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

PIROLA, CARLOS J.; SOOKOIAN, SILVIA

LIVER INTERNATIONAL

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2021 vol. 41 p. 2081 - 2804

1478-3223

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.