Association between IFNA genotype and the risk of sarcoidosis.
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.
Akahoshi
Mitsuteru
M
Laboratory for Genetics of Allergic Diseases, SNP Research Center, Institute of Physical and Chemical Research, RIKEN Yokohama Institute, Yokohama, Japan.
Ishihara
Mami
M
Remus
Natascha
N
Uno
Kazuko
K
Miyake
Katsuhisa
K
Hirota
Tomomitsu
T
Nakashima
Kazuko
K
Matsuda
Akira
A
Kanda
Mizuo
M
Enomoto
Tadao
T
Ohno
Shigeaki
S
Nakashima
Hitoshi
H
Casanova
Jean-Laurent
JL
Hopkin
Julian M
JM
Tamari
Mayumi
M
Mao
Xiao-Quan
XQ
Shirakawa
Taro
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D001681:Biological Assay; D016022:Case-Control Studies; D002648:Child; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000097:blood / Q000378:metabolism; D007372:Interferons / Q000235:genetics*; D018664:Interleukin-12 / Q000097:blood / Q000378:metabolism; D007564:Japan; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012507:Sarcoidosis / Q000235:genetics*; D029082:Sendai virus / Q000378:metabolism
D017931:DNA Primers; C471357:IFNA17 protein, human; D016898:Interferon-alpha; D018664:Interleukin-12; D007372:Interferons