title: The amino acid variation within the binding pocket 7 and 9 of HLA-DRB1 molecules are associated with primary Sjögren's syndrome.
abstract: Primary Sjögren's syndrome (pSS) is associated with HLA-DRB1 loci, but the association of amino acid variations in the hypervariable region of the HLA-DR β1 chain with pSS is largely unknown. In this study, we aimed to identify the amino acid variations within the hypervariable region of HLA-DRB1 molecule which are associated with the susceptibility to pSS. We sequenced the 2nd exon of the HLA-DRB1 locus in 52 pSS patients and 179 controls. The HLA-DRB1*0803 is the allele that shows the strongest association with pSS in Chinese population (OR = 3.0, P = 2.4 × 10(-4)). Furthermore, amino acid variations within the binding pocket P7 and P9 are associated with the susceptibility to pSS. An interaction between two residues within P7, β47 and β67, is associated with pSS. Structural modeling studies demonstrated that the electrostatics of peptide binding pocket 9 are opposite in pSS-susceptible and -protective HLA-DRB1 alleles. In conclusion, our results suggest that structural heterogeneity of the HLA-DRB1 peptide binding pocket P7 and P9 might play a role in the pathogenesis of pSS.
authors.affiliation: The Medical College of Xiamen University, Xiamen University, 361005 Xiamen, China.
authors.forename: Renliang
authors.initials: R
authors.lastname: Huang
authors.affiliation: The Medical College of Xiamen University, Xiamen University, 361005 Xiamen, China.
authors.forename: Junping
authors.initials: J
authors.lastname: Yin
authors.affiliation: The Medical College of Xiamen University, Xiamen University, 361005 Xiamen, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: The Medical College of Xiamen University, Xiamen University, 361005 Xiamen, China.
authors.forename: Fengyuan
authors.initials: F
authors.lastname: Deng
authors.affiliation: First Affiliated Hospital of Xiamen University, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Xiamen University Hospital, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Gao
authors.affiliation: The Medical College of Xiamen University, Xiamen University, 361005 Xiamen, China.
authors.forename: Zuguo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: The Medical College of Xiamen University, Xiamen University, 361005 Xiamen, China; Priority Area Asthma and Allergy, Research Center Borstel, 23845 Borstel, Germany; Airway Research Center North (ARCN), UGMLC, Member of the German Center for Lung Research, Germany.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Yu
authors.affiliation: The Medical College of Xiamen University, Xiamen University, 361005 Xiamen, China; First Affiliated Hospital of Xiamen University, China. Electronic address: zjf075@gmail.com.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000328:Adult; D000483:Alleles; D000596:Amino Acids / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D012859:Sjogren's Syndrome / Q000235:genetics*
chemical_list: D000596:Amino Acids; D059811:HLA-DRB1 Chains
keywords: Autoimmunity; HLA; Homology modeling; Peptide binding groove; Sjögren's syndrome