• Hitomi Suzuki, Masao Ota, Akira Meguro, Yoshihiko Katsuyama, Tatukata Kawagoe, Mami Ishihara, Yuri Asukata, Masaki Takeuchi, Norihiko Ito, Etsuko Shibuya, Eiichi Nomura, Riyo Uemoto, Tadayuki Nishide, Kenichi Namba, Nobuyoshi Kitaichi, Shin-ichiro Morimoto, Toshikatsu Kaburaki, Yasutaka Ando, Shinobu Takenaka, Jutaro Nakamura, Kozou Saeki, Shigeaki Ohno, Hidetoshi Inoko, and Nobuhisa Mizuki.
• Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
• Invest. Ophthalmol. Vis. Sci. 2012 Oct 1;53(11):7109-15.

PurposeSarcoidosis is a heterogeneous and multisystem granulomatous disorder. The etiology still is uncertain, but the disease currently is thought to be triggered by various genetic as well as environmental factors. Recently, an association between sarcoidosis and the butyrophilin-like 2 (BTNL2) gene located in close proximity to the HLA-DRB1 gene was reported. The purpose of our study was to verify the relationship between BTNL2 and HLA risk alleles for the susceptibility to sarcoidosis, and to assess whether the BTNL2 association is independent of the HLA risk alleles.MethodsIn our study, 11 single nucleotide polymorphisms (rs28362677, rs2076533, rs2076530, rs2076529, rs2294881, rs3763304, rs2076523, rs28362682, rs3806156, rs9268499, rs3763317), including the functional rs2076530 (G > A) of the BTNL2 gene, and HLA-DRB1 and -DQB1 alleles, were genotyped in 237 Japanese patients diagnosed with sarcoidosis and 287 healthy Japanese control subjects.ResultsIn the patient group, the HLA-DRB1*08:03 (P = 6.15 × 10(-5), odds ratio [OR] = 2.43) and BTNL2 rs2076530_A (P = 6.90 × 10(-6), OR = 1.84) were associated with disease susceptibility. Upon stratification analysis in search for a synergistic effect given the extensive linkage disequilibrium between BTNL2 rs2076530_A and HLA-DRB1*08:03, our results suggested that the risk-bearing allele of these two loci interact negatively. No significant differences were observed in allele frequencies for alleles in patients with ocular and other systemic sarcoidosis.ConclusionsOur studies implicated that the HLA-DRB1 allele is a major contributing genetic factor in the development of sarcoidosis in Japan. However, further studies are needed to verify how HLA or BTNL2 alleles confer the disease phenotype, severity of sarcoidosis.

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