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SP0009 The Expanding Spectrum of Autoinflammation
  1. E. F. Remmers1
  1. 1MGB/Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, United States


The term autoinflammation was coined by McDermott and colleagues in 1999 to describe inflammatory conditions with apparently unprovoked inflammation without high titer autoantibodies or antigen-specific T lymphocytes. Unlike autoimmune diseases, in which inflammation is driven by adaptive immune responses of lymphocytes with antigen receptors that somatically rearrange and mutate, the autoinflammatory syndromes are characterized by inflammation driven by dysregulated innate immune responses involving myeloid effector cells with germ-line receptors for pathogen-associated molecular patterns and danger signals. In 1999, the genetic causes of two monogenic autoinflammatory diseases were identified (MEFV for familial Mediterranean fever and TNFRSF1A for TRAPS), however these genes accounted for only a minority of patients with clinically defined autoinflammatory syndromes. Since then, the list of genes harboring mutations that cause rare monogenic autoinflammatory diseases has exploded and now includes: NLRP3, NLRP7, NLRP12, CARD15, MVK, PSTPIP1, IL1RN, LPIN2, GBA, SH3BP2, LYST, CARD14, RAB27A, PSMB8, IL36RN, PLCG2, the complement factor genes responsible for atypical hemolytic-uremic syndromes and age-related macular degeneration (CFH, MCP, CFI, and CFB), the nucleic acid catabolism and interferon responsive genes responsible for Aicardi-Goutieres disease (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR1), and the cytotoxic effector function genes responsible for familial hemophagocytic lymphohistiocytosis (UNC13D, PRF1, STX11, and STXBP2).

In addition to these rare monogenic autoinflammatory diseases, some relatively common, genetically complex diseases also have features of autoinflammation. These complex autoinflammtory diseases include several disorders that have been subjected to genome-wide association studies (GWAS), including atherosclerosis, type 2 diabetes, Crohn’s disease, and gout. However, with the exception of CARD15 in Crohn’s disease, for which disease-associated coding variants of up to 5% frequency have been identified, no disease-associated variants have been identified by GWAS in the genes mutated in the monogenic autoinflammatory diseases or in other genes involved in innate immune responses. Our recent GWAS of Behçet’s disease, a complex genetic disease which exhibits autoinflammatory features, also failed to reveal common disease-associated variants in autoinflammatory genes.

We hypothesized that rare and low frequency variants that are not interrogated by standard genome-wide association studies might contribute to disease susceptibility. Using next generation sequencing technology, we identified rare and low frequency non-synonymous variants by deeply resequencing a panel of autoinflammatory genes (IL1B, IL1R1, IL1RN, NLRP3, MEFV, TNFRSF1A, PSTPIP1, CASP1, PYCARD, NOD2, and TLR4) in pooled DNAs. We then genotyped the identified variants in 2461 Behçet’s cases and 2458 controls. We applied 3 different burden tests to determine if the combined rare and low frequency variants of a gene were collectively associated with disease. By stringent criteria requiring at least one burden test with study-wide significance and a corroborating test with at least nominal significance, rare and low frequency non-synonymous variants in TLR4 (p = 8.0 x 10-4) were associated with disease. In addition, damaging or rare damaging NOD2 variants were nominally significant across all 3 burden tests applied (p = 0.0063 to 0.045). Furthermore, carriage of MEFV-M694V, known to cause recessively inherited familial Mediterranean fever, conferred Behçet’s disease risk in the Turkish population (OR = 2.65, p = 1.8 x 10-12). MEFV and TLR4 implicate innate immune and bacterial sensing mechanisms in BD pathogenesis.

Identifying and evaluating rare and low frequency variants of autoinflammatory pathway genes allowed us to detect their contribution to Behçet’s disease susceptibility and therefore confirm the contribution of autoinflammation to disease pathogenesis. Similar contributions of rare autoinflammatory gene variants to common genetically complex diseases may further expand the spectrum of pathogenic autoinflammation.

Disclosure of Interest None Declared

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