title: Genetic characterization and susceptibility for sarcoidosis in Japanese patients: risk factors of BTNL2 gene polymorphisms and HLA class II alleles.
abstract: OBJECTIVE
  Sarcoidosis 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.
  
  
  METHODS
  In 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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Masao
authors.initials: M
authors.lastname: Ota
authors.forename: Akira
authors.initials: A
authors.lastname: Meguro
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Katsuyama
authors.forename: Tatukata
authors.initials: T
authors.lastname: Kawagoe
authors.forename: Mami
authors.initials: M
authors.lastname: Ishihara
authors.forename: Yuri
authors.initials: Y
authors.lastname: Asukata
authors.forename: Masaki
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Norihiko
authors.initials: N
authors.lastname: Ito
authors.forename: Etsuko
authors.initials: E
authors.lastname: Shibuya
authors.forename: Eiichi
authors.initials: E
authors.lastname: Nomura
authors.forename: Riyo
authors.initials: R
authors.lastname: Uemoto
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Nishide
authors.forename: Kenichi
authors.initials: K
authors.lastname: Namba
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Kitaichi
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Morimoto
authors.forename: Toshikatsu
authors.initials: T
authors.lastname: Kaburaki
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Ando
authors.forename: Shinobu
authors.initials: S
authors.lastname: Takenaka
authors.forename: Jutaro
authors.initials: J
authors.lastname: Nakamura
authors.forename: Kozou
authors.initials: K
authors.lastname: Saeki
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Ohno
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Inoko
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Mizuki
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics* / Q000706:statistics & numerical data*; D000071797:Butyrophilins; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D059866:HLA-DQ beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D007564:Japan / Q000453:epidemiology; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012507:Sarcoidosis / Q000208:ethnology* / Q000235:genetics*; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: C408263:BTNL2 protein, human; D000071797:Butyrophilins; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; D008562:Membrane Glycoproteins