Genetic Background of Japanese Patients with Nonalcoholic Steatohepatitis (NASH)

Summary. The pathogenesis of nonalcoholic steatohepatitis (NASH) is not understood well. Therefore, it is necessary to examine genetic influences on NASH pathogenesis. Two functional polymorphisms were studied: the -493 G/T polymorphism in the promoter of microsomal triglyceride transfer protein (MTP) and the 1183 T/C polymorphism in the mitochondrial targeting sequence of manganese superoxide dismutase (MnSOD). The G allele in the MTP promoter leads to decreased MTP transcription, less export of triglyceride from hepatocytes, and greater intracellular triglyceride accumulation. In addition, glucose intolerance with hyperinsulinemia, which may be responsible for down-regulating MTP mRNA expression, is frequent among NASH patients, as observed in caucasians. The T allele in the MnSOD mitochondrial targeting sequence leads to less transport of MnSOD to the mitochondria. Blood samples from patients with biopsy-proven NASH and healthy controls were analyzed by the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Functional polymorphisms in MTP and MnSOD were revealed to be involved in determining susceptibility to NASH in Japanese