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

PIROLA, CARLOS JOSE; SALATINO, ADRIAN; SOOKOIAN, SILVIA

WORLD JOURNAL OF GASTROENTEROLOGY

W J G PRESS

Lugar: Beijing; Año: 2021 vol. 27 p. 305 - 320

1007-9327

Genome-wide association studies of complex diseases, including nonalcoholicfatty liver disease (NAFLD), have demonstrated that a large number of variantsare implicated in the susceptibility of multiple traits ? a phenomenon known aspleiotropy that is increasingly being explored through phenome-wide associationstudies. We focused on the analysis of pleiotropy within variants associated withhematologic traits and NAFLD. We used information retrieved from large publicNational Health and Nutrition Examination Surveys, Genome-wide associationstudies, and phenome-wide association studies based on the general populationand explored whether variants associated with NAFLD also present associationswith blood cell-related traits. Next, we applied systems biology approaches toassess the potential biological connection/s between genes that predisposeaffected individuals to NAFLD and nonalcoholic steatohepatitis, and genes thatmodulate hematological-related traits?specifically platelet count. We reasonedthat this analysis would allow the identification of potential molecular mediatorsthat link NAFLD with platelets. Genes associated with platelet count are mosthighly expressed in the liver, followed by the pancreas, heart, and muscle.Conversely, genes associated with NAFLD presented high expression levels in thebrain, 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 withvariants influencing platelet traits was noted in metabolic-related pathways.Hence, this approach yields novel mechanistic insights into NAFLD pathogenesis.