Genetics may be responsible for asymptomatic COVID-19

In the crowd-sourced COVID-19 Citizen Science Study, a common genetic mutation was tied to asymptomatic COVID-19.

“[A]mong participants reporting a positive result for SARS-CoV-2, human leukocyte antigen (HLA)-B*15:01 was significantly associated with asymptomatic infection,” said the researchers.

This common HLA class I allele was significantly overrepresented in asymptomatic vs symptomatic individuals (frequency=0.1103 vs 0.0495, odds ratio [OR], 2.38; p=3×10⁻⁵, Bonferroni-corrected p [p_adj]=0.002). [Nature 2023;620:128-136]

The significant association between HLA-B*15:01 and asymptomatic infection was sustained after adjusting for age and sex (OR, 2.40; p=5.67×10⁻⁵; p_adj=0.002). “No other HLA allele at any locus was significantly associated after correction for multiple comparisons,” they said.

There was also a notable effect of HLA-B*15:01 homozygosity increasing the chance of remaining asymptomatic by more than eight times. Participants carrying two copies of HLA-B*15:01 were more likely to remain asymptomatic than those carrying other genotypes (OR, 8.58; p=0.001).

“We were pretty stunned by the magnitude of this effect,” commented study co-author Dr Jill Hollenbach from the University of California, San Francisco, California, US, in a separate report.  [Nature 2023;619:679-680]

Overall, 20 percent of those who remained asymptomatic after being infected with SARS-CoV-2 carried HLA-B*15:01 as opposed to only 9 percent of symptomatic patients.

Replication in independent studies

In a re-analysis of primary HLA genotype data in a UK cohort, HLA-B*15:01 was also strongly associated with asymptomatic infection after adjusting for age and sex (OR, 3.56; p=0.02). Carrier frequency for HLA-B*15:01 was 17 percent in asymptomatic individuals vs 7 percent in those with symptoms. [HLA 2021;98:14-22]

Using data from the combined CHIRP/LIINC^# cohorts, carrier frequency of HLA-B*15:01 was exceptionally high in asymptomatic vs symptomatic individuals (25 percent vs 9 percent). Although the power was limited by the study sample size, the findings strongly trended in support of our finding of a strong association of this allele with asymptomatic disease (OR, 3.44; p=0.13), the researchers said.

A meta-analysis of these two independent studies and the current dataset validated the strong and consistent association between HLA-B*15:01 and asymptomatic infection (OR, 2.55; p<10⁻⁴).

Groundwork for vaccine, drug development

The final discovery cohort of this smartphone-based study comprised 1,428 unvaccinated individuals who tested positive for SARS-CoV-2 (median age 34 years, 81 percent female). Of these, 136 remained asymptomatic (median age 41 years, 74 percent female).

Dr Jean-Laurent Casanova from the Rockefeller University, New York City, New York, US, noted that the study “deserves a round of applause”. Although the association was “modest, it is stronger than any other association for a common gene published” on COVID-19, he said. [Nature 2023;619:679-680]

Evaluating asymptomatic infection provides a unique opportunity to consider early disease and immunologic features that promote rapid viral clearance, said the researchers. “Our results have important implications for understanding early infection and the mechanism underlying early viral clearance and may lay the groundwork for refinement of vaccine development and therapeutic options in early disease.”

Several limitations must be taken into context, the researchers noted. Symptoms and test results were self-reported, most participants self-identified as White, and only four SARS-CoV-2 peptides were tested in the ex vivo analysis. Further investigation is thus necessary to corroborate the findings.