Pleiotropy within gene variants associated with nonalcoholic fatty liver disease and traits of the hematopoietic system

Abstract

Genome-wide association studies of complex diseases, including nonalcoholic fatty liver disease (NAFLD), have demonstrated that a large number of variants are implicated in the susceptibility of multiple traits — a phenomenon known as pleiotropy that is increasingly being explored through phenome-wide association studies. We focused on the analysis of pleiotropy within variants associated with hematologic traits and NAFLD. We used information retrieved from large public National Health and Nutrition Examination Surveys, Genome-wide association studies, and phenome-wide association studies based on the general population and explored whether variants associated with NAFLD also present associations with blood cell-related traits. Next, we applied systems biology approaches to assess the potential biological connection/s between genes that predispose affected individuals to NAFLD and nonalcoholic steatohepatitis, and genes that modulate hematological-related traits—specifically platelet count. We reasoned that this analysis would allow the identification of potential molecular mediators that link NAFLD with platelets. Genes associated with platelet count are most highly expressed in the liver, followed by the pancreas, heart, and muscle. Conversely, genes associated with NAFLD presented high expression levels in the brain, lung, spleen, and colon. Functional mapping, gene prioritization, and functional analysis of the most significant loci ( P < 1 × 10 -8 ) revealed that loci involved in the genetic modulation of platelet count presented significant enrichment in metabolic and energy balance pathways. In conclusion, variants in genes influencing NAFLD exhibit pleiotropic associations with hematologic traits, particularly platelet count. Likewise, significant enrichment of related genes with variants influencing platelet traits was noted in metabolic-related pathways. Hence, this approach yields novel mechanistic insights into NAFLD pathogenesis.

Genetics in non-alcoholic fatty liver disease: The role of risk alleles through the lens of immune response

“…The genomic tools, including GWAS complemented by expression quantitative trait locus (eQTL) analyses, are powerful instruments for understanding how disease-linked variants regulate the expression of quantitative molecular phenotypes across diverse tissues. GWAS of complex diseases, including NAFLD and NASH, showed that some gene variants are implicated in the susceptibility of multiple traits-a phenomenon known as pleiotropy 42 . This feature involves not only the rs738409 variant in PNPLA3 but also variants in TM6SF2, HSD17B13, and MBOAT7 that are associated with diverse laboratory measurements related to hematological traits 42 .…”

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

“…Genetic variants associated with the risk of NAFLD and NASH exhibit pleiotropic effects 1,2 . Specifically, the non‐synonymous rs738409 C/G variant in PNPLA3 (patatin‐like phospholipase domain‐containing protein 3), which encodes I148 M 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 haematological traits associated with variants in PNPLA3 extracted from different data sources.…”

“…Finally, Phenome‐wide association ( PheWAS ) analysis on data of the UK Biobank denotes not only beta positive ('risk') effects of rs738409 on liver‐related traits but also beta negative ('protective') effects on many non‐liver traits, including respiratory diseases and haematological‐related traits, such as neutrophil and platelet count 2 . Of note, platelet count was associated with over fivefold enhanced risk of severe COVID‐19 (OR, 5.1) 12 .…”

“…Specifically, the intron rs2294915 C/G/T (chr22:44340904) variant that is not only in high linkage disequilibrium with rs738409 (r 2 0.85) 9 but also modifies the expression of Finally, Phenome-wide association (PheWAS) analysis on data of the UK Biobank denotes not only beta positive ('risk') effects of rs738409 on liver-related traits but also beta negative ('protective') effects on many non-liver traits, including respiratory diseases and haematological-related traits, such as neutrophil and platelet count. 2 Of note, platelet count was associated with over fivefold enhanced risk of severe COVID-19 (OR, 5.1). 12 In addition, a higher neutrophil/monocytes ratio is another predictor of COVID19 worse outcome.…”

Effects of Biopolymers from Cassava Implanted with Rodent Bait on Wistar Rats

“…The platelets as well as fibrinogen are responsible for the repair of all damaged blood vessels as well as blood clotting, and in the prevention of bleeding. It plays major role in controlling haemorrhage which can be summarized as primary aggregation, secondary aggregation, blood coagulation, clot retraction, and clot removal [39][40][41][42]. Platelets concentrations as well as PCV are determinants of blood viscosity, which correlates positively to blood pressure [43][44][45].…”