title: Association Between Dentin Matrix Protein 1 (rs10019009) Polymorphism and Ankylosing Spondylitis in a Chinese Han Population from Shandong Province.
abstract: BACKGROUND
  Ankylosing spondylitis (AS) is the most common rheumatic condition that is slowly progressive and predominantly affects adolescents. Pathological bone formation associated with AS is an important cause of disability. The aim of the study was to investigate the possible involvement of the genes related to endochondral ossification and ectopia ossification in genetic susceptibility to AS in a Chinese Han population.
  
  
  METHODS
  Sixty-eight single nucleotide polymorphisms (SNPs) from 13 genes were genotyped in discovery cohorts including 300 AS patients and 180 healthy controls. The rs10019009 in dentin matrix protein 1 (DMP1) gene shown as association with AS after multiple testing corrections in discovery cohorts was replicated in a validation independent cohort of 620 AS patients and 683 healthy controls. The rs10019009 was assessed with bioinformatics including phylogenetic context, F-SNP and FastSNP functional predictions, secondary structure prediction, and molecular modeling. We performed a functional analysis of rs10019009 via reverse transcription-polymerase chain reaction, alkaline phosphatase (ALP) activity in human osteosarcoma U 2 OS cells.
  
  
  RESULTS
  Interestingly, the SNP rs10019009 was associated with AS in both the discovery cohort (P = 0.0012) and validation cohort (P = 0.0349), as well as overall (P = 0.0004) in genetic case-control association analysis. After a multivariate logistic regression analysis, the effect of this genetic variant was observed to be independent of linkage disequilibrium. Via bioinformatics analysis, it was found that the amino acid change of the rs10019009 led to changes of SNP function, secondary structure, tertiary conformation, and splice mode. Finally, functional analysis of rs10019009 in U 2 OS cells demonstrated that the risk T allele of the rs10019009 increased enzymatic activity of ALP, compared to that of the nonrisk allele (P = 0.0080).
  
  
  CONCLUSIONS
  These results suggested that the DMP1 gene seems to be involved in genetic predisposition to AS, which may contribute to the ectopic mineralization or ossification in AS. In addition, DMP1 gene may be a promising intervention target for AS in the future.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Liu
authors.forename: Ya-Zhou
authors.initials: YZ
authors.lastname: Cui
authors.forename: Geng-Lin
authors.initials: GL
authors.lastname: Zhang
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zhou
authors.forename: Jing-Xiang
authors.initials: JX
authors.lastname: Pang
authors.forename: Xue-Zheng
authors.initials: XZ
authors.lastname: Wang
authors.affiliation: National Laboratory for Bio Drugs of Ministry of Health, Provincial Laboratory for Modern Medicine and Technology of Shandong, Research Center for Medicinal Biotechnology, Shandong Academy of Medical Sciences, Jinan, Shandong 250062, China.
authors.forename: Jin-Xiang
authors.initials: JX
authors.lastname: Han
mesh_terms: D000328:Adult; D002681:China / Q000208:ethnology; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008297:Male; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013167:Spondylitis, Ankylosing / Q000209:etiology / Q000235:genetics*
chemical_list: C513309:DMP1 protein, human; D016326:Extracellular Matrix Proteins; D010750:Phosphoproteins