Sarcoidosis and NOD1 variation with impaired recognition of intracellular Propionibacterium acnes.
Sarcoidosis is a systemic granulomatous disease of unknown etiology. NOD2 mutations have been shown to predispose to granulomatous diseases, including Crohn's disease, Blau syndrome, and early-onset sarcoidosis, but not to adult sarcoidosis. We found that intracellular Propionibacterium acnes, a possible causative agent of sarcoidosis, activated NF-kappaB in both NOD1- and NOD2-dependent manners. Systematic search for NOD1 gene polymorphisms in Japanese sarcoidosis patients identified two alleles, 796G-haplotype (156C, 483C, 796G, 1722G) and 796A-haplotype (156G, 483T, 796A, 1722A). Allelic discrimination of 73 sarcoidosis patients and 215 healthy individuals showed that the frequency of 796A-type allele was significantly higher in sarcoidosis patients and the ORs were significantly elevated in NOD1-796G/A and 796A/A genotypes (OR [95% CI]=2.250 [1.084, 4.670] and 3.243 [1.402, 7.502], respectively) as compared to G/G genotype, showing an increasing trend across the 3 genotypes (P=0.006 for trend). A similar association was found when 52 interstitial pneumonia patients were used as disease controls. Functional studies showed that the NOD1 796A-allele was associated with reduced expression leading to diminished NF-kappaB activation in response to intracellular P. acnes. The results indicate that impaired recognition of intracellular P. acnes through NOD1 affects the susceptibility to sarcoidosis in the Japanese population.
Tanabe
Tsuyoshi
T
Age Dimension Research Center, National Institute of Advanced Industrial Science and Technology, Tsukuba 305-8566, Japan.
Ishige
Ikuo
I
Suzuki
Yoshimi
Y
Aita
Yukie
Y
Furukawa
Asuka
A
Ishige
Yuki
Y
Uchida
Keisuke
K
Suzuki
Takashige
T
Takemura
Tamiko
T
Ikushima
Soichiro
S
Oritsu
Masaru
M
Yokoyama
Tetsuji
T
Fujimoto
Yukari
Y
Fukase
Koichi
K
Inohara
Naohiro
N
Nunez
Gabriel
G
Eishi
Yoshinobu
Y
D016022:Case-Control Studies; D002460:Cell Line; D004847:Epithelial Cells / Q000382:microbiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006790:Host-Parasite Interactions; D006801:Humans; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics* / Q000502:physiology*; D011110:Polymorphism, Genetic; D011425:Propionibacterium acnes / Q000302:isolation & purification / Q000502:physiology*; D012044:Regression Analysis; D012507:Sarcoidosis / Q000209:etiology / Q000235:genetics* / Q000382:microbiology; D014162:Transfection
C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein