P273: Common polygenic background modifies risk for asthma among individuals with primary atopic disorders

Introduction: Primary atopic disorders (PADs) are a subgroup of inborn errors of immunity encompassing over 50 monogenic diseases that present clinically with severe atopic manifestations like atopic dermatitis, eosinophilia, elevated IgE, and asthma.PADs are marked by reduced penetrance and variable expressivity, presenting challenges for risk prediction and management.Genetic counseling for patients with PAD often includes discussion of the effect of environmental and additional genetic factors beyond the monogenic condition; however, current studies have not quantified the risk related to genetic background in the context of PAD.Here we addressed this question by focusing specifically on asthma stemming from (1) diverse, well-powered genetic studies of asthma and (2) asthma is elevated in PAD.We assessed the joint effect of polygenic risk scores (PRS) on asthma among patients with PAD with the aim of elucidating risk associated with common genetic variants on asthma in PAD.Methods: A cohort of 2,067 unrelated probands with known or suspected rare primary immune disorders enrolled in research at the National Institutes of Health underwent clinical genome sequencing.Asthma history was ascertained based on medical records review or clinical evaluation.Molecular diagnosis of PAD vs non-PAD was determined for all probands.PAD consisted of pathogenic and likely pathogenic variants meeting American College of Medical Genetics and Genomics guidelines in genes known to confer monogenic conditions with increased atopic disease.Variants with allele frequency >0.01 (n=834,809) were used to calculate asthma PRS using optimized effects based on discovery and training sets in the Global Biobank Meta-Analysis Initiative.Association with asthma was tested using logistic models controlling for sex, age, and 10 ancestry principal components.We modeled PRS on a continuous scale to test for its association with asthma on its own or jointly with PAD.We also modeled PRS as quintiles to assess risk associated with the lowest and highest 20% of PRS vs the medium 60% of PRS.Results: Participants were primarily female (53.1%, n=1098/2067), White (77.6%, n=1605/2067) and adults (median age 38; range 0-98).Asthma prevalence was 17.8% (n=368/2067) and PAD prevalence was 4.7% (n=98/2067).PRS and molecular diagnosis of PAD were each associated with asthma (OR=1.56[1.38,1.77],OR=2.06[1.31,3.19],p=0.00138, respectively). A oint model with PRS and PAD supported independent additive risk without interaction (no change in ORs in joint model; interaction p-value=0.78).Individuals with PAD with a low PRS did not have significantly different asthma risk compared to individuals without PAD with medium PRS (p=0.16). Conclusion:We found a modifying effect of PRS on asthma risk in individuals with PAD.PAD encompasses a heterogeneous group of diseases each with different mechanisms of risk for atopy, however, the PRS modified asthma risk across PAD.Having a low PRS attenuated the risk for asthma in PAD.This research is an important first step in quantifying the joint effect of rare and common genetic variation on asthma risk in PAD.These results can inform more nuanced counseling discussions of variable expressivity for asthma in PAD.Although PRS cannot be used as a stand-alone measure for risk prediction, when coupled with other risk factors PRS has potential clinical utility by aiding genetic counseling, helping individuals with rare immune conditions understand their personal risk, and informing clinical decision making for treatment and prevention.