Liver function markers and obesity-associated phenotypes: genetic and association studies



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The primary goal was to study the influence of adipocyte number and volume, inflammation, insulin resistance, and genetic factors on indicators of liver injury, surrogate marker of non alcoholic fatty liver disease (NAFLD). The secondary goal was to explore the occurrence of NAFLD and its relationship with variations in liver function biomarkers. The first objective was to determine the association of plasma levels of monocyte chemoattractant protein-1 (MCP-1) with omental adipocyte number, insulin resistance and circulating concentrations of liver injury markers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in unrelated baboons. Significant associations of MCP-1 with other measured traits were established. The second objective was to examine if adiposity-related parameters are under genetic influence and to evaluate their genetic correlations with AST in pedigreed baboons. Adipocyte volume and number, body weight and plasma AST were heritable. Genetic correlations between adiposity-related phenotypes and AST were significant. A genome wide scan yielded a strong signal for adipocyte volume on chromosome 6. The third aim was to explore the genetic factors that influence variations in plasma levels of [gamma] glutamyl transferase (GGT) and albumin (ALB), and to evaluate their genetic correlations with cardiovascular risk factors in pedigreed baboons. Significant linkages for GGT and albumin were identified on chromosome 20_22 and chromosome 10, respectively. Genetic correlations between ALB and cardiovascular risk factors were significant. No statistically significant associations were found between GGT and cardiovascular-related phenotypes. The fourth objective was to investigate the prevalence of NAFLD and its association with altered liver protein levels in unrelated baboons. The influence of weight and insulin resistance on the occurrence of NAFLD was inconclusive. Significant relationships between the variations in plasma levels of liver injury biomarkers and severity of the disease could not be established. In conclusion, the first three studies provided observational and genetic evidence of a relationship between liver function markers and adiposity-related factors in baboons. However, the results of the fourth study do not provide conclusive evidence to suggest that body weight and insulin resistance play a significant role in the development of NAFLD in these baboons.