analyzing two SNPs in FFAR1 found clues for a possible association between genotypes and insulin secretion (23). However, no association between FFAR1 and insulin secretion could be shown in genome-wide association studies for the SNPs rs387083, rs2301151, rs12975589, rs12462800, rs417030, and rs1573611 in up to 46,186 individuals (24).…”

Genetic and Molecular Basis of QTL of Diabetes in Mouse: Genes and Polymorphisms

“…Ffar1 (free fatty acid receptor 1) was shown to be highly expressed in rodent pancreatic ß cells, and its down-regulation by RNAi caused impaired fatty acid stimulated insulin secretion [ 89 ]. Variants in the Ffar1 gene are associated with ß cell function in T2D [ 90 ], but the role of this gene in T1D is unclear. Up-regulation of FLIP, caspase-8 inhibitor, enhanced NF-κB activity via NF- κB-inducing kinase and RELB can lead to increased PDX-1 and insulin production independent of changes in cell turnover [ 91 ].…”

Minireview: The Effects of Species Ortholog and SNP Variation on Receptors for Free Fatty Acids

“…In addition to the missense polymorphisms, there are also 2 SNPs upstream of the FFA1 gene (rs1978013 and rs1978014) that have been associated with β-cell function ( 44 ). Although this study did not find a statistical link between either of these SNPs and type 2 diabetes alone, the haplotype consisting of the T and G alleles did confer protection ( 44 ).…”

“…In addition to the missense polymorphisms, there are also 2 SNPs upstream of the FFA1 gene (rs1978013 and rs1978014) that have been associated with β-cell function ( 44 ). Although this study did not find a statistical link between either of these SNPs and type 2 diabetes alone, the haplotype consisting of the T and G alleles did confer protection ( 44 ). Taken together, although several studies have examined polymorphisms of FFA1, there is at present no clear evidence indicating that any of these significantly alter FFA1 function or increase risk of obesity and type 2 diabetes.…”