Variations in the MHC region confer risk to esophageal squamous cell carcinoma on the subjects from high-incidence area in northern China

PLoS One. 2014 Mar 4;9(3):e90438. doi: 10.1371/journal.pone.0090438. eCollection 2014.

Abstract

Background: The human major histocompatibility complex (MHC) is the most important region in vertebrate genome, and is crucial in innate immunity. Recent studies have demonstrated the possible role of polymorphisms in the MHC region to high risk for esophageal squamous cell carcinoma (ESCC). Our previous genome-wide association study (GWAS) has indicated that the MHC region may confer important risk loci for ESCC, but without further fine mapping. The aim of this study is to further identify the risk loci in the MHC region for ESCC in Chinese population.

Methods: Conditional logistic regression analysis (CLRA) was performed on 24 single nucleotide polymorphisms (SNPs) within the MHC region, which were obtained from the genetically matched 937 cases and 692 controls of Chinese Han population. The identified promising SNPs were further correlated with clinical and clinicopathology characteristics. Immunohistochemistry was performed to explore the protein expression pattern of the related genes in ESCC and neighboring normal tissues.

Results: Of the 24 promising SNPs analyzed, we identified three independent SNPs in the MHC region associated with ESCC: rs35399661 (P = 6.07E-06, OR = 1.71, 95%CI = 1.36-2.17), rs3763338 (P = 1.62E-05, OR = 0.63, 95%CI = 0.50-0.78) and rs2844695 (P = 7.60E-05, OR = 0.74, 95%CI = 0.64-0.86). These three SNPs were located at the genes of HLA-DQA1, TRIM27, and DPCR1, respectively. Further analyses showed that rs2844695 was preferentially associated with younger ESCC cases (P = 0.009). The positive immunostaining rates both for HLA-DQA1 and TRIM27 were much higher in ESCC tissues than in neighboring normal tissues (69.4% vs. 26.8% for HLA-DQA1 and 77.6% vs. 47.8% for TRIM27, P<0.001). Furthermore, the overexpression of HLA-DQA1 is correlated significantly with age (P = 0.001) and family history (P<0.001).

Conclusion: This study for the first time provides evidence that multiple genetic factors within the MHC region confer risk to ESCC on the subjects from high-risk area in northern China.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Squamous Cell / epidemiology*
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • China / epidemiology
  • DNA-Binding Proteins / genetics
  • Esophageal Neoplasms / epidemiology*
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / pathology
  • Esophageal Squamous Cell Carcinoma
  • Genetic Predisposition to Disease*
  • Genotyping Techniques
  • HLA-DQ alpha-Chains / genetics
  • Humans
  • Immunohistochemistry
  • Incidence
  • Linkage Disequilibrium / genetics
  • Logistic Models
  • Major Histocompatibility Complex / genetics*
  • Nuclear Proteins / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Quality Control
  • Risk Factors

Substances

  • DNA-Binding Proteins
  • HLA-DQ alpha-Chains
  • HLA-DQA1 antigen
  • Nuclear Proteins
  • TRIM27 protein, human

Grants and funding

his project was funded by National Natural Science Foundations (30670956, 30971133), 863 HighTech Key Projects (2006AA02A403, 2007AA02Z161), China Key Program on Basic Research (2007CB516812), Special Scientific Programs from Science and Technology Department (2009-8), Health Department (2009-10) and Education Department (2008-7) of Henan Province. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.