Association between IFNA genotype and the risk of sarcoidosis

• Published in: Human genetics 2004-04, Vol.114 (5), p.503-509
• Main Authors: AKAHOSHI, Mitsuteru, ISHIHARA, Mami, OHNO, Shigeaki, NAKASHIMA, Hitoshi, CASANOVA, Jean-Laurent, HOPKIN, Julian M, TAMARI, Mayumi, MAO, Xiao-Quan, SHIRAKAWA, Taro, REMUS, Natascha, UNO, Kazuko, MIYAKE, Katsuhisa, HIROTA, Tomomitsu, NAKASHIMA, Kazuko, MATSUDA, Akira, KANDA, Mizuo, ENOMOTO, Tadao
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Biological and medical sciences; Biological Assay; Case-Control Studies; Child; Classical genetics, quantitative genetics, hybrids; Development and progression; DNA Primers; Enzyme-Linked Immunosorbent Assay; Female; Fundamental and applied biological sciences. Psychology; Gene Frequency; Genes; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Haplotypes - genetics; Human; Humans; Interferon-alpha - blood; Interferon-alpha - metabolism; Interferons - genetics; Interleukin-12 - blood; Interleukin-12 - metabolism; Japan; Male; Medical research; Medical sciences; Medicine, Experimental; Middle Aged; Polymorphism, Single Nucleotide - genetics; Risk Factors; Sarcoidosis - genetics; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Sendai virus - metabolism; Single nucleotide polymorphisms; Tuberculosis
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-004-1099-5

Sarcoidosis is known to be a systemic granulomatous disorder characterized by a cell-mediated Th1-type inflammatory response. To identify a key genetic factor in the pathogenesis of sarcoidosis, we investigated single nucleotide polymorphisms within 10 candidate genes involved in type 1 immune process ( IFNA17, IFNB, IFNG, IFNGR1, IFNGR2, IL12B, IL12RB1, IL12RB2, ETA-1, and NRAMP1) in an association-based study of 102 Japanese patients with sarcoidosis, 114 with tuberculosis, and 110 control subjects. After correction for multiple testing, an IFNA17 polymorphism (551T-->G) was found to be associated with susceptibility to sarcoidosis (odds ratio 3.27 [95% CI: 1.44-7.46], P=0.004, P(c)=0.04), but not to tuberculosis. We observed no significant associations with the other polymorphisms of the Th1-related genes. We further typed another IFNA polymorphism ( IFNA10 60T-->A) and confirmed two major haplotypes of the IFNA gene, viz., allele 1: IFNA10 [60T]- IFNA17 [551T] and allele 2: IFNA10 [60A]- IFNA17 [551G], in the Japanese population. In healthy subjects, IFNA allele 2, which is over-represented in patients with sarcoidosis, was significantly associated with increased IFN-alpha and IL-12p70 production induced by Sendai virus in vitro. This study suggests that possession of the IFNA allele with higher levels of IFN-alpha significantly increases the risk of sarcoidosis.