Genetic susceptibility loci for PFAPA

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

We hypothesize that PFAPA is a complex genetic disorder. Recently, we screened a cohort of 231 individuals with PFAPA for candidate variants previously associated with two other oropharyngeal ulcerative disorders: Behcet's disease and recurrent aphthous ulcers. With this approach, we identified several significant genetic risk loci for PFAPA near genes involved in antigen-presenting cell activation and Th1 and Th17 differentiation, including IL12A, STAT4, IL10, and CCR1-CCR3. In particular, the variant near IL12A is the most significant, and we found that it is associated with elevated IL-12 production by monocytes. During fever flares, patients had been noted to have heightened monocyte and T helper (Th)-1 activation with upregulation of interferon (IFN)-induced transcripts and increased levels of IL-12, IFN-gamma, and Th1-associated chemokines in the peripheral blood, which supported the functionality of these variants. The commonality of genetic risk loci among PFAPA, Behcet's disease, and recurrent aphthous ulcers also suggested that these disorders lie on a common spectrum, which we proposed calling Behcet's spectrum disorders (BSD). In addition, we identified unique class I and II HLA susceptibility alleles for PFAPA, suggesting that HLA may be one factor that influences where on the Behcet's spectrum a patient's disease phenotype will be. HLA associations also suggest that particular microbial antigens may stimulate T cells. In order to more fully characterize the genetic architecture of PFAPA, we propose to do a genome-wide association study (GWAS) to identify common, low-penetrance variants associated with the disease. We believe that a GWAS for PFAPA will reveal additional genetic risk loci for the disorder, allow for a more comprehensive comparison of risk loci among the BSDs, facilitate creation of a polygenic risk score for PFAPA, and identify genetic predictors of disease course or treatment response. It is possible that some individuals with BSDs have a monogenic form of disease caused by rare high-penetrance variants; therefore, we also propose to perform additional genomic assays to identify these rare variants or copy number alterations in particular individuals or families to identify disease-causing variants and, thereby, implicated immunologic pathways. We are also assessing the role of trisomy 8 mosaicism in PFAPA and characterizing a cohort of patients with trisomy-8-associated autoinflammatory disease. We are currently recruit patients with PFAPA at NIH on protocol #1043. We will soon add Children's National Hospital in Washington, DC and Indiana University Health in Indianapolis, IN with NIH sites (NIH is the IRB of record and the site where all biologic samples will be analyzed in order to perform a GWAS).