Candidate gene association study of esophageal squamous cell carcinoma in a high-risk region in Iran

Abstract

There is a region with a high risk for esophageal squamous cell carcinoma (ESCC) in the northeast of Iran. Previous studies suggest that hereditary factors play a role in the high incidence of cancer in the region. We selected 22 functional variants (and 130 related tagSNPs) from 15 genes that have been associated previously with the risk of ESCC. We genotyped a primary set of samples from 451 Turkmens (197 cases and 254 controls). Seven of 152 variants were associated with ESCC at the P = 0.05 level; these single nucleotide polymorphisms were then studied in a validation set of 549 cases and 1,119 controls, which included both Turkmens and non-Turkmens. The association observed for a functional variant in ADH1B was confirmed in the validation set, and that of a tagSNP in MGMT, the association was borderline significant in the validation set, after correcting for multiple testing. The other 5 variants that were associated in the primary set were not significantly associated in the validation set. The histidine allele at codon 48 of ADH1B gene was associated with a significantly decreased risk of ESCC in the joint data set (primary and validation set) under a recessive model (odds ratio, 0.41; 95% confidence interval, 0.29-0.76; P = 4 x 10(-4)). The A allele of the rs7087131 variant of MGMT gene was associated with a decreased risk of ESCC under a dominant model (odds ratio, 0.79; 95% confidence interval, 0.64-0.96; P = 0.02). These results support the hypothesis that genetic predisposition plays a role in the high incidence of ESSC in Iran.

Figure 1

Eigenvectors of the first two principle components with the largest Eigenvalues have been plotted for the primary sample set using genotyping data of 152 SNPs.

Figure 2

The Suggested Metabolic Pathway for 1- Methylpyrene (1-MP). 1-MP is first metabolized to 1-Hydroxymethypyrene (1-HMP) by CYP450 enzymes. The Majority (~80%) of 1-HMP is detoxified by alcohol dehydrogenase (ADH1B) to 1-Formylpyrene (1-FP) and then to 1-Pyrenyl carboxylic acid (1-PCA) by aldehyde dehydrogenase (ALDH). 1-PCA and its glucoronic acid conjugates are excreted in urine. Some of (~20%) 1-HMP is transformed to 1-Sulfooxymethylpyrene (1-SMP) of which the majority form DNA- adducts and tiny of it (~2%) detoxified by nucleophile glutathione and form Methylpyrenyl mercapturic acid (MPMA).