title: Association of PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with rheumatoid arthritis: A meta-analysis update.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) is a common autoimmune disease with a complex genetic background. The genes encoding protein tyrosine phosphatase non-receptor type 22 (PTPN22) and signal transducer and activator of transcription 4 (STAT4) have been reported to be associated with RA in several ethnic populations.
  
  
  OBJECTIVE
  This work aims to assess the association between PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with RA susceptibility through an updated meta-analysis of available case-control studies.
  
  
  METHODS
  A literature search of all relevant studies published from January 2007 up to December 2014 was conducted using Pubmed and Science Direct databases. The observed studies that were related to an association between PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with RA susceptibility were identified. Meta-analysis of the pooled and stratified data was done and assessed using varied genetic models.
  
  
  RESULTS
  Thirty-seven case-control studies with a total of 47 comparisons (29 for PTPN22 rs2476601 polymorphism and 18 for STAT4 rs7574865 polymorphism) met our inclusion criteria. The meta-analysis showed an association between PTPN22 T allele, CT+TT and TT genotypes with RA susceptibility. Furthermore, The meta-analysis showed an association between STAT4 T allele, GT+TT and TT genotypes with RA susceptibility. Stratification of RA patients according to ethnic groups showed that PTPN22 T allele, CT+TT genotypes, STAT4 T allele and STAT4 GT+TT were significantly associated with RA in European, Asian, African subjects, while PTPN22 TT genotype was significantly associated with RA in European but not in Asian and African subjects and STAT4 TT genotype was significantly associated with RA in European and Asian but not in African subject. A subgroup analysis according to the presence or absence of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies revealed that the association between PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with RA susceptibility may not be dependent on RF and anti-CCP antibodies.
  
  
  CONCLUSIONS
  Our meta-analysis demonstrated that PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms confers susceptibility to RA in total subjects and in major ethnic groups. The association may not be dependent on RF and anti-CCP antibodies.
authors.affiliation: Department of Biochemistry, Faculty of Science, Tanta University, Tanta, Egypt. Electronic address: Biolab100@gmail.com.
authors.forename: Rami
authors.initials: R
authors.lastname: Elshazli
authors.affiliation: Genetics Unit, Children Hospital, Mansoura University, Mansoura, Egypt.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Settin
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D005006:Ethnicity; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D050797:STAT4 Transcription Factor / Q000235:genetics*
chemical_list: D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22
keywords: Anti-CCP; Meta-analysis; PTPN22; Polymorphism; RF; Rheumatoid arthritis; STAT4