The rs738409 G Allele in PNPLA3 Is Associated With a Reduced Risk of COVID-19 Mortality and Hospitalization

Assessing causal relationships between COVID-19 and non-alcoholic fatty liver disease

“… 2 , 6 On the contrary, Innes et al found that the rs738409 C>G variant in patatin-like phospholipase domain-containing protein 3 ( PNPLA3 ), which is well studied in the genetic regulation of NAFLD and liver injury, played a protective role in COVID-19 severity. 7 Previous observational studies revealed that COVID-19 infected patients had an increased risk of liver injury 8 , 9 , however unmeasured/unmeasurable confounding cannot be ruled out in the conventional multivariable regression analysis. In fact, our findings derived from the MR analysis could minimize confounding bias or reverse causation.…”

Liver specific, systemic and genetic contributors to alcohol-related liver disease progression

“…4). Some variants were also found to be associated with other chronic liver diseases such as haemochromatosis (PNPLA3, TM6SF2) [73], chronic hepatitis C (PNPLA3) [74], or to variably modulate the course of other diseases, such as cardiovascular diseases (TM6SF2) [75] or COVID-19 (PNPLA3) [76].…”

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

“…To detect reproducible causal variants associated with complex diseases, a sample size with statistical power is critical to the robustness of the conclusion/s of the study. For instance the study of Innes et al involved a sample of 267 patients who died due to COVID‐19 and 1318 who survived 7 . Unfortunately, the statistical power for the sample size used in the additive model to infer the presumed protective effect is ~0.52 (considering the informed frequency of the rs738409 G‐allele (20%), the COVID‐19 death prevalence of ~3%, and the explained effect of ~25% lower odds of COVID‐19 death) 7 .…”

“…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.…”

“…Graph discloses association scores higher than 0.3 (score ranges from 0 to 1; the higher the score, the stronger the association) TA B L E 1 Summary of current evidence of the putative role of PNPLA3-rs738409 in protecting against severe COVID-19 outcomes who survived. 7 Unfortunately, the statistical power for the sample size used in the additive model to infer the presumed protective effect is ~0.52 (considering the informed frequency of the rs738409 G-allele (20%), the COVID-19 death prevalence of ~3%, and the explained effect of ~25% lower odds of COVID-19 death). 7 Thereby, the results of this meta-analysis need to be interpreted with caution until the presumed association be consistently reproduced in larger cohorts.…”