title: Precursor miR-499a Variant but not miR-196a2 is Associated with Rheumatoid Arthritis Susceptibility in an Egyptian Population.
abstract: Rheumatoid arthritis (RA) has a complex component induced by several genes that interact together with environmental and hormonal factors. We aimed to investigate the association of miR-196a2 rs11614913 (C/T) and miR-499a rs3746444 (A/G) polymorphisms and their combination with RA susceptibility and disease activity in an Egyptian population, and to evaluate their impact on methotrexate drug response and toxicity.
  
  
  
  Bioinformatics databases were searched to select potential micro RNA (miRNA)-messenger RNA (mRNA) interactions involved in RA pathogenesis. Ninety-five RA patients diagnosed according to the American College of Rheumatology and 200 healthy controls were genotyped using real-time polymerase chain reaction technology.
  
  
  
  In overall and stratified analysis, miR-499a, but not miR-196a2, was associated with RA risk. Heterozygote carriers with rs3746444*A/G displayed protection against developing RA (p = 0.005) with an odds ratio of 0.2 (95 % confidence interval 0.17-0.62). The carriage of the combinations (miR499a*AG + miR196a2*CC) and (miR499a*AA + miR196a2*TT) were 3 and 7.5 times more likely to develop RA, respectively, while the combinations (miR499a*GG + miR196a2*CC), (miR499a*AG + miR196a2*TT) and (miR499a*AA + miR196a2*CT) show less susceptibility to have RA disease (all p < 0.05). rs3746444*AA genotype had a higher disease activity score (DAS28) [p = 0.023], tender joint count (TJC) (p = 0.007), and methotrexate-induced gastrointestinal toxicity (p = 0.043) compared with both AG/GG genotypes. rs11614913*C carriers were associated with higher DAS28 activity (p = 0.021). Homozygote male patients (CC and TT) had higher TJC (p = 0.046) and higher rheumatoid factor levels (p = 0.026), whereas, TT homozygote females had higher levels of ALT (p = 0.022).
  
  
  
  Different genotypes of miR-499a rs3746444 single nucleotide polymorphisms (SNPs) are associated with RA risk, disease activity, and methotrexate toxicity in our population. In combination with specific miR-196a2 rs11614913 genotypes, this risk could increase or decrease according to the type of combination. Further functional analysis of the SNP and its impact on mRNA targets is required to confirm the relationship between genotype and phenotype.
authors.affiliation: Department of Histology and Cell Biology (Genetics Unit), Faculty of Medicine, Suez Canal University, Ismailia, Egypt. emantoraih@gmail.com.
authors.forename: Eman A
authors.initials: EA
authors.lastname: Toraih
authors.affiliation: Department of Rheumatology and Rehabilitation, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
authors.forename: Nesreen M
authors.initials: NM
authors.lastname: Ismail
authors.affiliation: Department of Orthopedic Surgery, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Toraih
authors.affiliation: Department of Chest Disease, Faculty of Medicine, Cairo University, Giza, Egypt.
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Hussein
authors.affiliation: Department of Medical Biochemistry, Faculty of Medicine, Suez Canal University, PO 41522, Ismailia, Egypt. manal2_khashana@ymail.com.
authors.forename: Manal S
authors.initials: MS
authors.lastname: Fawzy
mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000453:epidemiology* / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D016000:Cluster Analysis; D004534:Egypt / Q000453:epidemiology; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D058977:Molecular Sequence Annotation; D016017:Odds Ratio; D011159:Population Surveillance; D012306:Risk
chemical_list: C546783:MIRN192 microRNA, human; C548683:MIRN499 microRNA, human; D035683:MicroRNAs