title: Association and expression of the antigen-processing gene PSMB8, coding for low-molecular-mass protease 7, with vitiligo in North India: case-control study.
abstract: Vitiligo is a multifactorial, autoimmune, depigmenting disorder of the skin where aberrant presentation of autoantigens may have a role.
  
  
  
  To study the association of two antigen-processing genes, PSMB8 and PSMB9, with vitiligo.
  
  
  
  In total 1320 cases of vitiligo (1050 generalized and 270 localized) and 752 healthy controls were studied for the PSMB9 exon 3 G/A single-nucleotide polymorphism (SNP), PSMB8 exon 2 C/A SNP and PSMB8 intron 6 G/T SNP at site 37 360 using polymerase chain reaction (PCR)-restriction fragment length polymorphism. Real-time PCR was used for transcriptional expression of PSMB8 and cytokines. Expression of ubiquitinated proteins and phosphorylated-p38 (P-p38) was studied by Western blotting.
  
  
  
  Significant increases in PSMB8 exon 2 allele A (P < 2.07 × 10-6, odds ratio 1·93) and genotypes AA (P < 1.03 × 10-6, odds ratio 2·51) and AC (P < 1.29 × 10-6, odds ratio 1·63) were observed in patients with vitiligo. Interferon-γ stimulation induced lower expression of PSMB8 in peripheral blood mononuclear cells of cases compared with controls, suggesting impaired antigen processing, which was confirmed by accumulation of ubiquitinated proteins in both lesional and nonlesional skin of patients with vitiligo. Expression of proinflammatory cytokines - interleukin (IL)-6, IL-1β and IL-8 - was higher in the lesional skin. P-p38 expression was variable but correlated with the amount of ubiquitinated proteins in the lesional and nonlesional skin, suggesting that the inflammatory cytokine responses in lesional skin could be a result of both P-p38-dependent and -independent pathways.
  
  
  
  The PSMB8 exon 2 SNP is significantly associated with vitiligo. Accumulation of ubiquitinated proteins in skin of cases of vitiligo suggests their aberrant processing, which may promote the development of the disease.
authors.affiliation: Molecular Immunogenetics Group, National Institute of Immunology, New Delhi, 110067, India.
authors.forename: P
authors.initials: P
authors.lastname: Dani
authors.affiliation: Molecular Immunogenetics Group, National Institute of Immunology, New Delhi, 110067, India.
authors.forename: N
authors.initials: N
authors.lastname: Patnaik
authors.affiliation: Molecular Immunogenetics Group, National Institute of Immunology, New Delhi, 110067, India.|Systems Biology Group, CSIR - Institute of Genomics and Integrative Biology, New Delhi, 110025, India.
authors.forename: A
authors.initials: A
authors.lastname: Singh
authors.affiliation: Molecular Immunogenetics Group, National Institute of Immunology, New Delhi, 110067, India.
authors.forename: A
authors.initials: A
authors.lastname: Jaiswal
authors.affiliation: Molecular Immunogenetics Group, National Institute of Immunology, New Delhi, 110067, India.
authors.forename: B
authors.initials: B
authors.lastname: Agrawal
authors.affiliation: Molecular Immunogenetics Group, National Institute of Immunology, New Delhi, 110067, India.
authors.forename: A A
authors.initials: AA
authors.lastname: Kumar
authors.affiliation: Molecular Immunogenetics Group, National Institute of Immunology, New Delhi, 110067, India.
authors.forename: S R
authors.initials: SR
authors.lastname: Varkhande
authors.affiliation: Molecular Immunogenetics Group, National Institute of Immunology, New Delhi, 110067, India.
authors.forename: A
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Molecular Immunogenetics Group, National Institute of Immunology, New Delhi, 110067, India.
authors.forename: U
authors.initials: U
authors.lastname: Vaish
authors.affiliation: Systems Biology Group, CSIR - Institute of Genomics and Integrative Biology, New Delhi, 110025, India.
authors.forename: P
authors.identifier: 0000-0003-3015-8602
authors.initials: P
authors.lastname: Ghosh
authors.affiliation: Department of Dermatology, All India Institute of Medical Sciences, New Delhi, 110029, India.
authors.forename: V K
authors.initials: VK
authors.lastname: Sharma
authors.affiliation: Department of Dermatology, PGIMER, Dr Ram Manohar Lohia Hospital, New Delhi, 110001, India.
authors.forename: P
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Department of Dermatology, PGIMER, Dr Ram Manohar Lohia Hospital, New Delhi, 110001, India.
authors.forename: G
authors.initials: G
authors.lastname: Verma
authors.affiliation: Department of Dermatology, PGIMER, Dr Ram Manohar Lohia Hospital, New Delhi, 110001, India.
authors.forename: H K
authors.initials: HK
authors.lastname: Kar
authors.affiliation: Department of Dermatology, All India Institute of Medical Sciences, New Delhi, 110029, India.
authors.forename: S
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Systems Biology Group, CSIR - Institute of Genomics and Integrative Biology, New Delhi, 110025, India.
authors.forename: V T
authors.initials: VT
authors.lastname: Natarajan
authors.affiliation: Molecular Immunogenetics Group, National Institute of Immunology, New Delhi, 110067, India.|Systems Biology Group, CSIR - Institute of Genomics and Integrative Biology, New Delhi, 110025, India.
authors.forename: R S
authors.initials: RS
authors.lastname: Gokhale
authors.affiliation: Molecular Immunogenetics Group, National Institute of Immunology, New Delhi, 110067, India.|Systems Biology Group, CSIR - Institute of Genomics and Integrative Biology, New Delhi, 110025, India.
authors.forename: R
authors.identifier: 0000-0002-4767-5879
authors.initials: R
authors.lastname: Rani
mesh_terms: D000328:Adult; D017668:Age of Onset; D017951:Antigen Presentation / Q000235:genetics; D016022:Case-Control Studies; D003546:Cysteine Endopeptidases / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007194:India; D008297:Male; D010447:Peptide Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D014820:Vitiligo / Q000235:genetics*; D055815:Young Adult
chemical_list: C071313:LMP-2 protein; D010447:Peptide Hydrolases; C040106:peptidase 7; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex