title: Distribution of MEFV gene mutations and R202Q polymorphism in the Serbian population and their influence on oxidative stress and clinical manifestations of inflammation.
abstract: BACKGROUND
  The Mediterranean fever (MEFV) gene codes for protein pyrin, one of the regulators of inflammasome activity in innate immune cells. Mutations in this gene are considered the primary cause of Familial Mediterranean fever, but are also found in other monogenic and multifactorial autoinflammatory diseases. The aim of the study was to determine if healthy carriers of MEFV gene mutations and R202Q polymorphism have clinical manifestations of inflammation and impaired oxidative stress parameters.
  
  
  METHODS
  One hundred DNA samples from healthy volunteers (13.3 ± 8.87 years of age (mean ± SD); range 2-35) were sequenced by ABI PRISM 310 automated sequencer (PE Applied Biosystems, Norwalk, USA). The Eurofever questionnaire was used to collect retrospectively medical history data. Oxidative stress was determined by measuring spectrophotometrically thiobarbituric acid reactive substances (TBARS) in plasma and erythrocytes, as well as advanced oxidation protein products in plasma. Superoxide dismutase (SOD) activity was determined by McCord and Fridovich method in plasma and erythrocytes, while the catalase erythrocyte activity was assessed using a catalase ELISA kit.
  
  
  RESULTS
  We found heterozygous carriers of K695R/N mutations in 5 %, E148Q/N mutations in 6 %, R202Q homozygous polymorphism in 10 % and heterozygous R202Q alterations in 45 % of healthy volunteers. The MEFV mutation carriers and R202Q polymorphism homozygotes reported significantly more often recurrent febrile episodes (p = 0.009), diffuse abdominal pain (p = 0.025), and malaise (p = 0.012) compared to non-carriers. Erythrocyte TBARS levels and plasma SOD activity were higher in persons with MEFV mutations and R202Q/R202Q (p = 0.03 and p = 0.049, respectively).
  
  
  CONCLUSIONS
  Healthy individuals may bear E148Q and K695R MEFV gene mutations, as well as R202Q polymorphism in homozygous state. The determined gene alterations contribute to a subtle oxidative stress and may be associated with more frequent episodes of fever and unspecific inflammatory manifestations. An incomplete penetrance or variable expressivity of R202Q in populations of different ethnicity could influence the expression of autoinflammatory diseases phenotype.
authors.affiliation: Institute of Pathophysiology, Faculty of Medicine, University of Niš, Bul. Zorana Đinđića 81, 18000, Niš, Serbia. jelenaradovic982@gmail.com.
authors.forename: Jelena
authors.initials: J
authors.lastname: Milenković
authors.affiliation: Department of Pediatric Rheumatology, Clinical Center, Faculty of Medicine, University of Niš, Bul. Zorana Đinđića 81, 18000, Niš, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Vojinović
authors.affiliation: Unit for Special Laboratory Diagnostics, Bohoričeva 20, 1000, Ljubljana, Slovenia.
authors.forename: Maruša
authors.initials: M
authors.lastname: Debeljak
authors.affiliation: Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Center; Faculty of Medicine, University of Ljubljana, Bohoričeva 20, 1000, Ljubljana, Slovenia.
authors.forename: Nataša
authors.initials: N
authors.lastname: Toplak
authors.affiliation: Department of Pediatric Rheumatology, Clinical Center, Faculty of Medicine, University of Niš, Bul. Zorana Đinđića 81, 18000, Niš, Serbia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Lazarević
authors.affiliation: Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Center; Faculty of Medicine, University of Ljubljana, Bohoričeva 20, 1000, Ljubljana, Slovenia.
authors.forename: Tadej
authors.initials: T
authors.lastname: Avčin
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Niš, Bul. Zorana Đinđića 81, 18000, Niš, Serbia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Jevtović-Stoimenov
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Niš, Bul. Zorana Đinđića 81, 18000, Niš, Serbia.
authors.forename: Dušica
authors.initials: D
authors.lastname: Pavlović
authors.affiliation: Institute of Pathophysiology, Faculty of Medicine, University of Niš, Bul. Zorana Đinđića 81, 18000, Niš, Serbia.
authors.forename: Vladmila
authors.initials: V
authors.lastname: Bojanić
authors.affiliation: Institute of Pathophysiology, Faculty of Medicine, University of Niš, Bul. Zorana Đinđića 81, 18000, Niš, Serbia.
authors.forename: Maja
authors.initials: M
authors.lastname: Milojković
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Niš, Bul. Zorana Đinđića 81, 18000, Niš, Serbia.
authors.forename: Gordana
authors.initials: G
authors.lastname: Kocić
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Niš, Bul. Zorana Đinđića 81, 18000, Niš, Serbia.
authors.forename: Andrej
authors.initials: A
authors.lastname: Veljković
mesh_terms: D000293:Adolescent; D000328:Adult; D002374:Catalase / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics*; D011110:Polymorphism, Genetic; D000071198:Pyrin / Q000235:genetics*; D055771:Serbia; D013053:Spectrophotometry; D013482:Superoxide Dismutase / Q000378:metabolism; D011795:Surveys and Questionnaires; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: C000604192:MEFV protein, human; D000071198:Pyrin; D017392:Thiobarbituric Acid Reactive Substances; D002374:Catalase; D013482:Superoxide Dismutase
keywords: Autoinflammation; MEFV gene mutations; Oxidative stress; R202Q polymorphism; Recurrent fevers