key: cord-0907451-2am0tm89 authors: Pirola, Carlos J.; Sookoian, Silvia title: PNPLA3 and COVID‐19 outcomes: Thinking outside the box might explain the biology behind pleiotropic effects of rs738409 on the immune system date: 2021-09-06 journal: Liver Int DOI: 10.1111/liv.15043 sha: bce9cd01d4a2cc8a390108b960b434f7f72f2ab8 doc_id: 907451 cord_uid: 2am0tm89 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 1, 2 . Figure 1 discloses the laboratory measurements and / or hematological traits associated with variants in PNPLA3 extracted from different data sources. it was postulated that variants that predispose to NAFLD may also indirectly condition the severity of the COVID-19 infection. This hypothesis motivated interesting candidate gene association studies. For example the UKBB (UK Biobank) dataset was initially used to develop a genetic risk score for NAFLD based on the weighted effect of variants involved in the accumulation of fat in the liver (PNPLA3-TM6SF2-MBOAT7-GCKR). 5 Thus, leveraging this information, Valenti et al examined the impact of that NAFLD-genetic risk score on the risk of COVID-19, 5 and detected a trend of protection against COVID-19 conferred by rs738409. 5 In addition, the authors observed a trend towards differential gene expression levels of SARS-CoV-2 receptors (ACE2) in a cohort of 125 obese subjects. 5 More recently, two studies from Europe highlighted the potential involvement of the rs738409 in modifying the severity of COVID-19, including hospitalization and death rate. 6,7 Grimaudo et al found a direct association between the rs738409 G-allele and severe COVID-19 outcomes among patients aged 65 years or less. 6 On the other side, Innes et al reported a striking inverse association analysis between the rs738409 and COVID-19 severity outcomes in 1585 UKBB participants. 7 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. 7 In addition, Innes et al 7 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- 6 The pooled analysis of the abovementioned 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. 7 However, it appears that there was a trend for association with a reduced risk of COVID-19 hospitalization/severe disease that did not reach statistical significance. 7 Likewise, Bianco et al found that the rs738409 G allele has a tendency not only to be associated with protection against COVID-19 but also it was associated with lower C-reactive protein levels despite higher ALT and lower albumin in severe COVID-19 patients of European ancestry. 8 Table 1 shows a summary of current evidence of the putative association between rs738409 and COVID-19 outcomes. These remarkable findings deserve several reflections before raising unequivocal conclusions of the putative role of rs738409 on the course of COVID-19, one concerning the sample size of the studies and another concerning the biological plausibility of the reported association. Specifically, a note of caution must be added to the initial en- the results of this meta-analysis need to be interpreted with caution until the presumed association be consistently reproduced in larger cohorts. Yet, the reported association is not only clinically relevant, but it seems to be also plausible. Hence, the COVID-19 pandemic has brought attention to the importance of having a complete understanding not only of the PNPLA3 gene-attributed associations with liver-related traits but also a thorough understanding of the protein interactions, the active protein ligands, and most importantly, an accurate and comprehensive assessment of the impact of the variant pleiotropic effects. This study was partially supported by grants PICT 2018-889, and None. 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