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Differential circulating proteomic responses associated with ancestry during severe COVID-19 infection


Background: COVID-19 led to a disruption in nearly all aspects of society, yet these impacts were not the same across populations. During the pandemic, it became apparent that ancestry was associated with COVID-19 severity and morbidity, such that individuals of African descent tended to have worse outcomes than other populations. One factor that may influence COVID-19 outcomes is the circulating proteomic response to infection. This study examines how different ancestries had differential circulating protein levels in response to severe COVID-19 infection. Methods: 4,979 circulating proteins from 1,272 samples were measured using the SomaScan platform. We used a linear mixed model to assess the ancestry-specific association between the level of each protein and severe COVID-19 illness, accounting for sex, age, and days since symptom onset. We then compared each ancestry-specific effect size of severe COVID-19 illness on protein level to one another in a pairwise manner to generate Z-scores. These Z-scores were then converted into p-values and corrected for multiple comparisons using a Benjamini-Hochberg false discovery rate of 5%. Results: Comparing ancestries, we found that 62% of the tested proteins are associated with severe COVID-19 in European-ancestry individuals, compared to controls. We found that 45% and 22% of the tested proteins were different between COVID-19 infected and control individuals in people of African and East Asian ancestry, respectively. There was a strong correlation in effect size between ancestries. We found that individuals of European and African ancestry had the most similar response with a Pearson correlation of 0.868, 95% CI [0.861, 0.875] while European and East Asian ancestries had a Pearson correlation of 0.645, 95% CI [0.628, 0.661] and, East Asian and African ancestries had a Pearson correlation of 0.709, 95% CI [0.695, 0.722]. However, we found 39 unique proteins that responded differently (FDR < 0.05) between the three ancestries. Conclusions: Examining 4,979 protein levels in 1,272 samples, we identified that the majority of measured proteins had similar responses to infection across individuals of European, African and East Asian ancestry. However, there were 39 proteins that may have a differential response to infection, when stratified by ancestry. These proteins could be investigated to assess whether they explain the differences in observed severity of COVID-19 between ancestral populations.