Capsaicin consumption, Helicobacter pylori CagA status and IL1B-31C > T genotypes: A host and environment interaction in gastric cancer

Abstract

Gastric cancer (GC) has been associated with a complex combination of genetic and environmental factors. In contrast to most countries, available information on GC mortality trends showed a gradual increase in Mexico. Our aim was to explore potential interactions among dietary (chili pepper consumption), infectious (Helicobacter pylori) and genetic factors (IL1B-31 genotypes) on GC risk. The study was performed in three areas of Mexico, with different GC mortality rates. We included 158 GC patients and 317 clinical controls. Consumption of capsaicin (Cap), the pungent active substance of chili peppers, was estimated by food frequency questionnaire. H. pylori CagA status was assessed by ELISA, and IL1B-31 genotypes were determined by TaqMan assays and Pyrosequencing in DNA samples. Multivariate unconditional logistic regression was used to estimate potential interactions. Moderate to high Cap consumption synergistically increased GC risk in genetically susceptible individuals (IL1B-31C allele carriers) infected with the more virulent H. pylori (CagA+) strains. The combined presence of these factors might explain the absence of a decreasing trend for GC in Mexico. However, further research on gene–environment interactions is required to fully understand the factors determining GC patterns in susceptible populations, with the aim of recommending preventive measures for high risk individuals.

Introduction

Gastric cancer (GC) is the world’s 5th most frequent cancer, is still the second most common cause of cancer-related death in the world, and is thought to be associated with a complex combination of genetic and environmental factors. In contrast to most countries, available information on the GC mortality trends showed a gradual increase in Mexico (Tovar-Guzman et al., 2001). Previous epidemiological studies have independently reported an increased GC risk due to chili pepper consumption (Lopez-Carrillo et al., 2003, Sipetic et al., 2003, Mathew et al., 2000), to Helicobacter pylori (H. pylori) CagA seropositivity (Eslick, 2006, Huang et al., 2003), or to interleukin 1 beta (IL1B) genotypes (IL1B-31C > T) (Kumar et al., 2009, Vincenzi et al., 2008, Lee et al., 2007b, Wang et al., 2007, Camargo et al., 2006, Kamangar et al., 2006).

Chili pepper consumption has been related to an increased risk of GC in studies performed in Spain (Goiriena de Gandarias et al., 1988), Serbia (Sipetic et al., 2003), Korea (Lee et al., 1995), and India (Mathew et al., 2000, Gajalakshmi and Shanta, 1996). Similar adjusted results have been obtained in México where high consumption of chili is also customary (Lopez-Carrillo et al., 1994, Lopez-Carrillo et al., 2003). Capsaicin (Cap) is the pungent active substance of chili peppers, and experimental evidence suggests that Cap ingestion significantly increases the number of lymphocytes and produces exfoliation of the intestinal epithelium (Johnson, 2007, Diaz Barriga et al., 1995). Several studies using diverse initiation–promotion protocols have shown that chili extract has tumor promoting effects in rodent stomach, liver and colon (Johnson, 2007). In addition, Marques et al. (2002) reported that Cap (10–200 μM) significantly induced micronuclei and sister chromatid exchanges in cultured peripheral human blood lymphocytes. Both reports illustrated the carcinogenic and genotoxic properties of Cap.

H. pylori infection is considered a necessary but not sufficient cause of gastric adenocarcinoma (IARC, 1994), because less than 3% of infected patients develop this neoplasia (Uemura et al., 2001). H. pylori strain virulence, host genetic characteristics and variations in dietary patterns are considered concomitant risk factors for GC development (World Cancer Research Fund/American Institute for Cancer Research, 2007, Stewart and Kleihues, 2003, Gonzalez et al., 2002). The key pathophysiological event in H. pylori infection is the initiation of an inflammatory response (Hatakeyama, 2006). IL1B is a proinflammatory host gene up-regulated by H. pylori infection encoding IL1β, the cytokine which initiates and amplifies the inflammatory response to H. pylori infection, besides being the most powerful acid inhibitor known. Moreover, virulent H. pylori strains, such as those bearing the Cag pathogenicity island, produce more aggressive mucosal damage (El Omar et al., 2000).

Several IL1B gene polymorphisms, including IL1B-31C > T (IL1B-31), have been associated with increased expression of IL1β (Vilaichone et al., 2005, Hwang et al., 2002, Pociot et al., 1992). Inconsistent epidemiological evidence has related those single nucleotide polymorphisms (SNPs) with GC risk in Caucasian and Asian populations (Wang et al., 2007, Camargo et al., 2006, Kamangar et al., 2006). However, limited information is available for Mexican populations. Only two studies have been published and both reported an increased risk for GC among carriers of the IL1B-31C allele (Sicinschi et al., 2006, Garza-Gonzalez et al., 2005).

Our research group has previously evaluated the interaction between Cap consumption and H. pylori antibodies on GC risk and showed no significant interaction between these factors, probably because the virulence of H. pylori was not considered (Lopez-Carrillo et al., 2003). We later examined the interaction between H. pylori CagA positive infections and host IL1B-31 genotypes and showed a significantly adjusted increased risk of intestinal-type GC (OR 3.19; 95% CI 51.05–9.68) in CagA positive subjects with the IL1B-31CC genotype (Sicinschi et al., 2006). Therefore, our aim was to explore a potential interaction among dietary (Cap consumption), infectious (H. pylori) and genetic factors (IL1B-31C genotypes) on GC risk.