The Relationship Between Autoimmune Diseases and Gastric Cancer Risk in the British Population

Background Introduction

Despite the overall incidence of gastric cancer has declined over the past few decades, the incidence of gastric cancer among young people in some Western countries has increased in recent years. This trend may be related to the increase in autoimmune conditions. Autoimmune diseases usually cause inflammation, and inflammation has been found to be a precursor to many cancers, especially pernicious anaemia, which is strongly associated with gastric cancer. Pernicious anaemia is caused by autoimmune gastritis, involving the destruction of stomach wall cells and leading to a reduced ability to bind vitamin B12 in the body, thus increasing the risk of gastric cancer. Therefore, exploring the association between autoimmune diseases and gastric cancer in epidemiological research has great significance and urgency.

Source of the Paper

This paper is a collaborative effort among researchers from multiple institutions, including the National Cancer Institute in the United States and the Centre for Health Data Science at the University of Aberdeen in the UK. The paper was published in the “British Journal of Cancer” on May 22, 2024, and co-authored by John D. Murphy, Shahinaz M. Gadalla, Lesley A. Anderson, and others.

Research Design and Methods

Study Subjects and Data Source

The study used the UK’s “Clinical Practice Research Datalink (CPRD),” a large longitudinal database containing UK primary care records, which can be linked to other data sources. A nested case-control study was conducted within this database. Gastric cancer cases were matched to up to ten cancer-free controls by age and sex.

Experimental Design

The study considered 39 common autoimmune diseases, analyzed by different organ systems, including systemic/connective tissue diseases, blood diseases, cardiovascular diseases, endocrine diseases, skin and eye diseases, gastrointestinal diseases, and neurological diseases. Exposure to autoimmune diseases was defined as having a clinical diagnosis of these diseases two years before the case was diagnosed with gastric cancer. The association between these diseases and gastric cancer was assessed using odds ratios (OR) and 95% confidence intervals (CI) calculated using conditional logistic regression.

Data Analysis Methods

To minimize the risk of reverse causality bias, a two-year lag period was set between exposure and outcome. Outcomes and exposures were determined based on the International Classification of Diseases, Tenth Revision (ICD-10) codes, and medical and read codes in the CPRD. Smoking status was also determined using medical and read codes in the CPRD. A Bonferroni correction was applied for multiple hypothesis testing adjustments. Four sensitivity analyses were also performed to ensure the reliability of the study results. Finally, a fixed-effect meta-analysis of the prospective cohort studies in the existing literature and this study was also conducted.

Research Results

Overall Analysis

Among 64,812 controls, 10.2% had any autoimmune disease, compared to 11.5% among 6,586 gastric cancer cases. The study found an association between any autoimmune disease and gastric cancer (OR = 1.10, 95% CI: 1.01-1.20). However, this association became non-significant after excluding pernicious anaemia (OR = 1.00, 95% CI: 0.92-1.10). Pernicious anaemia itself significantly increased the risk of gastric cancer (OR = 2.75, 95% CI: 2.19-3.44).

Subgroup Analysis by Gender, Age, and Anatomical Site

The strength of the association was similar between men and women. Age-group analysis found that the association was more significant in the ≥50 years group (OR = 2.74, 95% CI: 2.18–3.43), but not significant in younger groups. Analysis by anatomical site showed that pernicious anaemia was significantly associated with non-cardia gastric cancer (OR = 3.91, 95% CI: 2.31–6.62), but not with cardia gastric cancer (OR = 1.71, 95% CI: 0.80–3.65).

Sensitivity Analysis

Even after adjusting for pernicious anaemia, the association of gastric cancer with aplastic anaemia remained nominally significant (OR = 14.00, 95% CI: 2.33–84.30). Moreover, the results of the complete case analysis were consistent with the overall analysis, indicating that other covariates did not have a strong bias effect on the outcome estimates.

Discussion

This study confirmed the positive correlation between pernicious anaemia and gastric cancer and extended its association with other autoimmune diseases. These results support the role of inflammation in the mechanism of cancer development, involving cell proliferation and DNA damage. The study also further supports the conclusion that gastric cancer risk is associated with a variety of autoimmune diseases, such as primary biliary cirrhosis, bridging syndrome, and myasthenia gravis, through meta-analysis.

This paper reveals the potential mechanisms and trends of autoimmune diseases in causing gastric cancer, especially through the pathway of pernicious anaemia. Further study of autoimmune gastritis as a pathway is necessary when considering other possible carcinogenic mechanisms.

Conclusion

This study and a large-scale meta-analysis confirmed the positive correlation between autoimmune diseases and the risk of gastric cancer. Patients with pernicious anaemia should consider gastric cancer screening. Future efforts need international consensus diagnostic standards and a large-scale international registry system to link autoimmune patients with cancer incidence and mortality data, expanding understanding of this relationship. Meanwhile, there is an urgent need for more research to elucidate the biological mechanisms underlying these associations.