Genetic Variant rs1205 is Associated with COVID-19 Outcomes: The Strong Heart Study and Strong Heart Family Study
Authors: Best LG , Erdei E , Haack K , Kent JW , Malloy K , Newman DE , O’Leary M , O’Leary R , Sun Q , Navas-Acien A , Franceschini N , Cole SA 
Published: August 2023

AbstractBackgroundAlthough COVID-19 infection has been associated with a number of clinical and environmental risk factors, host genetic variation has also been associated with the incidence and morbidity of infection. TheCRPgene codes for a critical component of the innate immune system andCRPvariants have been reported associated with infectious disease and vaccination outcomes. We investigated possible associations between COVID-19 outcome and a limited number of candidate gene variants including rs1205.Methodology/Principal FindingsThe Strong Heart and Strong Heart Family studies have accumulated detailed genetic, cardiovascular risk and event data in geographically dispersed American Indian communities since 1988. Chi-square tests, logistic regression and generalized linear mixed models (implemented in SOLAR) were used in analysis. Genotypic data and 91 COVID-19 adjudicated deaths or hospitalizations from 2/1/20 through 3/1/23 were identified among 3,780 participants in two subsets. Among 21 candidate variants including genes in the interferon response pathway,APOE,TMPRSS2,TLR3, the HLA complex and the ABO blood group, only rs1205, a 3’ untranslated region variant in theCRPgene, showed nominally significant association in T-dominant model analyses (odds ratio 1.859, 95%CI 1.001-3.453, p=0.049) after adjustment for age, sex, center, body mass index, and a history of cardiovascular disease. Within the younger subset, association with the rs1205 T-Dom genotype was stronger, both in the same adjusted logistic model and in the SOLAR analysis also adjusting for other genetic relatedness.ConclusionA T-dominant genotype of rs1205 in theCRPgene is associated with COVID-19 death or hospitalization, even after adjustment for relevant clinical factors and potential participant relatedness. Additional study of other populations and genetic variants of this gene are warranted.Author summaryConsiderable inter-individual variability in COVID-19 clinical outcome has been noted from the onset of this pandemic. Some risk factors, such as age, diabetes, obesity, prior cardiovascular disease (CVD) are well established. The possibility of inherited, host genetic risk factors has also been examined and a number validated in very large, population based datasets. The present study leveraged on-going clinical surveillance of CVD and available genetic information in an American Indian population to investigate potential host genetic contributors to COVID-19 morbidity and mortality. Although the number of cases ascertained was relatively small, a novel variant in the C-reactive protein gene was found to be associated with COVID-19 outcome. This protein constitutes a critical component of the innate immune system andCRPvariants have been reported associated with infectious disease and vaccination outcomes. Improved understanding of the pathophysiology of this infection may allow more targeted therapy.