Abstract
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 (PGxE) < 0.05 in at least one PFAS-clinical outcome association, five of which passed False Discovery Rate (FDR) correction (PGxE-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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 115600 |
| Tidsskrift | Environmental Research |
| Vol/bind | 226 |
| ISSN | 0013-9351 |
| DOI | |
| Status | Udgivet - 1. jun. 2023 |
Bibliografisk note
Funding Information:The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Damaskini Valvi reports financial support was provided by National Institute of Environmental Health Sciences. Philippe Grandjean reports a relationship with PFAS-exposed communities that includes: consulting or advisory. Damaskini Valvi reports financial support was provided by National Institute of Environmental Health Sciences. Philippe Grandjean reports financial support was provided by National Institute of Environmental Health Sciences. Pal Weihe reports financial support was provided by Faroese Research Council. Philippe Grandjean reports financial support was provided by Danish Environmental Protection Agency. Karine Audouze reports financial support was provided by European Union Horizon program. Philippe Grandjean reports a relationship with PFAS-exposed communities that includes: paid expert testimony.The authors are grateful to the study participants for their generous collaboration in the Faroese cohort studies, and to Ms. Meizhen Yao at Icahn School of Medicine at Mount Sinai for her assistance in data visualization. This study received funding from the National Institute of Environmental Health Sciences (NIEHS) of the NIH (grant number R01 ES021477), the Faroese Research Council and the Danish Environmental Protection Agency (EPA). DV is supported by NIEHS P30 ES023515 and R21 ES029328. PG is supported by P42 ES027706. KA is supported by the European Union's Horizon 2020 research and innovation programme: OBERON (https://oberon-4eu.com, grant agreement no. 825712).
Funding Information:
The authors are grateful to the study participants for their generous collaboration in the Faroese cohort studies, and to Ms. Meizhen Yao at Icahn School of Medicine at Mount Sinai for her assistance in data visualization. This study received funding from the National Institute of Environmental Health Sciences ( NIEHS ) of the NIH (grant number R01 ES021477 ), the Faroese Research Council and the Danish Environmental Protection Agency (EPA). DV is supported by NIEHS P30 ES023515 and R21 ES029328 . PG is supported by P42 ES027706 . KA is supported by the European Union's Horizon 2020 research and innovation programme: OBERON ( https://oberon-4eu.com , grant agreement no. 825712 ).