Interaction of Genetic Variations in NFE2L2 and SELENOS Modulates the Risk of Hashimoto's Thyroiditis.

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Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_D7B155BB39D0
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Interaction of Genetic Variations in NFE2L2 and SELENOS Modulates the Risk of Hashimoto's Thyroiditis.
Journal
Thyroid
Author(s)
Santos L.R., Durães C., Ziros P.G., Pestana A., Esteves C., Neves C., Carvalho D., Bongiovanni M., Renaud C.O., Chartoumpekis D.V., Habeos I.G., Simões M.S., Soares P., Sykiotis G.P.
ISSN
1557-9077 (Electronic)
ISSN-L
1050-7256
Publication state
Published
Issued date
09/2019
Peer-reviewed
Oui
Volume
29
Number
9
Pages
1302-1315
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Background:
Several single-nucleotide polymorphisms (SNPs) are known to increase the risk of Hashimoto's thyroiditis (HT); such SNPs reside in thyroid-specific genes or in genes related to autoimmunity, inflammation, and/or cellular defense to stress. The transcription factor Nrf2, encoded by NFE2L2, is a master regulator of the cellular antioxidant response. This study aimed to evaluate the impact of genetic variation in NFE2L2 on the risk of developing HT.
Methods:
In a case-control candidate gene association study, functional SNPs in the NFE2L2 promoter (rs35652124, rs6706649, and rs6721961) were examined either as independent risk factors or in combination with a previously characterized HT risk allele (rs28665122) in the gene SELENOS, encoding selenoprotein S (SelS). A total of 997 individuals from the north of Portugal (Porto) were enrolled, comprising 481 HT patients and 516 unrelated healthy controls. SELENOS and NFE2L2 SNPs were genotyped using TaqMan <sup>®</sup> assays and Sanger sequencing, respectively. Odds ratios (ORs) were calculated using logistic regression, with adjustment for sex and age. Expression of SelS was analyzed by immunohistochemistry in thyroid tissue from HT patients and control subjects. Molecular interactions between the Nrf2 and SelS pathways were investigated in thyroid tissues from mice and in rat PCCL3 thyroid follicular cells.
Results:
When all three NFE2L2 SNPs were considered together, the presence of one or more minor alleles was associated with a near-significant increased risk (OR = 1.43, p = 0.072). Among subjects harboring only major NFE2L2 alleles, there was no increased HT risk associated with heterozygosity or homozygosity for the SELENOS minor allele. Conversely, in subjects heterozygous or homozygous for the SELENOS risk allele, the presence of an NFE2L2 minor allele significantly increased HT risk by 2.8-fold (p = 0.003). Immunohistochemistry showed reduced expression of SelS in thyroid follicular cells of HT patients. In Nrf2 knockout mice, there was reduced expression of SelS in thyroid follicular cells; conversely, in PCCL3 cells, reducing SelS expression caused reduced activity of Nrf2 signaling.
Conclusions:
The NFE2L2 promoter genotype interacts with the SELENOS promoter genotype to modulate the risk of HT in a Portuguese population. This interaction may be due to a bidirectional positive feedback between the Nrf2 and SelS pathways.
Keywords
NFE2L2, Nrf2, SELENOS, oxidative stress, selenium, selenoprotein S
Pubmed
Web of science
Research datasets
Open Access
Yes
Funding(s)
FOUNDATION_LEENAARDS//2016 Fellowship for Academic Promotion in Clinical Medicine SNF/Projects/31003A_153062 SNF/Projects/31003A_182105 SEFRI//C15.0045-174626 SNF/Projects/IZCOZ0_177070 OTHER//3R FoundationSwitzerland ProjectGrantNo. 146–15 EC/FP7/RG268266
Create date
03/09/2019 9:36
Last modification date
09/12/2019 8:09
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