Common genetic susceptibility loci link PFAPA syndrome, Behcet's disease, and recurrent aphthous stomatitis

Manthiram K., Preite S., Dedeoglu F., Demir S., ÖZEN S., Edwards K. M., ...Daha Fazla

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, cilt.117, sa.25, ss.14405-14411, 2020 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 117 Sayı: 25
  • Basım Tarihi: 2020
  • Doi Numarası: 10.1073/pnas.2002051117
  • Dergi Adı: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Agricultural & Environmental Science Database, Animal Behavior Abstracts, Aquatic Science & Fisheries Abstracts (ASFA), Artic & Antarctic Regions, BIOSIS, CAB Abstracts, EconLit, EMBASE, Food Science & Technology Abstracts, INSPEC, Linguistic Bibliography, MathSciNet, MEDLINE, Pollution Abstracts, Psycinfo, Public Affairs Index, Veterinary Science Database, zbMATH, DIALNET
  • Sayfa Sayıları: ss.14405-14411
  • Anahtar Kelimeler: PFAPA, periodic fever, Behcet's disease, aphthous ulcers, tonsillitis, GENOME-WIDE ASSOCIATION, CERVICAL ADENITIS SYNDROME, MHC CLASS-I, PERIODIC FEVER, T-CELLS, INTERFERON-GAMMA, B-CELLS, PHARYNGITIS, APREMILAST, RISK
  • Eskişehir Osmangazi Üniversitesi Adresli: Hayır

Özet

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the patho- genesis is unknown. We queried two European-American cohorts and one Turkish cohort (total n = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behcet's disease and recurrent aphthous sto- matitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 x 10(-9)). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce sig- nificantly higher levels of IL-12p70 upon IFN-gamma and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4 , IL10 , and CCR1-CCR3 were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behcet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behcet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behcet's spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behcet's disease and recurrent aphthous stomatitis.