Lupus can cause genetic changes that support type I interferon (IFN) pathway activation. But the reason behind people continue to have a high frequency of lupus-associated risk alleles in the immune system remains poorly understood. Timothy B. Niewold of the Colton Center for Autoimmunity at the NYU Grossman School of Medicine and colleagues hypothesized that the continued presence of IFN pathway autoimmune disease risk alleles is because they play a protective role against viral infection.

Study: Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19. Image Credit: vchal / Shutterstock

The COVID-19 pandemic allowed an unprecedented opportunity to test this theory. The type I IFN response is a key player in the immune system’s defense against the severe acute respiratory coronavirus 2 (SARS-CoV-2). However, in a new study, single nucleotide polymorphisms appear to inhibit IFN response and are associated with increased mortality risk from COVID-19 disease. Additionally, genetic variants against systemic lupus erythematosus are linked to a higher risk of dying.

Having risk alleles that increased type, I IFN pathway activation added more protection from COVID-19 mortality. For people of European-American ancestry, the researchers found a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent I (PRKGI) linked to the risk of COVID-19 death.

“These data support the idea that type I IFN pathway risk alleles for autoimmune disease may persist in high frequency in modern human populations due to a benefit in our defense against viral infections,” concluded the research team.

The study “Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19” was recently published on the preprint medRxiv* server.

Results

The research team created several multivariate prediction models combining genetics and other biomarkers to forecast a person’s mortality risk if they were infected with COVID-19.

They looked at the genetic ancestry of 756 European-Americans and 398 African-Americans who were hospitalized for acute COVID-19 illness.

Their findings recorded multiple associations between lupus-association functional polymorphisms in the type I IFN pathway and COVID-19 mortality.

The researchers confirm the critical role type I IFN plays in warding off COVID-19 infection. Genetic mutations such as loss-of-function alleles and gain-of-function alleles in the type I pathway influenced viral defense and provided different outcomes to COVID-19 mortality.

Genetic alleles in European-American descent increase mortality risk

The presence of IRF5 haplotypes increases the risk for lupus. In this study, people of European-American descent showed a specific haplotype of IRF5 was associated with lower serum IFN and an increased risk for COVID-19 mortality.

Having PRKG1 alleles also increased the mortality risk in European-Americans. In addition, younger people were more likely to have these genetic alleles as their mortality risk exceeded 25% compared to less than 5% of deaths in the 45-54 age group.

Younger European-American participants who lacked the risk genotypes did not die from COVID-19 infection.

Correlation plot between type I IFN ratio by genotype and odds ratio for mortality related to acute COVID-19 by the same genotype. The IFN ratios are calculated from our previous published studies in SLE noted in the Methods section, computing a ratio of median circulating IFN values between the genotype groups. Genotype categories used are the same for both the IFN analysis and the COVID-19 mortality analysis. 95% confidence is shown with the blue shading. TCTA indicates carriage of the associated IRF5 COVID-19 risk haplotype.

Genetic alleles in African-American descent modulate risk

People of African-American descent infected with COVID-19 had genetic variants in the IRF7 and IRF8 genes associated with mortality.

Specifically, the G allele of the IRF7 SNP rs702966 gene was linked to increased mortality and is also associated with decreasing type I IFN response in patients with lupus. The rs4963128 single nucleotide polymorphism in the adjacent PHRF1 gene has also been linked to changes in type I IFN levels in lupus and accounted for differences in mortality in viral infection.

“It seems likely that the PHRF1 SNP could tag a functional genetic element that modulates the adjacent IRF7 gene to influence type I IFN, as PHRF1 is not thought to function in the type I IFN pathway,” explained the researchers.

Having IRF7 alleles had a more significant effect on mortality amongst older African-American patients.

In contrast, lupus-associated risk alleles in the IRF8 gene were linked to increased protection from COVID-19 mortality in African-Americans but not European-Americans.

Study limitations

The study’s pool of participants may have affected the study’s results. During the COVID-19 pandemic wave in New York City (NYC) in 2020, the researchers successfully enrolled a large group of people for the study. However, since NYC COVID-19 cases have decreased and remained low, it has been challenging to replicate a similar cohort.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.