Background/Purpose: The current scientific opinion holds that gene and environment (G X E) interactions contribute to certain human diseases. Systemic autoinflammatory diseases (SAIDs) are usually associated with genetic variations. Unlike classic monogenic disease (Huntington’s disease), some genetic mutations associated with SAIDs are of low frequency and low penetrance. In other words, a small proportion of healthy people carry these mutations. Therefore, a gene of interest or candidate gene, genetic background, and environment are hypothesized to collectively cause disease. COVID19 is an environmental factor. Herein, we report a case series of SAID patients to support the above proposition.

Methods: In this retrospective single center study, a cohort of adult patients were enrolled and fulfilled the diagnostic criteria for certain SAIDs as confirmed by molecular analysis. After extensive negative workup for systemic autoimmune and related diseases, genetic testing of periodic fever syndrome 6-gene panel and an extended SAID gene panel were performed at Commercial Diagnostic Molecular Laboratories.

Results: Of the 6 Caucasian patients, there were 4 females and 2 males with a mean age of 46.5(26 to 76). These patients were essentially healthy prior and developed autoinflammatory features following COVID19 infection (4 cases) or vaccinations (2). They experienced recurrent symptoms such as fever, rash, arthralgia and gastrointestinal symptoms among others. All patients were identified to carry NOD2 mutations, and 3 of them carried concurrent mutations in other SAID genes, such as MEFV, NLRP3, NLRP12, TNFRSF1A, and UBA1(Table 1 to be presented). Two of the NOD2 mutations are rare and other mutations are of low frequency/penetrance and are known to increase susceptibility to certain SAIDs, such as Yao syndrome (NOD2), Familial Mediterranean fever (MEFV E148Q, R408Q, P369S), NLRP3-autoinflammatory disease (NLRP3 Q703K), and NLRP12-autoinflammatory disease (NLRP12 F402L). UBA1 mutation is associated with VEXAS syndrome. These SAIDs associated with the low penetrance variants are currently regarded in the new category of Genetically Transitional Disease, where mutation is necessary but not sufficient to cause disease. Genetic background refers to all other related genes that may interact with the gene of interest to potentially influence specific phenotype in concert with environment. Since all our patients carry NOD2 variants as the denominator, the NOD2 is considered as the gene of interest, and other SAID gene variants may be entertained as genetic background. Although most NOD2 variants are low penetrants in this study, their penetrance could be upwardly influenced by genetic background. While these patients carry germline mutations, their disease onsets started following the COVID19 infection or vaccination. These data strongly suggest that candidate genes, genetic background and environment together may contribute to these SAIDs. Our data may also explain some patients with Long COVID Syndrome.

Conclusion: Our study supports the interactive role of genes and environment in the pathogenesis of some autoinflammatory diseases. Further study of large cohort patients is warranted.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gene-x-environment-paradigm-exemplified-by-selected-cases-of-autoinflammatory-diseases/