Tags

Type your tag names separated by a space and hit enter

Transethnic associations among immune-mediated diseases and single-nucleotide polymorphisms of the aryl hydrocarbon response gene ARNT and the PTPN22 immune regulatory gene.
J Autoimmun. 2020 Feb; 107:102363.JA

Abstract

BACKGROUND

Because immune responses are sensitive to environmental changes that drive selection of genetic variants, we hypothesized that polymorphisms of some xenobiotic response and immune response genes may be associated with specific types of immune-mediated diseases (IMD), while others may be associated with IMD as a larger category regardless of specific phenotype or ethnicity.

OBJECTIVE

To examine transethnic gene-IMD associations for single nucleotide polymorphism (SNP) frequencies of prototypic xenobiotic response genes-aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), AHR repressor (AHRR) - and a prototypic immune response gene, protein tyrosine phosphatase, non-receptor type 22 (PTPN22), in subjects from the Environmental Polymorphisms Registry (EPR).

METHODS

Subjects (n = 3731) were genotyped for 14 SNPs associated with functional variants of the AHR, ARNT, AHRR, and PTPN22 genes, and their frequencies were compared among African Americans (n = 1562), Caucasians (n = 1838), and Hispanics (n = 331) with previously reported data. Of those genotyped, 2015 EPR subjects completed a Health and Exposure survey. SNPs were assessed via PLINK for associations with IMD, which included those with autoimmune diseases, allergic disorders, asthma, or idiopathic pulmonary fibrosis. Transethnic meta-analyses were performed using METAL and MANTRA approaches.

RESULTS

ARNT SNP rs11204735 was significantly associated with autoimmune disease by transethnic meta-analyses using METAL (odds ratio, OR [95% confidence interval] = 1.29 [1.08-1.55]) and MANTRA (ORs ranged from 1.29 to 1.30), whereas ARNT SNP rs1889740 showed a significant association with autoimmune disease by METAL (OR = 1.25 [1.06-1.47]). For Caucasian females, PTPN22 SNP rs2476601 was significantly associated with autoimmune disease by allelic association tests (OR = 1.99, [1.30-3.04]). In Caucasians and Caucasian males, PTPN22 SNP rs3811021 was significantly associated with IMD (OR = 1.39 [1.12-1.72] and 1.50 [1.12-2.02], respectively) and allergic disease (OR = 1.39 [1.12-1.71], and 1.62 [1.19-2.20], respectively). In the transethnic meta-analysis, PTPN22 SNP rs3811021 was significantly implicated in IMD by METAL (OR = 1.31 [1.10-1.56]), and both METAL and MANTRA suggested that rs3811021 was associated with IMD and allergic disease in males across all three ethnic groups (IMD METAL OR = 1.50 [1.15-1.95]; IMD MANTRA ORs ranged from 1.47 to 1.50; allergic disease METAL OR = 1.58 [1.20-2.08]; allergic disease MANTRA ORs ranged from 1.55 to 1.59).

CONCLUSIONS

Some xenobiotic and immune response gene polymorphisms were shown here, for the first time, to have associations across a broad spectrum of IMD and ethnicities. Our findings also suggest a role for ARNT in the development of autoimmune diseases, implicating environmental factors metabolized by this pathway in pathogenesis. Further studies are needed to confirm these data, assess the implications of these findings, define gene-environment interactions, and explore the mechanisms leading to these increasingly prevalent disorders.

Authors+Show Affiliations

Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, USA; Research Triangle Park, NC, USA. Electronic address: schurmansh@mail.nih.gov.Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, USA; Bethesda, MD, USA. Electronic address: ohanlont@niehs.nih.gov.Social and Scientific Systems, Durham, NC, USA. Electronic address: jmcgrath@s-3.com.Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA. Electronic address: artiom.gruzdev@nih.gov.Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. Electronic address: bektasar@mail.nih.gov.Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA. Electronic address: xuh2@niehs.nih.gov.Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, USA; Research Triangle Park, NC, USA. Electronic address: garantziotis@niehs.nih.gov.Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA. Electronic address: zeldin@niehs.nih.gov.Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, USA; Research Triangle Park, NC, USA; Bethesda, MD, USA. Electronic address: millerf@mail.nih.gov.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31759816

Citation

Schurman, Shepherd H., et al. "Transethnic Associations Among Immune-mediated Diseases and Single-nucleotide Polymorphisms of the Aryl Hydrocarbon Response Gene ARNT and the PTPN22 Immune Regulatory Gene." Journal of Autoimmunity, vol. 107, 2020, p. 102363.
Schurman SH, O'Hanlon TP, McGrath JA, et al. Transethnic associations among immune-mediated diseases and single-nucleotide polymorphisms of the aryl hydrocarbon response gene ARNT and the PTPN22 immune regulatory gene. J Autoimmun. 2020;107:102363.
Schurman, S. H., O'Hanlon, T. P., McGrath, J. A., Gruzdev, A., Bektas, A., Xu, H., Garantziotis, S., Zeldin, D. C., & Miller, F. W. (2020). Transethnic associations among immune-mediated diseases and single-nucleotide polymorphisms of the aryl hydrocarbon response gene ARNT and the PTPN22 immune regulatory gene. Journal of Autoimmunity, 107, 102363. https://doi.org/10.1016/j.jaut.2019.102363
Schurman SH, et al. Transethnic Associations Among Immune-mediated Diseases and Single-nucleotide Polymorphisms of the Aryl Hydrocarbon Response Gene ARNT and the PTPN22 Immune Regulatory Gene. J Autoimmun. 2020;107:102363. PubMed PMID: 31759816.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transethnic associations among immune-mediated diseases and single-nucleotide polymorphisms of the aryl hydrocarbon response gene ARNT and the PTPN22 immune regulatory gene. AU - Schurman,Shepherd H, AU - O'Hanlon,Terrance P, AU - McGrath,John A, AU - Gruzdev,Artiom, AU - Bektas,Arsun, AU - Xu,Hong, AU - Garantziotis,Stavros, AU - Zeldin,Darryl C, AU - Miller,Frederick W, Y1 - 2019/11/21/ PY - 2019/09/04/received PY - 2019/11/06/revised PY - 2019/11/08/accepted PY - 2021/02/01/pmc-release PY - 2019/11/25/pubmed PY - 2019/11/25/medline PY - 2019/11/25/entrez KW - ARNT KW - Allergic disease KW - Autoimmune disease KW - Immune-mediated disease KW - PTPN22 KW - SNP SP - 102363 EP - 102363 JF - Journal of autoimmunity JO - J. Autoimmun. VL - 107 N2 - BACKGROUND: Because immune responses are sensitive to environmental changes that drive selection of genetic variants, we hypothesized that polymorphisms of some xenobiotic response and immune response genes may be associated with specific types of immune-mediated diseases (IMD), while others may be associated with IMD as a larger category regardless of specific phenotype or ethnicity. OBJECTIVE: To examine transethnic gene-IMD associations for single nucleotide polymorphism (SNP) frequencies of prototypic xenobiotic response genes-aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), AHR repressor (AHRR) - and a prototypic immune response gene, protein tyrosine phosphatase, non-receptor type 22 (PTPN22), in subjects from the Environmental Polymorphisms Registry (EPR). METHODS: Subjects (n = 3731) were genotyped for 14 SNPs associated with functional variants of the AHR, ARNT, AHRR, and PTPN22 genes, and their frequencies were compared among African Americans (n = 1562), Caucasians (n = 1838), and Hispanics (n = 331) with previously reported data. Of those genotyped, 2015 EPR subjects completed a Health and Exposure survey. SNPs were assessed via PLINK for associations with IMD, which included those with autoimmune diseases, allergic disorders, asthma, or idiopathic pulmonary fibrosis. Transethnic meta-analyses were performed using METAL and MANTRA approaches. RESULTS: ARNT SNP rs11204735 was significantly associated with autoimmune disease by transethnic meta-analyses using METAL (odds ratio, OR [95% confidence interval] = 1.29 [1.08-1.55]) and MANTRA (ORs ranged from 1.29 to 1.30), whereas ARNT SNP rs1889740 showed a significant association with autoimmune disease by METAL (OR = 1.25 [1.06-1.47]). For Caucasian females, PTPN22 SNP rs2476601 was significantly associated with autoimmune disease by allelic association tests (OR = 1.99, [1.30-3.04]). In Caucasians and Caucasian males, PTPN22 SNP rs3811021 was significantly associated with IMD (OR = 1.39 [1.12-1.72] and 1.50 [1.12-2.02], respectively) and allergic disease (OR = 1.39 [1.12-1.71], and 1.62 [1.19-2.20], respectively). In the transethnic meta-analysis, PTPN22 SNP rs3811021 was significantly implicated in IMD by METAL (OR = 1.31 [1.10-1.56]), and both METAL and MANTRA suggested that rs3811021 was associated with IMD and allergic disease in males across all three ethnic groups (IMD METAL OR = 1.50 [1.15-1.95]; IMD MANTRA ORs ranged from 1.47 to 1.50; allergic disease METAL OR = 1.58 [1.20-2.08]; allergic disease MANTRA ORs ranged from 1.55 to 1.59). CONCLUSIONS: Some xenobiotic and immune response gene polymorphisms were shown here, for the first time, to have associations across a broad spectrum of IMD and ethnicities. Our findings also suggest a role for ARNT in the development of autoimmune diseases, implicating environmental factors metabolized by this pathway in pathogenesis. Further studies are needed to confirm these data, assess the implications of these findings, define gene-environment interactions, and explore the mechanisms leading to these increasingly prevalent disorders. SN - 1095-9157 UR - https://www.unboundmedicine.com/medline/citation/31759816/Transethnic_associations_among_immune-mediated_diseases_and_single-nucleotide_polymorphisms_of_the_aryl_hydrocarbon_response_gene_ARNT_and_the_PTPN22_immune_regulatory_gene L2 - https://linkinghub.elsevier.com/retrieve/pii/S0896-8411(19)30554-2 DB - PRIME DP - Unbound Medicine ER -
Try the Free App:
Prime PubMed app for iOS iPhone iPad
Prime PubMed app for Android
Prime PubMed is provided
free to individuals by:
Unbound Medicine.