The Relationship Between Environmental Exposure and Genetic Architecture of the 2q33 Locus With Esophageal Cancer in South Africa.

Marco Matejcic,M Iqbal Parker,Christopher G Mathew

doi:10.3389/fgene.2019.00406

Abstract

Esophageal squamous cell carcinoma (ESCC) has a high prevalence in several countries in Africa and Asia. Previous genome-wide association studies (GWAS) in Chinese populations have identified several ESCC susceptibility loci, including variants on chromosome 2q33 and 6p21, but the contribution of these loci to risk in African populations is unknown. In this study we tested the association of 10 genetic variants at these two risk loci on susceptibility to ESCC in two South African ethnic groups. Variants at 2q33 (rs3769823, rs10931936, rs13016963, rs7578456, rs2244438) and 6p21 (rs911178, rs3763338, rs2844695, rs17533090, rs1536501) were genotyped in a set of Black Xhosa (463 cases and 480 controls) and Mixed Ancestry (269 cases and 288 controls) individuals. Genotyping was performed using TaqMan allelic discrimination assays. The Pearson’s chi-squared test was used to compare the allele frequency between cases and controls. Gene-environment interactions with tobacco smoking and alcohol consumption were investigated in a case-control analysis. A logistic regression analysis was further performed to elucidate the independent effect of each association signal on the risk of ESCC. The 2q33 variants rs10931936, rs7578456, and rs2244438 were marginally associated with higher risk of ESCC in the Mixed Ancestry population (ORs = 1.39–1.58, p ≤ 0.035), of which rs7578456 and rs2244438 remained significant after multiple correction (p < 0.005). The associations with rs7578456 and rs2244438 were also observed across strata of tobacco smoking (ORs = 1.47–2.75, p ≤ 0.035) and alcohol consumption (ORs = 1.45–2.06, p ≤ 0.085) status. However, only the association with rs2244438, which lies within an exon of TRAK2, remained significant after adjustment for the other variants in the region. Interestingly, none of the variants tested were significantly associated with ESCC in the Black South African population. These finding implicate TRAK2 as a casual gene for ESCC risk in the Mixed Ancestry population of South Africa and confirm prior evidence of population-specific differences in the genetic contribution to ESCC, which may reflect differences in genetic architecture and environmental exposure across ethnic groups.

Highlights

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies in low- and middle-income countries and is a disease of major public health importance because of its poor prognosis and high mortality
In this study we investigated whether single nucleotide polymorphisms (SNPs) at 2q33 and 6p21 reported to be associated with ESCC in the northern Chinese populations contributed to the increased risk of ESCC in the South African populations
This study investigated the association between common genetic polymorphisms at 2q33 and 6p21 and the risk of ESCC in two South African populations

Summary

Introduction

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies in low- and middle-income countries and is a disease of major public health importance because of its poor prognosis and high mortality. Individuals within a specific geographical area may be exposed to the same environmental factors and share similar dietary habits, not all of them have the same risk of developing ESCC. Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of the 456,000 esophageal cancer cases reported each year (Abnet et al, 2018), and approximately 80% of the cases worldwide occur in low-to-middle income countries (LMIC) including South Africa (Ferlay et al, 2015; Wong et al, 2018). Tobacco smoking and alcohol consumption are the major environmental risk factors in South Africa (Dandara et al, 2015)

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