Gene–environment interactions in the associations of PFAS exposure with insulin sensitivity and beta-cell function in a Faroese cohort followed from birth to adulthood

Background: Exposure to perfluoroalkyl substances (PFAS) has been associated with changes in insulin sensitivity and pancreatic beta-cell function in humans. Genetic predisposition to diabetes may modify these associations; however, this hypothesis has not been yet studied. Objectives: To evaluate genetic heterogeneity as a modifier in the PFAS association with insulin sensitivity and pancreatic beta-cell function, using a targeted gene–environment (GxE) approach. Methods: We studied 85 single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes, in 665 Faroese adults born in 1986–1987. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were measured in cord whole blood at birth and in participants’ serum from age 28 years. We calculated the Matsuda-insulin sensitivity index (ISI) and the insulinogenic index (IGI) based on a 2 h-oral glucose tolerance test performed at age 28. Effect modification was evaluated in linear regression models adjusted for cross-product terms (PFAS*SNP) and important covariates. Results: Prenatal and adult PFOS exposures were significantly associated with decreased insulin sensitivity and increased beta-cell function. PFOA associations were in the same direction but attenuated compared to PFOS. A total of 58 SNPs were associated with at least one PFAS exposure variable and/or Matsuda-ISI or IGI in the Faroese population and were subsequently tested as modifiers in the PFAS-clinical outcome associations. Eighteen SNPs showed interaction p-values (P_GxE) < 0.05 in at least one PFAS-clinical outcome association, five of which passed False Discovery Rate (FDR) correction (P_GxE-FDR<0.20). SNPs for which we found stronger evidence for GxE interactions included ABCA1 rs3890182, FTO rs9939609, FTO rs3751812, PPARG rs170036314 and SLC12A3 rs2289116 and were more clearly shown to modify the PFAS associations with insulin sensitivity, rather than with beta-cell function. Discussion: Findings from this study suggest that PFAS-associated changes in insulin sensitivity could vary between individuals as a result of genetic predisposition and warrant replication in independent larger populations.