Fulltext
Nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease and a major public health problem worldwide (1). Simple fatty liver is generally considered a benign pathological process. However, 20% of simple fatty liver patients display lobular inflammation and hepatocyte injury, a condition designated as “nonalcoholic steatohepatitis” (NASH), which may even progress toward liver cirrhosis and hepatocellular carcinoma (2, 3). The detailed pathogenesis of NAFLD remains unclear. Generally, it is believed that the genetic factor is important in the development of NAFLD (4-6), and specific ethnic groups or environmental conditions have been proven to influence the results. Identifying genetic associations with NAFLD in different ethnic groups will lead to the development of new noninvasive biomarkers for the early diagnosis of NAFLD and may allow early preventive and therapeutic strategies for people at high risk in different ethnic groups.
Recently, 3 single nucleotide polymorphisms (SNPs), viz rs738491, rs2143571, and rs3761472, in the sorting and assembly machinery component 50 homolog (SAMM50) gene were shown to be deeply associated with NAFLD after adjusting for age, gender, and body mass index (BMI) in the Japanese population (7). In Indian subjects, a subsequent study demonstrated a significant link between rs2143571 and NAFLD (8).
Now, NAFLD has been confirmed as the fastest growing etiology for hepatocellular carcinoma in China.
Because the association between the 3 SNPs and NAFLD susceptibility in a Chinese Han population had not been investigated previously, the present study sought to explore the association between the genetic variants in rs738491, rs2143571, and rs3761472 in the SAMM50 gene and susceptibility to NAFLD in a Chinese Han population. The findings should, in turn, provide new insights into the pathophysiology and genetics of NAFLD.
This study aimed to identify NAFLD susceptibility of the genetic variants in rs738491, rs2143571, and rs3761472 in the SAMM50 gene in a Chinese Han population. The GMDR analysis was employed to determine the SNP-SNP interactions.
Previous studies have indicated that the rs738491 T allele, rs2143571 A allele, and rs3761472 G allele in the SAMM50 gene may contribute to the progression from simple fatty liver to NASH, not only significantly associated with predisposition to NAFLD (7, 8), but also with decreased levels of serum TG and increased levels of ferritin and hyaluronic acid, which are high in NASH. However, our data demonstrated a controversial association inasmuch as the rs2143571 A allele and the rs3761472 G allele were both deeply associated with increased serum TG levels, whereas the rs738491 T allele did not show a significant P value. Furthermore, the ALT and AST levels of serum were significantly different between the carriers and the noncarriers of the rs2143571 A allele and the rs3761472 G allele, while the rs738491 T allele was only associated with increased levels of serum ALT. It is worthy of note that a similar finding has been confirmed in Indian subjects (8). This suggested that the genetic variants in rs2143571 and rs3761472, but not in rs738491, were associated with hepatic fat accumulation, as well as liver injury (13). Furthermore, adjusting for gender, age, and BMI, we demonstrated that the carriers of the rs738491 T allele, rs2143571 A allele, and rs3761472 G allele increased the predisposition to NAFLD compared with the noncarriers. However, the current results should be confirmed by future studies including larger and multiple ethnic populations.
The Sam50, encoded by the SAMM50 gene, is a part of the sorting and assembly machinery (SAM) required for the assembly pathway of the mitochondrial outer membrane β-barrel proteins (14). It is crucial for maintaining mitochondrial shape, morphology of mitochondrial cristae, and assembly of respiratory chain complexes (14, 15). Ott et al. confirmed that a moderate reduction in the Sam50 could result in changes in mitochondrial shape and the morphology of cristae and that depletion of the Sam50 could influence mitochondrial respiratory complexes (14). Various studies have established that mitochondrial dysfunction (loss of mitochondrial cristae and paracrystalline inclusions) plays an important role in insulin resistance (16, 17). Hepatic insulin resistance is known as the major pathophysiological contributor to the development and progression of NAFLD (18). In addition, mitochondrial abnormalities have been observed in the liver biopsy specimens of patients with NASH (19). These findings and our data indicate that the rs738491 T allele, rs2143571 A allele, and rs3761472 G allele in the SAMM50 gene may be involved in mitochondrial dysfunction and subsequent insulin resistance, resulting in the development and progression of NAFLD.
Given that NAFLD represents a complex disorder influenced by the interplay between genetic and environmental factors, multi-gene or SNP-SNP interaction studies may help discover the risk factors for NAFLD. Accordingly, we performed the MDR (12) and GMDR (20) to determine the potential SNP-SNP interactions between the 3 SNPs in the SAMM50 gene. The analysis of the SNP-SNP interactions showed a strong interaction between rs738491, rs2143571, and rs3761472 regarding susceptibility to NAFLD. As is described in Table 5, the results of the GMDR indicated that a synergistic relationship might exist between rs738491, rs2143571, and rs3761472 in the SAMM50 gene and the pathophysiology and genetic background of NAFLD. Additionally, a combination of rs2143571 and rs3761472 was the best model to predict the susceptibility to NAFLD compared to the single SNP alone.
However, several limitations existed in our study. First, the lack of liver biopsy is the main limitation of the present study. Liver biopsy is recognized as the gold standard in providing an accurate diagnosis of NAFLD; it is, however, expensive and not ethically feasible for uninvestigated subjects in epidemiological studies. We determined the hepatic fat content employing liver ultrasonography, which is widely utilized for the measurement of fatty liver disease (9) but cannot provide reliable quantitative information (21, 22). Moreover, liver ultrasonography cannot detect small changes in hepatic fat content over time, and its sensitivity and specificity are decreased in diagnosing obese NAFLD patients (23). Second, the underlying molecular mechanisms of the association and the SNP-SNP interactions should be explored by future basic and clinical studies.
We first demonstrated that genetic variants in rs738491, rs2143571, and rs3761472 in the SAMM50 gene created susceptibility to NAFLD in a Chinese Han population. The SNP-SNP interaction studies showed that a combination of the 3 SNPs in the SAMM50 gene might have synergism to predict the predisposition to NAFLD. The present study will help identify high-risk populations and perform appropriate interventions. Meanwhile, it will provide new ideas for the prevention and treatment of NAFLD.
