TY - JOUR
T1 - Genetic analysis of interferon induced thyroiditis (IIT)
T2 - Evidence for a key role for MHC and apoptosis related genes and pathways
AU - Hasham, Alia
AU - Zhang, Weijia
AU - Lotay, Vaneet
AU - Haggerty, Shannon
AU - Stefan, Mihaela
AU - Concepcion, Erlinda
AU - Dieterich, Douglas T.
AU - Tomer, Yaron
N1 - Funding Information:
This work was supported in part by a VA Merit award 1I01BX002031 from the Department of Veterans Affairs, and by grants DK61659 , and DK073681 from NIDDK (to YT). We thank Dr. David A. Greenberg (Battelle Center for Mathematical Medicine and Department of Neurology, Nationwide Children's Hospital, Columbus, Ohio) for his suggestions and expert review of this manuscript.
PY - 2013/8
Y1 - 2013/8
N2 - Autoimmune thyroid diseases (AITD) have become increasingly recognized as a complication of interferon-alpha (IFNα) therapy in patients with chronic Hepatitis C virus (HCV) infection. Interferon-induced thyroiditis (IIT) can manifest as clinical thyroiditis in approximately 15% of HCV patients receiving IFNα and subclinical thyroiditis in up to 40% of patients, possibly resulting in either dose reduction or discontinuation of IFNα treatment. However, the exact mechanisms that lead to the development of IIT are unknown and may include IFNα-mediated immune-recruitment as well as direct toxic effects on thyroid follicular cells. We hypothesized that IIT develops in genetically predisposed individuals whose threshold for developing thyroiditis is lowered by IFNα. Therefore, our aim was to identify the susceptibility genes for IIT. We used a genomic convergence approach combining genetic association data with transcriptome analysis of genes upregulated by IFNα. Integrating results of genetic association, transcriptome data, pathway, and haplotype analyses enabled the identification of 3 putative loci, SP100/110/140 (2q37.1), HLA (6p21.3), and TAP1 (6p21.3) that may be involved in the pathogenesis of IIT. Immune-regulation and apoptosis emerged as the predominant mechanisms underlying the etiology of IIT.
AB - Autoimmune thyroid diseases (AITD) have become increasingly recognized as a complication of interferon-alpha (IFNα) therapy in patients with chronic Hepatitis C virus (HCV) infection. Interferon-induced thyroiditis (IIT) can manifest as clinical thyroiditis in approximately 15% of HCV patients receiving IFNα and subclinical thyroiditis in up to 40% of patients, possibly resulting in either dose reduction or discontinuation of IFNα treatment. However, the exact mechanisms that lead to the development of IIT are unknown and may include IFNα-mediated immune-recruitment as well as direct toxic effects on thyroid follicular cells. We hypothesized that IIT develops in genetically predisposed individuals whose threshold for developing thyroiditis is lowered by IFNα. Therefore, our aim was to identify the susceptibility genes for IIT. We used a genomic convergence approach combining genetic association data with transcriptome analysis of genes upregulated by IFNα. Integrating results of genetic association, transcriptome data, pathway, and haplotype analyses enabled the identification of 3 putative loci, SP100/110/140 (2q37.1), HLA (6p21.3), and TAP1 (6p21.3) that may be involved in the pathogenesis of IIT. Immune-regulation and apoptosis emerged as the predominant mechanisms underlying the etiology of IIT.
KW - Autoimmunity
KW - Interferon
KW - Thyroid
KW - Thyroiditis
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U2 - 10.1016/j.jaut.2013.04.002
DO - 10.1016/j.jaut.2013.04.002
M3 - Article
C2 - 23683877
AN - SCOPUS:84881370610
SN - 0896-8411
VL - 44
SP - 61
EP - 70
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
ER -