The role of genetic predisposition in the potentially diabetogenic effect of PFAS exposure

Abstract

Background: Early life and adult exposure to perfluoroalkyl substances (PFAS) has been associated with insulin resistance and pancreatic beta-cell dysfunction in observational and animal studies. Genetic predisposition to diabetogenic effects from environmental toxicants may modify these associations; however this hypothesis has not been previously studied. Methods: We examined 97 single-nucleotide polymorphisms (SNPs) as effect modifiers of the PFAS association with markers of glucose homeostasis in 665 Faroese adults born in 1986-1987. SNPs were selected based on their suspected associations with the kinetics of environmental toxicants and/or type 2 diabetes risk. 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 2h oral glucose tolerance test performed at age 28. Effect modification was evaluated in linear regression models adjusted for cross-product terms (PFAS*SNP) and confounders. Results: PFOS was associated with decreased insulin sensitivity (β [95% CI] for logISI per PFOS doubling= -0.05 [-0.12, 0.01] for prenatal exposure, and -0.05 [-0.09, -0.01] for adult exposure) and increased beta-cell function (β [95% CI] for logIGI per PFOS doubling=0.12 [0.02, 0.22] for prenatal exposure and 0.04 [-0.03, 0.11] for adult exposure). PFOA associations were in the same direction as for PFOS but more attenuated. In preliminary analysis, we found 25 SNPs which adversely modified the associations of PFOS with ISI and/or IGI, from which 15 SNPs further modified the associations of PFOA with ISI and/or IGI (p-value for interaction<0.05). Most of these SNPs were in genes that encode important proteins for energy homeostasis and metabolism, such as the FTO and PPARG genes. Conclusions: These findings suggest that genetic predisposition may play a role in the effects of PFAS exposures on insulin resistance and beta-cell function.