Journal article
Common genetic susceptibility loci link PFAPA syndrome, Behçet's disease, and recurrent aphthous stomatitis
Proceedings of the National Academy of Sciences - PNAS, Vol.117(25), pp.14405-14411
06/23/2020
DOI: 10.1073/pnas.2002051117
PMID: 32518111
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
= 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
(rs17753641) is strongly associated with PFAPA (OR 2.13,
= 6 × 10
). 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
,
, and
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.
alleles may be factors that influence phenotypes along this spectrum as we found new class I and II
associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis.
Details
- Title: Subtitle
- Common genetic susceptibility loci link PFAPA syndrome, Behçet's disease, and recurrent aphthous stomatitis
- Creators
- Kalpana Manthiram - National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; kalpana.manthiram@nih.gov dan.kastner@nih.govSilvia Preite - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892Fatma Dedeoglu - Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115Selcan Demir - Department of Pediatric Rheumatology, Hacettepe University Faculty of Medicine, 06100 Ankara, TurkeySeza Ozen - Department of Pediatric Rheumatology, Hacettepe University Faculty of Medicine, 06100 Ankara, TurkeyKathryn M Edwards - Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232Sivia Lapidus - Division of Pediatric Rheumatology, Joseph M. Sanzari Children's Hospital, Hackensack Meridian Health, Hackensack, NJ 07601Alexander E Katz - National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892Henry M Feder Jr - Department of Pediatrics, Connecticut Children's Medical Center, Hartford, CT 06106Maranda Lawton - Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115Greg R Licameli - Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115Peter F Wright - Department of Pediatrics, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756Julie Le - National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892Karyl S Barron - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892Amanda K Ombrello - National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892Beverly Barham - National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892Tina Romeo - National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892Anne Jones - National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892Hemalatha Srinivasalu - Division of Pediatric Rheumatology, Children's National Hospital, The George Washington University School of Medicine and Health Sciences, Washington, DC 20010Pamela A Mudd - Division of Pediatric Otolaryngology, Children's National Hospital, The George Washington University School of Medicine and Health Sciences, Washington, DC 20010Roberta L DeBiasi - Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC 20010Ahmet Gül - Department of Internal Medicine, Division of Rheumatology, Istanbul Faculty of Medicine, Istanbul University, 34093 Istanbul, TurkeyGary S Marshall - Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40202Olcay Y Jones - Division of Pediatric Rheumatology, Walter Reed National Military Medical Center, Bethesda, MD 20889Settara C Chandrasekharappa - National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892Yuriy Stepanovskiy - Department of Pediatric Infectious Diseases and Pediatric Immunology, Shupyk National Medical Academy of Postgraduate Education, 04112 Kiev, UkrainePolly J Ferguson - Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52242Pamela L Schwartzberg - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892Elaine F Remmers - National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892Daniel L Kastner - National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; kalpana.manthiram@nih.gov dan.kastner@nih.gov
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.117(25), pp.14405-14411
- DOI
- 10.1073/pnas.2002051117
- PMID
- 32518111
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences; United States
- Grant note
- name: Division of Intramural Research, National Human Genome Research Institute, award: N/A; DOI: 10.13039/100006492, name: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, award: N/A; name: Department of Rheumatology, Boston, Children's Hospital, award: N/A; name: The Childhood Arthritis and Rheumatology Research Alliance, award: N/A; name: Private donation from family of child with PFAPA, award: N/A; name: National Institutes of Health Director Challenge Fund, award: N/A; name: Istanbul University Research Fund, award: N/A
- Language
- English
- Date published
- 06/23/2020
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Rheumatology, Allergy, and Immunology
- Record Identifier
- 9984070591002771
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