Major Histocompatibility Complex Class I-Related Chain A Alleles and Histology of Nonalcoholic Fatty Liver Disease

Abstract

Major histocompatibility complex class I-related chain A (MICA) is a highly polymorphic gene that modulates immune surveillance by binding to its receptor on natural killer cells, and its genetic polymorphisms have been associated with chronic immune-mediated diseases. The progressive form of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), is characterized by accumulation of fat and inflammatory cells in the hepatic parenchyma, potentially leading to liver cell injury and fibrosis. To date, there are no data describing the potential role of MICA in the pathogenesis of NAFLD. Therefore, our aim was to assess the association between MICA polymorphism and NASH and its histologic features. A total of 134 subjects were included. DNA from patients with biopsy-proven NAFLD were genotyped using polymerase chain reaction-sequence-specific oligonucleotide for MICA alleles. Liver biopsies were assessed for histologic diagnosis of NASH and specific pathologic features, including stage of fibrosis and grade of inflammation. Multivariate analysis was performed to draw associations between MICA alleles and the different variables; P ≤ 0.05 was considered significant. Univariate analysis showed that MICA*011 (odds ratio [OR], 7.14; 95% confidence interval [CI], 1.24-41.0; P = 0.04) was associated with a higher risk for histologic NASH. Multivariate analysis showed that MICA*002 was independently associated with a lower risk for focal hepatocyte necrosis (OR, 0.24; 95% CI, 0.08-0.74; P = 0.013) and advanced fibrosis (OR, 0.11; 95% CI, 0.02-0.70; P = 0.019). MICA*017 was independently associated with a higher risk for lymphocyte-mediated inflammation (OR, 5.12; 95% CI, 1.12-23.5; P = 0.035). Conclusion: MICA alleles may be associated with NASH and its histologic features of inflammation and fibrosis. Additional research is required to investigate the potential role of MICA in increased risk or protection against NAFLD.

Fig. 1

E‐gel verification of isolated DNA from patients and MICA alleles. (A) Representative image showing the validation of 10 DNA samples from patients with NAFLD and controls (wells 2‐11). Well 1 contains the DNA ladder, and well 12 contains the negative control (no DNA). (B) E‐gel verification for MICA alleles. The DNA ladder is in well 2, and wells 3‐12 contain patient and control products. Molecular weights of MICA are 38 to 62 kDa. The image on the far right illustrates the pattern of interpretation for PCR product verification. There are three positive MICA controls (exons 4 and 5, ~600 bp; exon 3, ~430 bp; exon 2, ~250 bp) and 1 primer set (~100 bp), which matches to an allele or group of alleles. Eventually, it produces a PCR product with a specified size for each reaction in the well. Abbreviation: bp, base pairs.

Fig. 2

Frequency of MICA alleles in NAFLD versus control. The P value shows results of the χ² test for categorical variables; *P  ≤ 0.05 is significant. Categorical data are shown as frequency and percentage. No analysis was included for alleles that were present for a total of fewer than 5 patients.

Fig. 3

Independent associations of MICA alleles with histologic features of NAFLD. Immunohistochemical images of liver sections showing (A) NASH, (B) lobular inflammation and focal necrosis, and (C) advanced fibrosis (bridging fibrosis and cirrhosis). Sections are stained with Masson’s trichrome stain. Multivariate models (tables) show that MICA*011 is significantly and positively associated with NASH, MICA*002 is independently and negatively associated with focal necrosis and advanced fibrosis, and MICA*017 is positively associated with lobular inflammation after adjusting for significant cofounders (ZDG). A: X40, B: X20, C: X10.