BackgroundNonalcoholic fatty liver disease (NAFLD) includes a broad range of liver pathologies from simple steatosis to cirrhosis and fibrosis, in which a subtype accompanying hepatocyte degeneration and fibrosis is classified as nonalcoholic steatohepatitis (NASH). NASH accounts for approximately 10–30% of NAFLD and causes a higher frequency of liver-related death, and its progression of NASH has been considered to be complex involving multiple genetic factors interacting with the environment and lifestyle.Principal FindingsTo identify genetic factors related to NAFLD in the Japanese, we performed a genome-wide association study recruiting 529 histologically diagnosed NAFLD patients and 932 population controls. A significant association was observed for a cluster of SNPs in PNPLA3 on chromosome 22q13 with the strongest p-value of 1.4×10−10 (OR = 1.66, 95%CI: 1.43–1.94) for rs738409. Rs738409 also showed the strongest association (p = 3.6×10−6) with the histological classifications proposed by Matteoni and colleagues based on the degree of inflammation, ballooning degeneration, fibrosis and Mallory-Denk body. In addition, there were marked differences in rs738409 genotype distributions between type4 subgroup corresponding to NASH and the other three subgroups (p = 4.8×10−6, OR = 1.96, 95%CI: 1.47–2.62). Moreover, a subgroup analysis of NAFLD patients against controls showed a significant association of rs738409 with type4 (p = 1.7×10−16, OR = 2.18, 95%CI: 1.81–2.63) whereas no association was obtained for type1 to type3 (p = 0.41). Rs738409 also showed strong associations with three clinical traits related to the prognosis of NAFLD, namely, levels of hyaluronic acid (p = 4.6×10−4), HbA1c (p = 0.0011) and iron deposition in the liver (p = 5.6×10−4).ConclusionsWith these results we clearly demonstrated that Matteoni type4 NAFLD is both a genetically and clinically different subset from the other spectrums of the disease and that the PNPLA3 gene is strongly associated with the progression of NASH in Japanese population.

The results in this study suggest that the long-term EZ therapy can lead to improvement in metabolic, biochemical, and histological abnormalities of NAFLD. Therefore, EZ may be a promising agent for treatment of NAFLD.

OBJECTIVE -The aim of this study was to determine the distribution of serum extracellular superoxide dismutase (EC-SOD) concentrations in patients with type 2 diabetes and to assess whether increased EC-SOD concentration is associated with the development of diabetic vascular complications.RESEARCH DESIGN AND METHODS -Serum EC-SOD concentrations were determined in 222 patients with type 2 diabetes and 75 healthy control subjects by an enzyme-linked immunosorbent assay. All subjects had the EC-SOD domain genotyped.RESULTS -The serum EC-SOD concentrations showed a distinct bimodal distribution in both patients with diabetes and control subjects. All subjects with the high-level phenotype carried the Arg213Gly mutation. The frequency of this variant was similar in the diabetes and control groups. Within the group of subjects with the common EC-SOD phenotype, the serum EC-SOD concentration (mean Ϯ SE) was significantly higher in patients with type 2 diabetes (99.3 Ϯ 1.3 ng/ml) compared with the control subjects (68.4 Ϯ 2.3 ng/ml, P Ͻ 0.01). Stepwise multiple regression analysis of the data from the diabetic common phenotype group showed a significant relationship between serum EC-SOD concentration and duration of diabetes (F ϭ 5.31), carotid artery intimal-media thickness (F ϭ 8.24), and severity of nephropathy (F ϭ 16.05) and retinopathy (F ϭ 4.43).CONCLUSIONS -We observed a strong relationship between the serum concentration of EC-SOD and the severity of both micro-and macrovascular diabetic complications. These findings suggest that serum EC-SOD concentration levels may be a marker of vascular injury, possibly reflecting hyperglycemia-induced oxidative injury to the vascular endothelium and decreased binding of EC-SOD to the vascular wall. Diabetes Care 26:1246 -1250, 2003H yperglycemia is a major factor in the development of diabetic complications, although the mechanisms of how increased glucose levels contribute to these changes have not been fully elucidated. Adverse biochemical changes associated with hyperglycemia include increased flux of glucose through the polyol pathway, enhanced nonenzymatic glycation, and activation of the diacylglycerol-protein kinase C pathway. Hyperglycemia may also result in increased production of the reactive oxygen species within numerous biochemical pathways that have the potential to initiate adverse changes in endothelial function (1).Extracellular superoxide dismutase (EC-SOD) is a secretory glycoprotein with an affinity for heparan-like substances (2-4), and it is the principal enzymatic scavenger of superoxide in the extracellular space (5). It has been shown that Ͼ99% of the enzyme is bound to heparan sulfate proteoglycans in vascular walls and to a lesser extent within the interstitium, and Ͻ1% is contained within the circulation in equilibrium between the plasma phase and the glycocalyx of the endothelium (6 -8). Molecular genetic studies have shown that a single-base substitution causing exchange of glycine for arginine-213 (Arg213Gly) in the heparin binding domain of...

These results suggest that hepatic SMP30 is closely associated with the pathogenesis of NAFLD, although it is not known whether decreased hepatic SMP30 is a result or a cause of cirrhosis.

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It has been reported that polymorphisms of human leukocyte antigen (HLA) genes and several cytokine genes are associated with an increased risk of developing gastric cancer (GC). However, the results of studies from different geographic regions, ethnic groups and study groups are inconsistent. The aim of this study was to evaluate the influence of H. pylori infection and host genetic factors on GC susceptibility in Japanese patients with GC. We analyzed genotypes for HLA class I and II, tumor necrosis factor a, interleukin (IL)-1b, IL-1 receptor, IL-4, IL-4Ra and IL-10 in 330 H. pyloriinfected noncardia patients with GC and 190 H. pylori-infected nonulcer dyspeptic controls. Haplotype analyses indicated that the frequencies of the HLA DRB1*0405 and DQB1*0401 alleles were increased in the patients with intestinal-type GC when compared with controls (both DRB1*0405 and DQB1*0401: p 5 0.015, OR 5 1.57, 95% CI 5 1.09-2.26), but the changes were not statistically significant after correction for multiple comparisons. None of the cytokine gene polymorphisms were associated with GC susceptibility, whether patients with GC were analyzed as a group according to the histological subtype. Of interest was the comparison of controls and patients with intestinal-type GC. The frequency of an IL-10-592AA homozygote showing concomitant carriage of the HLA DRB1*0405-DQB1*0401 haplotype was significantly higher in patients with intestinal-type GC (v 2 5 6.369, p 5 0.0116, p c 5 0.0464, OR 5 2.43, 95% CI 5 1.21-4.48). Our results suggest that the HLA class II and IL-10-592A/C polymorphisms synergistically affect the susceptibility to GC development of H. pylori-infected individuals in the Japanese population. ' 2009 UICC Key words: gastric cancer; Helicobacter pylori; polymorphic variation; HLA class II alleles; cytokines Gastric cancer (GC) remains one of the most frequently diagnosed malignant diseases worldwide, and even more so in Japan. Several studies have shown that Helicobacter pylori infection is an important risk factor for GC. [1][2][3][4] Although about half of the world's population is believed to be infected with H. pylori, only a small proportion of those people develop GC, suggesting that additional factors such as host genetic factors and environmental factors, as well as the diversity of H. pylori virulence genes, must be involved in the development and progression of GC. Therefore, this belief has generated interest in host factors, especially immune-and inflammatory-related host genetic factors.Human leukocyte antigen (HLA) genes play a key role in the body's immune response and exhibit very high degrees of polymorphism. HLA molecules bind antigen peptides and present them to T cells, which differentiate into cytotoxic or helper T cells upon specific recognition of the antigen peptide-HLA molecule complexes. Many investigators have reported an association of GC risk and HLA class II (DR and/or DQ) type in several ethnic populations. 5-14 However, different results have been obtained in different ethnic groups an...

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A decrease in serum TBA level reflected histological improvement in the liver more precisely than did changes in the other liver function test values following IFN therapy.