Abstract
BackgroundThe 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.MethodsConditional 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.ResultsOf 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).ConclusionThis 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.
Highlights
Esophageal cancer (EC) is one of the most aggressive gastrointestinal malignancies and prevalent in the developing world [1]
SNP genotyping and quality control and Conditional logistic regression analysis (CLRA) After strict quality control to the SNPs, the 24 promising SNPs selected for association testing are listed in Table 1 along with the Bonferroni corrected P values based on multiple testing of 3,515 SNPs
Since SNP rs17533090 was highly correlated with SNP rs35399661 and could be completely represented by the latter (D’ = 1/r2 = 1 in HapMap CHB data), only the rs35399661 locus was kept for further statistical analysis
Summary
Esophageal cancer (EC) is one of the most aggressive gastrointestinal malignancies and prevalent in the developing world [1]. There are two main histological types for EC, squamous cell carcinoma (ESCC) and adenocarcinoma, each with distinct etiological and pathological characteristics [5]_ENREF_4. ESCC is the predominant histological type worldwide,especially in northern China, comprising more than 90% of all EC cases [6]_ENREF_5. Recent genome-wide association studies (GWAS) have identified couple of susceptibility loci for ESCC in Han Chinese [7,8,9]. 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
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