PNPLA3 and COVID-19 outcomes: thinking outside the box might explain the biology behind pleiotropic effects of rs738409 on the immune system

Abstract

Genetic variants associated with the risk of NAFLD and NASH exhibit pleiotropic effects 1, 2. Specifically, the nonsynonymous rs738409 C/G variant in PNPLA3 (patatin-like phospholipase domain-containing protein 3), which encodes I148M protein isoforms with a significant effect on the severity of several liver-related outcomes 3, presents pleiotropic effects on cells that mediate the immune response . Recently, two studies from Europe highlighted the potential involvement of the rs738409 in modifying the severity of COVID-19, including hospitalization and death rate. Grimaudo et al. found an association between the rs738409 G-allele and severe COVID-19 outcomes among patients aged 65 years or less 4. On the other side, Innes et al. reported a striking association analysis between the rs738409 and COVID-19 severity outcomes in 1585 UKB participants 5. The authors found that the rs738409-G allele was independently associated with a reduced risk of COVID-19 hospitalization and mortality; the protective effect remained significant after adjusting for major demographic and disease risk factors, including underlying metabolic and liver co-morbidities 5. In addition, Innes et al. performed a meta-analysis of three independent data sources that explored the potential association between rs738409 and COVID-19. This study included data from the FinnGen study (a population-based biobank comprising 83 patients with COVID-19 hospital admission and 274 SARS-CoV-2 positive patients without hospital admission), the Geisinger Health System (n= 854 subjects of European Ancestry, comprising 165 individuals COVID-19 hospitalization vs 689 SARS-CoV-2 positive patients without hospital admission), and the study of Grimaudo et al. (a total of 383 COVID-19 patients)4. The pooled analysis of the above-mentioned data sources showed that the presumed protective effect of the G- "NASH-risk allele" on the morbidity and mortality of COVID-19 could not be further validated.