title: Genetic analysis of interferon induced thyroiditis (IIT): evidence for a key role for MHC and apoptosis related genes and pathways.
abstract: 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.
authors.affiliation: Division of Endocrinology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Alia
authors.initials: A
authors.lastname: Hasham
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.forename: Vaneet
authors.initials: V
authors.lastname: Lotay
authors.forename: Shannon
authors.initials: S
authors.lastname: Haggerty
authors.forename: Mihaela
authors.initials: M
authors.lastname: Stefan
authors.forename: Erlinda
authors.initials: E
authors.lastname: Concepcion
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Dieterich
authors.forename: Yaron
authors.initials: Y
authors.lastname: Tomer
mesh_terms: D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D016174:Hepacivirus / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013966:Thyroiditis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology
chemical_list: D016898:Interferon-alpha
keywords: Autoimmunity; Interferon; Thyroid; Thyroiditis