Background/Purpose: A widely recognized model of disease pathogenesis is the potential interplay of gene x gene x environment. Low penetrance variants in the NOD-like receptor and MEFV genes together may constitute a genetic background and contribute to genetically transitional disease. We utilized the All of Us Research Program (All of Us) to study the impact of genetic backgound in a large cohort of patients with autoinflammatory disease.

Methods: We conducted a retrospective analysis of adult patients with systemic autoinflammatory diseases (SAIDs). All patients underwent testing for a periodic fever syndrome gene panel designed to capture low penetrance variants of clinical significance. The distribution of gene variants and their frequencies were compared with 128,196 participants of European ancestry from the All of Us control.

Results: In total, 471 patients were genotyped and were divided into genotype-positive and -negative groups. Individual patients with positive genotyping carried variants in one or more SAID genes. SAIDs diagnosed among patients were Yao syndrome, Familial Medeteranean fever, Cryopyrin-associated periodic syndrome, NLRP12-Autoinflammatory disease and Mixed NOD-like receptor associated autoinflamamtory disease among others. For 265 patients who carried digenic or oligogenic variants, various combinations of these SAID genes were computed. We found the following genotype combinations NOD2/NLRP12, NOD2/MEFV, NOD2/NLRP3 and NLRP3/NLRP12, MEFV/NLRP3/NOD2, MEFV/NLRP12/NOD2 in decreasing order of prevalence. The frequencies of digenic and oligogenic variants in our patient population were compared with 128,196 controls in the All of Us dataset. We found that certain combinations of gene variants (e.g., NLRP3 Q705K/NOD2 V955I or NLRP12 F402L/NOD2 IVS8+158, NOD2 V955I/NLRP12 F402L) were significantly more frequent (Table to be presented). These results indicate that digenic or oligogenic variants of low penetrance may constitute a related but divergent genetic backgroud susceptibility for several autoinflammatory diseases.

Conclusion: Comparison of a large cohort of SAID patients seen over a number years in a US referral center with the large All of Us control population underscores the impact of genetic background on disease expression. Genomic testing to search for digenic or oligogenic variants of even low penetrance is likely to significantly aid in disease diagnosis, and guide precision therapy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/utilization-of-the-all-of-us-research-program-to-study-the-impact-of-genetic-background-on-autoinflammatory-diseases/