Interactions between genetic polymorphisms in the apoptotic pathway and environmental factors on esophageal adenocarcinoma risk

Abstract

How genetic variations in apoptosis pathway interact with environmental factors to contribute to esophageal adenocarcinoma (EA) risk has not been comprehensively investigated. We conducted a case-only analysis in 335 Caucasian EA patients that were genotyped for 242 single nucleotide polymorphisms (SNPs) in 43 apoptotic genes. Gene-environment interactions were assessed using a two-step approach. First, random forest algorithm was used to screen for the potential interacting markers. Next, we used case-only logistic regression model to estimate the effects of gene-environment interactions on EA risk. Four SNPs (PERP rs648802; PIK3CA rs4855094, rs7644468 and TNFRSF1A rs4149579) had significant interaction with gastroesophageal reflux disease (GERD). The presence of variant alleles in TP53BP1 rs560191, CASP7 rs7907519 or BCL2 rs12454712 enhanced the risk of smoking by 2.08-2.58 times [interaction odds ratio (ORi) 5 2.08-2.58, adjusted P-value (P adj ) 5 0.02-0.04]. Compared with patients carrying £1 risk genotype, the risk of GERD on EA was increased in persons with two (ORi 5 1.89, P adj 5 0.016) or ‡3 (ORi 5 4.30, P adj < 0.0001) risk genotypes. Compared with cases with £1 risk genotype, smoking-associated EA risk increased by 3.15 times when ‡2 risk genotypes were present (ORi 5 3.15, P adj < 0.0001). In conclusion, interactions among apoptotic SNPs and GERD or smoking play an important role in EA development. IntroductionCumulative evidence has indicated that symptomatic gastroesophageal reflux disease (GERD), obesity, smoking and male gender are four major risk factors for developing esophageal adenocarcinoma (EA) (1,2). Although GERD is the strongest individual risk factor and subjects who have the most frequent reflux symptom carry .4-fold EA risk, most of them follow an indolent course for the entire life (3). On the other hand, nearly 50% of EA patients do not experience GERD-associated symptoms (2,4,5). Therefore, challenges arise when considering the benefit and cost of endoscopic surveillance for EA among subjects with these risk factors, especially GERD (6). One of the explanations for this phenomenon stems from the complex interactions between lifestyle/environmental exposure and genetic factors. Since most EA cases are sporadic, genetic influences are more probably to be polymorphisms in multiple genes instead of single gene mutation. Evidence from pathway-based studies suggests that genetic variance may modulate the susceptibility of developing EA (7-9). Incorporating one's genetic background in the clinical setting could be a better strategy for risk assessment and cancer surveillance, and possibly provide a better understanding about how complex factors contribute to EA risk jointly. However, fewer studies have assessed interactions using a more comprehensive approach.Apoptosis, or programmed cell death, is essential for normal tissues to regulate cell number and to eliminate unwanted or aging cells as an organism develops. Mutations and single nucleotide polymorphisms (SNPs) in apoptotic pathway...

Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus

“…A number of studies have pursued candidate-based gene-environment analyses of EA, and reported interactions between BMI, smoking or GERD symptoms and selected SNPs in genes related to detoxification, angiogenesis, DNA repair, apoptosis, and extracellular matrix degradation. 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 This body of work helped to establish the notion that the level of disease risk associated with GERD symptoms, in particular, may vary according to inherited genetic variation. All of these studies, however, were conducted in small samples (<350 cases) and were not replicated in independent populations.…”

Interaction between Arsenic Exposure from Drinking Water and Genetic Polymorphisms on Cardiovascular Disease in Bangladesh: A Prospective Case-Cohort Study

“…As mentioned above, we considered baseline well-water As as the main exposure because it better measured long-term exposure in our study population. Because > 50% of the 170 SNPs have a variant genotype frequency < 5% and the dominant genetic model is often highly correlated with the additive genetic model ( Lettre et al 2007 ), we conducted all tests for gene–As interactions using dominant genetic model for better statistical power, similar to other gene–environment interaction studies ( Garcia-Closas et al 2013 ; Wu et al 2011 ). SNPs were dichotomized under a dominant genetic model in which genotype with either one or two copies of a minor allele (variant allele) was combined; for SNPs with a negative β AG indicating an antagonistic interaction, we used genotype without the minor allele as the “at-risk” genotype for easy interpretation.…”

Sirolimus and Everolimus Pathway: Reviewing Candidate Genes Influencing Their Intracellular Effects

“…HIF-1 and VEGF ( VEGFA ) -dependent regulation of angiogenesis; 3. lipid biosynthesis; 4. mitochondrial biogenesis and function; 5. cell cycle and growth; and 6. autophagy. All of these effects are modulated/regulated by a large genetic encoding network ( Figure 1 ) ( Table 1 ) [ 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 ,…”