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  • Recent data from an investigation

    2022-08-09

    Recent data from an investigation conducted with beta-cell cultures and animals suggest that FFAR1 gene GSK2578215A is modulated by stimulation of peroxisome proliferator-activated receptor gamma (PPARG) [10]. Intriguingly, in 2001 we had demonstrated effects of the PPARG Pro12Ala single nucleotide polymorphism (SNP) on insulin secretion in an elevated NEFA milieu. In this investigation, carriers of the minor allele of the Pro12Ala polymorphism (rs1805192) had lower insulin secretion during hyperglycemic clamp studies conducted with a concomitant intravenous lipid infusion, but no difference was seen between the genotypes without increasing NEFA [11]. Given these data supporting a crosstalk between PPARG and FFAR1 signaling, we set out to look for evidence of a PPARG × FFAR1 interaction in humans. For this purpose, we analyzed insulin secretion effects of interactions between previously described tagging SNPs in FFAR1 [9] and the aforementioned diabetes-related SNP in PPARG, also accounting for NEFA levels.
    Methods
    Results As expected, PPARG genotypes alone did not impact insulin secretion in the study population (a table on the genotype-dependent distribution of key cohort phenotypes is provided as Supplementary Table 1). To test the hypothesis that there is an interaction between genetic variation in PPARG and FFAR1 on insulin secretion, we analyzed gene × gene interactions between rs1805192 in PPARG and 7 tagging SNPs of known frequent variants in FFAR1. Since the modulatory effect of PPARG on insulin secretion manifested only in a high-NEFA environment [11] and FFAR1 effects on insulin secretion were seen only in interaction with fasting NEFA [9], we additionally adjusted for fasting NEFA and added interaction terms of fasting NEFA with the FFAR1 SNPs and the PPARG SNP to the models. We adjusted insulin secretion as determined by the insulinogenic index for sex, age, insulin sensitivity, fasting NEFA, PPARG Pro12Ala genotype, FFAR1 genotypes and 4 interaction terms: between FFAR1 and PPARG genotypes, between PPARG genotype and NEFA level, between FFAR1 genotype and NEFA and, finally, a 3-way interaction term with PPARG × NEFA × FFAR1-SNP. We found a significant gene × gene interaction between the FFAR1 SNP rs10422744 and the PPARG Pro12Ala SNP (p = 0.005) with a concomitant nominally significant interaction between NEFA level and the PPARG SNP (p = 0.03). Additionally, a nominally significant interaction was found between rs12462800 and PPARG (p = 0.01) with a concomitant PPARG × NEFA interaction (p = 0.03). The 3-way interaction term did not reach statistical significance, although the p-value of 0.0592 suggested a trend for nominal significance in the case of rs12462800. Detailed results of the interaction tests are provided in Supplementary Table 2. An additional adjustment for obesity by adding BMI to the interaction models did not relevantly change the results (data not shown). Alternatively using DI as outcome variable, the gene × gene interaction term had a p-value of 0.01 and 0.001 for rs12462800 and rs10422744, respectively. Next, we conducted subgroup analyses with stratification along interaction variables, namely the PPARG SNP and fasting NEFA. The study population was thus stratified into high and low NEFA (along the median NEFA, 561 μmol/L), and PPARG minor allele (Ala) carriers. This stratification resulted in 4 subgroups (I: low NEFA and PPARG Pro homozygotes, n = 718, II: low NEFA and PPARG Ala carriers, n = 237, III: high NEFA and PPARG Pro homozygotes, n = 744, IV: high NEFA and PPARG Ala carriers, n = 229). An effect of the FFAR1 genotype on insulin secretion was only evident in the subgroup IV comprising participants with at least one PPARG Ala allele and high fasting NEFA (Figure 1A and B bottom right diagrams [diagrams IV]). In this subpopulation, carriers of the minor allele of rs10422744 and rs12462800 in FFAR1 had lower insulin secretion (β = −0.18, p = 0.001 and β = −0.19, p = 0.0006, respectively) than homozygotes of the major allele, after controlling for sex, age and insulin sensitivity.