Common genetic susceptibility loci link PFAPA syndrome, Behçet’s disease, and recurrent aphthous stomatitis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 25; pp. 14405 - 14411
• Main Authors: Manthiram, Kalpana, Preite, Silvia, Dedeoglu, Fatma, Demir, Selcan, Ozen, Seza, Edwards, Kathryn M., Lapidus, Sivia, Katz, Alexander E., Feder, Henry M., Lawton, Maranda, Licameli, Greg R., Wright, Peter F., Le, Julie, Barron, Karyl S., Ombrello, Amanda K., Barham, Beverly, Romeo, Tina, Jones, Anne, Srinivasalu, Hemalatha, Mudd, Pamela A., DeBiasi, Roberta L., Gül, Ahmet, Marshall, Gary S., Jones, Olcay Y., Chandrasekharappa, Settara C., Stepanovskiy, Yuriy, Ferguson, Polly J., Schwartzberg, Pamela L., Remmers, Elaine F., Kastner, Daniel L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.06.2020
• Subjects: Adaptive immunity; Adenitis; Alleles; Antigen-presenting cells; Antigens; Aphthous stomatitis; Behcet Syndrome - genetics; Behcet Syndrome - immunology; Behcet's syndrome; Biological Sciences; CCR1 protein; Child; Cohort Studies; Disorders; Fever; Fever - genetics; 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; Genetic Predisposition to Disease; Histocompatibility antigen HLA; Humans; Interleukin 1; Interleukin 10; Interleukin 12; Lipopolysaccharides; Loci; Lymphadenitis - genetics; Lymphadenitis - immunology; Lymphocytes; Lymphocytes T; Monocytes; Mucosa; Pathogenesis; Pharyngitis; Pharyngitis - genetics; Pharyngitis - immunology; Phenotypes; Polymorphism, Single Nucleotide; Risk Factors; Stat4 protein; Stomatitis, Aphthous - genetics; Stomatitis, Aphthous - immunology; Syndrome; Vein & artery diseases; γ-Interferon; aphthous ulcers; tonsillitis; PFAPA; Behçet’s disease; periodic fever
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2002051117

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 × 10−9). 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.