Abstract
BackgroundApolipoprotein E (ApoE) is a multifunctional protein playing both a key role in the metabolism of cholesterol and triglycerides, and in tissue repair and inflammation. The ApoE gene (19q13.2) has three major isoforms encoded by ε2, ε3 and ε4 alleles with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. An inverse relationship between cholesterol levels and gastric cancer (GC) has been previously reported, although the relationship between apoE genotypes and GC has not been explored so far.MethodsOne hundred and fifty-six gastric cancer cases and 444 hospital controls were genotyped for apoE polymorphism (ε2, ε3, ε4 alleles). The relationship between GC and putative risk factors was measured using the adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) from logistic regression analysis. A gene-environment interaction analysis was performed. The effect of the apoE genotypes on survival from GC was explored by a Kaplan–Meier analysis and Cox proportional hazard regression model.ResultsSubjects carrying at least one apoE ε2 allele have a significant 60% decrease of GC risk (OR=0.40, 95% CI: 0.19 – 0.84) compared with ε3 homozygotes. No significant interaction emerged between the ε4 or ε2 allele and environmental exposures, nor ε2 or ε4 alleles affected the median survival times, even after correcting for age, gender and stadium.ConclusionsOur study reports for the first time a protective effect of the ε2 allele against GC, that might be partly attributed to the higher antioxidant properties of ε2 compared with the ε3 or ε4 alleles. Given the study’s sample size, further studies are required to confirm our findings.
Highlights
Apolipoprotein E (ApoE) is a multifunctional protein playing both a key role in the metabolism of cholesterol and triglycerides, and in tissue repair and inflammation
Alcohol consumption was associated with an increased gastric cancer (GC) risk with Odds ratio (OR) of 1.84 and 3.29 for moderate and heavy drinkers, respectively
A nearly doubled GC risk (OR=1.95, 95% confidence interval (CI): 1.06 – 3.60) was detected among individuals smoking more than 25 pack-years
Summary
Apolipoprotein E (ApoE) is a multifunctional protein playing both a key role in the metabolism of cholesterol and triglycerides, and in tissue repair and inflammation. To fully answer the question whether a causal relationship exists between low cholesterol level and cancer, an alternative epidemiologic approach named “Mendelian randomization” can be used to overcome the problem of reverse causality and confounding. According to this approach, a genetic variation (e.g., apoE) that serves as a robust proxy for an environmentally modifiable exposure (e.g., serum cholesterol level) can be used in order to make causal inferences about a disease [12]. By adopting the Mendelian Randomization approach, Benn concluded that his results are in accordance with those emerged from a cohort of elderly subjects treated with pravastatin [14] and from the Atherosclerosis Risk in communities cohort study [15], all suggesting low LDL are probably due to the preclinical cancer stage and per se do not cause cancer
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