Nonalcoholic Fatty Liver Disease and Obesity
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Obesity is the major risk factor for nonalcoholic fatty liver disease (NAFLD), whereas an excessive intake of alcohol is the main driver of alcoholic fatty liver disease (AFLD). However, not all obese individuals have NAFLD, and not all individuals who consume large amounts of alcohol develop AFLD. Also, far from all individuals with simple steatosis (the first stage of both NAFLD and AFLD) go on to develop steatohepatitis, cirrhosis, or end-stage liver disease. A large part of this inter-individual variation is due to genetic factors. Some individuals carry susceptibility-increasing genetic variants that make them more vulnerable to developing NAFLD, and to the progression of the disorder. Conversely, some lucky individuals carry genetic variants that protect their livers from the deleterious effects of obesity or alcohol intake. Twin studies indicate that 50% of the risk of fatty liver disease is genetically determined. This heritability estimate is comparable to those of other complex traits such as obesity, type 2 diabetes, or ischemic heart disease. Additional evidence in support of a strong genetic component to NAFLD is the fact that the disorder varies greatly in prevalence among different ethnic groups. Three common (minor allele frequency > 0.05) steatogenic genetic variants with robust and replicable effects have been identified so far: PNPLA3 I148M, TM6SF2 E167K, and GCKR P446L. Together these variants explain less than 10% of the variation in hepatic fat content or approximately 20% of the total heritable component of hepatic steatosis. Thus, the major fraction of genetic variation that contributes to the development of fatty liver disease remains unknown. With only three genome-wide association studies GWAS published so far (two of these based on the same cohort), the field of fatty liver GWAS is still in its infancy. Nonalcoholic fatty liver disease is a complex disease in which genetic variations and environmental factors interact to determine disease phenotype and progression. Progress in the understanding of the genetic risk of NAFLD might offer the unique opportunity to translate this information into clinical practice. However, only a minor fraction of the genetic risk for fatty liver disease has been discovered. Furthermore, the relative importance of genetic and environmental factors will vary between populations depending on background modifier genes, lifestyle choices/challenges, and other factors such as the intestinal microbiome (Stender, Grarup, Hansen, 2019)
