**2.9 Genetic implication**

Identification of genetic factors to determine the risk of disease progression may assist to evaluate individuals who may have associated morbidity. Various genes associated with NAFLD have been investigated but the most frequent variant; p.I148M of the enzyme adiponectin gene is one of the major genetic determinants of steatosis and steatohepatitis, fibrosis, cirrhosis, and hepatocellular cancer [2]. Furthermore, polymorphism in the TM6SF2 gene (rs58542926c.449 C > T, p.Glu167Lys) has been associated with severe hepatic fibrosis and cirrhosis, but the underlying mechanisms responsible for these gene variants to influence liver damage are still lacking [2]. In addition to environmental factors, genes also affect NAFLD and through the genome-wide association analyses, several genes have been discovered, on which transmembrane 6 superfamily member 2 (TM6SF2) and patatin-like phospholipase domain containing 3 (PNPLA3) appear to be more implicated. Triacylglycerol hydrolysis is mediated by a 481 amino acid protein that is encoded by the PNPLA3 gene, which is found on chromosome 22. PNPLA3's

*Non-Alcoholic Fatty Liver Disease: Pathogenesis and the Significance of High-Density… DOI: http://dx.doi.org/10.5772/intechopen.108199*

I148M variant (rs738409), is substantially linked to NAFLD in adults, as well as obese kids and teenagers, although the precise mechanism is still unknown. The TM6SF2 gene, which is found on chromosome 19, contributes to the development of NAFLD. A single nucleotide polymorphism (rs58542926) that replaces the position 167 of cytosine to thymine has been associated with an elevated hepatic triglyceride level. The development of fibrosis has also been linked to this gene variant and the effects of PNLPA3 and TM6SF2 on NASH and severe fibrosis are cumulative [21]. Only a small percentage of people with obesity and IR develop NASH and cirrhosis, even though hepatic steatosis is widespread in these patients, indicating an essential interaction between genetic predisposition and environmental factors. NAFLD and NASH formations may be made more susceptible by polymorphisms in genes involved in lipid metabolism, IR, oxidative stress, cytokines, and fibrogenesis. Single nucleotide polymorphisms (SNPs) that affect fibrosis development in various liver diseases, including chronic hepatitis C, have been found in several reports. Existing evidence has shown that angiotensinogen and TGF-1 gene polymorphisms have been linked to progressive liver fibrosis in obese patients with NAFLD and NASH. Also, NAFLD and NAFLD-related fibrosis are linked to SNPs in the angiotensin II type 1 receptor [4].
