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Common genetic susceptibility loci link PFAPA syndrome, Behçet's disease, and recurrent aphthous stomatitis.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jun 23; Vol. 117 (25), pp. 14405-14411. Date of Electronic Publication: 2020 Jun 09. - Publication Year :
- 2020
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Abstract
- 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 pathogenesis 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, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 × 10 <superscript>-9</superscript> ). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ 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 Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet'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 Behçet's disease and recurrent aphthous stomatitis.<br />Competing Interests: Competing interest statement: F.D. is a consultant to Novartis and receives royalties from UpToDate. K.M.E. is on the Data Safety and Monitoring Board for Seqirus, Pfizer, Sanofi, Moderna, and X4 Pharma, and serves as an advisor to Bio-Net and Merck. P.F.W. is on the scientific advisory boards for GlaxoSmithKline, Sanofi-Pasteur, and Meissa Vaccines.<br /> (Copyright © 2020 the Author(s). Published by PNAS.)
- Subjects :
- Alleles
Behcet Syndrome immunology
Child
Cohort Studies
Fever immunology
Genes, MHC Class I genetics
Genes, MHC Class I immunology
Genes, MHC Class II genetics
Genes, MHC Class II immunology
Genetic Loci immunology
Humans
Lymphadenitis immunology
Pharyngitis immunology
Polymorphism, Single Nucleotide
Risk Factors
Stomatitis, Aphthous immunology
Syndrome
Behcet Syndrome genetics
Fever genetics
Genetic Predisposition to Disease
Lymphadenitis genetics
Pharyngitis genetics
Stomatitis, Aphthous genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 117
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 32518111
- Full Text :
- https://doi.org/10.1073/pnas.2002051117