To our knowledge this is the first large-scale systematic pathway-based study to investigate the role of common genetic variation in susceptibility to EA. In this case–control study, we analyzed 14 pathways that are potentially important in carcinogenic processes and found that the genetic variants in the apoptosis pathway to be significantly associated with EA risk after correction for multiple comparisons. Polymorphisms of rs3127075 in CASP7
0.0001, permutation P
0.05) and rs4661636 in CASP9
= 0.0004, permutation P
0.2) are the top SNPs in the apoptosis pathway associated with EA risk.
Apoptosis, a genetically controlled process of programmed cell death, provides a protective mechanism by removing DNA-damaged cells that could either interfere with normal function or lead to neoplastic proliferation (37
). Resistance to apoptosis is an important indicator related to esophageal carcinogenesis and chemotherapy resistance (38
). Apoptosis activation occurs through the caspase family in both mitochondrial and death receptor pathways (43
knockout mice were reported to be resistant to endotoxin-induced apoptosis (44
). An inactivation mutation of the caspase genes, CASP7
, has been found in esophageal cancer cells (42
). It is plausible that SNPs in multiple genes in this pathway could affect cancer risk, as caspase-8, -9 and -10 initiate a cascade of caspase activation by cleaving downstream effectors such as caspase-7, which consequently causes cell death (45
). Polymorphisms in CASP7
genes have found to be associated with several diseases including cancers (47
) but have not been investigated in the EA risk. Polymorphisms of rs3127075 in CASP7
and rs4661636 in CASP9
are the top SNPs in the apoptosis pathway were associated with EA risk in our study. Our tagSNP CASP7
rs12416109 is in complete linkage disequilibrium with CASP7
1), which has been found to be associated with different CASP7
expression level and rheumatoid arthritis by Garcia-Lozano et al.
), although the association of CASP7
rs2227309 with rheumatoid arthritis was not replicated in another study (52
). The tagSNP CASP7
rs12416109 in our study did not show significant association with EA risk (data not shown). The polymorphism rs4661636 in CASP9
was found to be associated with non-Hodgkin’s lymphoma in a pooled analysis of three population-based case–control studies (53
). In a Korean population, genetic polymorphisms in CASP7
were also found to be associated with survival in early-stage non-small-cell lung cancer and with worse outcome with the two genotypes combined (54
). Different genetic polymorphisms in CASP7
have been found to be associated with these different diseases, possibly because the reported SNPs are in linkage disequilibrium with a nearby functional SNP. The observed associations in our study provide additional molecular epidemiologic evidence supporting the proposed role of apoptosis genes in EA risk.
Another interesting finding of the study is the gene–gender interaction effect of the PGR
gene. A protective effect was observed among women carrying the variant G
allele (adjusted OR
0.19; 95% CI
0.08–0.46) but was not observed among men (adjusted OR
1.38; 95% CI
0.95–2.00). Since the high male to female rate ratios are not probably to be explained by the different lifestyle risk factors among males and females (55
), the different levels of hormones between genders may provide some further insights into the EA mechanisms. These results should be treated with caution due to the limited female cases in the current study. Further studies are needed to investigate the role of rs572483 in PGR
gene in relation to the EA susceptibility.
The controls were selected to represent the general middle-aged adult distribution of Massachusetts population (56
). While the case and control groups differed in several risk factors (), we did not find the observed genetic associations confounded by these risk factors. No confounding bias was detected using multiple logistic regression models adjusting for these variables alone or in combination on the associations of interest.
It is important that the observed associations be confirmed in a larger, independent study. Although functionality is not known for all of the genotyped SNPs on our platform, our results are biologically plausible given the connections between the variants in apoptosis genes and EA risk. However, associations with any specific SNP should be interpreted with caution until functionality is identified and these results are replicated.