title: Sarcoidosis and NOD1 variation with impaired recognition of intracellular Propionibacterium acnes.
abstract: 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.
authors.affiliation: Age Dimension Research Center, National Institute of Advanced Industrial Science and Technology, Tsukuba 305-8566, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Tanabe
authors.forename: Ikuo
authors.initials: I
authors.lastname: Ishige
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Yukie
authors.initials: Y
authors.lastname: Aita
authors.forename: Asuka
authors.initials: A
authors.lastname: Furukawa
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ishige
authors.forename: Keisuke
authors.initials: K
authors.lastname: Uchida
authors.forename: Takashige
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tamiko
authors.initials: T
authors.lastname: Takemura
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ikushima
authors.forename: Masaru
authors.initials: M
authors.lastname: Oritsu
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Yukari
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukase
authors.forename: Naohiro
authors.initials: N
authors.lastname: Inohara
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nunez
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Eishi
mesh_terms: 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
chemical_list: C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein