Genetic variants in the interleukin 1 alpha (IL1A) gene are associated with gastric cancer

This study is part of the EUR-GAST Project, established to elucidate the effects of Helicobacter pylori infection, genetic polymorphisms and environmental factors in gastric cancer etiology in European populations. The EUR-GAST Project is enclosed in a much larger European investigation (European Prospective Investigation into Cancer and Nutrition – EPIC) which is designed to investigate the relationships between diet, nutritional status, lifestyle and environmental factors and the incidence of cancer and other chronic diseases.

It is known that gastric cancer risk is related with the stomach infection by the bacterium H. pylori and consequent inflammation of the gastric mucosa. One of the aims of the EUR-GAST Project is to evaluate the role of genetic variation in inflammation-linked genes, specifically single nucleotide polymorphisms (SNPs) that are common in the population.

In this investigation, a collaboration between IPATIMUP and the Catalan Institute of Oncology in Barcelona, we studied the cluster of 9 inflammation genes on chromosome 2 in gastric cancer patients and a group of individuals without the disease, a total of 3500 samples. We identified new SNP variants and haplotypes (combination of genetic variants present in the same individual) which confer susceptibility to gastric cancer, particularly of the intestinal type and distal localisation, a region in the stomach where the infection by H. pylori is more prevalent. These variants are mainly localised in the interleukin 1 alpha gene (IL1A) region, important in inflammation signalling pathways. The identification of genetic variants associated with gastric cancer, in combination with other factors such as lifestyle and H. pylori virulence, contributes to increasing our understanding of gastric cancer development and helps identify people who are at risk.

Authors and affiliations:
Cecília Durães1, Xavier Muñoz2,3, Catalina Bonet4, Nadia García2,4, Adoración Venceslá2,4, Fátima Carneiro1,5,6, Bárbara Peleteiro5,7, Nuno Lunet5,7, Henrique Barros5,7, Björn Lindkvist8, Marie-Christine Boutron-Ruault9,10,11, H.Bas Bueno-de-Mesquita12,13, Cosmeri Rizzato14, Antonia Trichopoulou15,16, Elisabete Weiderpass17,18,19,20, Allessio Naccarati21, Ruth C. Travis22, Anne Tjønneland23, Aurelio Barricarte Gurrea24,25, Mattias Johansson26, Elio Riboli27, Céu Figueiredo1,5, Carlos Alberto González2, Gabriel Capellà3, José Carlos Machado1,5, Núria Sala2,4

1 Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal

2 Molecular Epidemiology Group, Translational Research Laboratory, Catalan Institute of Oncology (IDIBELL), Barcelona, Spain

3 Hereditary Cancer Program, Translational Research Laboratory, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain

4 Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (IDIBELL), Barcelona, Spain 5 Faculty of Medicine of the University of Porto, Porto, Portugal

6 Department of Pathology, Hospital of S. João, Porto, Portugal

7 Institute of Public Health of the University of Porto (ISPUP), Porto, Portugal

8 Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

9 Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women’s Health team, Villejuif, France

10 Université Paris-Sud, UMRS 1018, Villejuif, France

11 Institut Gustave Roussy (IGR), Villejuif, France

12 National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

13 Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands

14 German Cancer Research Center (DKFZ), Heidelberg, Germany

15 Hellenic Health Foundation, Athens Greece

16 WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece

17 Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway

18 Department of Research, Cancer Registry of Norway, Oslo, Norway

19 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

20 Samfundet Folkhälsan, Helsinki, Finland

21 HuGeF (Human Genetics Foundation), Molecular and Genetic Epidemiology Unit, Torino Italy

22 Cancer Epidemiology Unit, University of Oxford, Oxford, UK

23 Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark

24 Navarre Public Health Institute, Pamplona, Spain

25 Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiología y Salud Pública-CIBERESP), Madrid,Spain

26 International Agency for Research on Cancer (IARC-WHO), Lyon, France

27 School of Public Health, Imperial College London, St Mary’s Campus, Imperial College, London, UK

Abstract:
The most studied genetic susceptibility factors involved in gastric carcinoma (GC) risk are polymorphisms in the inflammation-linked genes interleukin 1 (IL1) B and IL1RN. Despite the evidence pointing to the IL1 region, definite functional variants reproducible across populations of different genetic background have not been discovered so far. A high density linkage disequilibrium (LD) map of the IL1 gene cluster was established using HapMap to identify haplotype tagSNPs. 87 SNPs were genotyped in a Portuguese case-control study (358 cases, 1485 controls) for the discovery analysis. A replication study, including a subset of those tagSNPs (43), was performed in an independent analysis (EPIC-EurGast) containing individuals from 10 European countries (365 cases, 1284 controls). Single SNP and haplotype block associations were determined for GC overall and anatomopathological subtypes. The most robust association was observed for SNP rs17042407, 16Kb upstream of the IL1A gene. Although several other SNP associations were observed, only the inverse association of rs17042407 allele C with GC of the intestinal type was observed in both studies, retaining significance after multiple testing correction (p=0.0042) in the combined analysis. The haplotype analysis of the IL1A LD block in the combined dataset revealed the association between a common haplotype carrying the rs17042407 variant and GC, particularly of the intestinal type (p=3.1x10-5) and non cardia localisation (p=4.6x10-3). These results confirm the association of IL1 gene variants with GC and reveal a novel SNP and haplotypes in the IL1A region associated with intestinal type GC in European populations.

Journal:
International Journal of Cancer

Link:
http://onlinelibrary.wiley.com/doi/10.1002/ijc.28776/abstract