CXADR polymorphism rs6517774 modifies islet autoimmunity characteristics and exhibits sex disparity
Nygård, Lucas; Valta, Milla; Laine, Antti-Pekka; Toppari, Jorma; Knip, Mikael; Veijola, Riitta; Hyöty, Heikki; Ilonen, Jorma; Lempainen, Johanna (2023-11-02)
Nygård, Lucas
Valta, Milla
Laine, Antti-Pekka
Toppari, Jorma
Knip, Mikael
Veijola, Riitta
Hyöty, Heikki
Ilonen, Jorma
Lempainen, Johanna
Frontiers Media
02.11.2023
Nygård L, Valta M, Laine A-P, Toppari J, Knip M, Veijola R, Hyöty H, Ilonen J and Lempainen J (2023), CXADR polymorphism rs6517774 modifies islet autoimmunity characteristics and exhibits sex disparity. Front. Genet. 14:1248701. doi: 10.3389/fgene.2023.1248701.
https://creativecommons.org/licenses/by/4.0/
© 2023 Nygård, Valta, Laine, Toppari, Knip, Veijola, Hyöty, Ilonen and Lempainen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
https://creativecommons.org/licenses/by/4.0/
© 2023 Nygård, Valta, Laine, Toppari, Knip, Veijola, Hyöty, Ilonen and Lempainen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
https://creativecommons.org/licenses/by/4.0/
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202312113638
https://urn.fi/URN:NBN:fi:oulu-202312113638
Tiivistelmä
Abstract
Enteroviral infections have been linked to the development of islet autoimmunity (IA) and type 1 diabetes (T1D), and the coxsackie and adenovirus receptor (CXADR) is one of the ligands used by adenoviruses and enteroviruses for cell internalization. Two CXADR single nucleotide polymorphisms (SNPs), rs6517774 and rs2824404, were previously associated with an increased susceptibility to IA in the international TEDDY study (The Environmental Determinants of Diabetes in the Young). This study aimed to replicate the results by genotyping 2886 children enrolled in the Finnish Diabetes Prediction and Prevention study (DIPP). In our preliminary analysis of the SNPs’ allelic distributions, we could not find any association with IA susceptibility. However, a stratified analysis revealed a sex disparity, since the allelic distribution of rs6517774 was different when comparing autoantibody positive females with males; a difference not seen in healthy subjects. By using HLA risk groups and sex as covariates, a Cox regression survival analysis found that the rs6517774 (A/G) SNP was associated with a lower age at seroconversion in females (Female*rs6517774-AA; HR = 1.53, p = 0.002), while introducing a protective effect in males. Accordingly, we propose that rs6517774 alters IA characteristics by modifying the age at seroconversion in a sex-dependent manner. In light of this observation, rs6517774 now joins a limited set on SNPs found to introduce sex-dependent risk effects on the age at IA initiation.
Enteroviral infections have been linked to the development of islet autoimmunity (IA) and type 1 diabetes (T1D), and the coxsackie and adenovirus receptor (CXADR) is one of the ligands used by adenoviruses and enteroviruses for cell internalization. Two CXADR single nucleotide polymorphisms (SNPs), rs6517774 and rs2824404, were previously associated with an increased susceptibility to IA in the international TEDDY study (The Environmental Determinants of Diabetes in the Young). This study aimed to replicate the results by genotyping 2886 children enrolled in the Finnish Diabetes Prediction and Prevention study (DIPP). In our preliminary analysis of the SNPs’ allelic distributions, we could not find any association with IA susceptibility. However, a stratified analysis revealed a sex disparity, since the allelic distribution of rs6517774 was different when comparing autoantibody positive females with males; a difference not seen in healthy subjects. By using HLA risk groups and sex as covariates, a Cox regression survival analysis found that the rs6517774 (A/G) SNP was associated with a lower age at seroconversion in females (Female*rs6517774-AA; HR = 1.53, p = 0.002), while introducing a protective effect in males. Accordingly, we propose that rs6517774 alters IA characteristics by modifying the age at seroconversion in a sex-dependent manner. In light of this observation, rs6517774 now joins a limited set on SNPs found to introduce sex-dependent risk effects on the age at IA initiation.
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