Gastric cancer, a leading cause of cancer-related mortality worldwide, is a multifactorial disease influenced by a complex interplay of genetic, environmental, and lifestyle factors. Among these, the role of psychological factors, particularly depression, has emerged as a potential contributor to the risk and progression of gastric cancer[16-19]. This paper aims to explore the association between depression and gastric cancer, leveraging data from the National Health and Nutrition Examination Survey (NHANES) and employing Mendelian randomization to elucidate the causal relationship between these conditions.
Depression is a common mental disorder characterized by persistent sadness, loss of interest, and a range of physical and cognitive symptoms that can significantly impair an individual's ability to function[20-23]. The bi-directional relationship between depression and physical health conditions has been well-documented, with depression not only resulting from the stress of coping with a chronic illness but also potentially exacerbating or even contributing to the development of such illnesses[15, 24, 25].
In a crowd-based analysis of NHANES data, depression has been identified as a risk factor for gastric cancer. The NHANES program, designed to assess the health and nutritional status of adults and children in the United States, provides a rich dataset for examining the prevalence and correlates of both depression and gastric cancer within a diverse population sample[26-28]. The analysis indicates that individuals with depression have a higher incidence of gastric cancer compared to those without depression, even after adjusting for various confounders such as age, sex, socioeconomic status, lifestyle factors, and other comorbidities.
Mendelian randomization (MR) is a method that uses genetic variants as instrumental variables to infer causal relationships between modifiable risk factors and disease outcomes[29]. This approach capitalizes on the random assortment of genes from parents to offspring that occurs during gamete formation and conception, which mimics the randomization process in a controlled trial. MR can therefore provide evidence for causality in the absence of confounding factors that often plague observational studies. Single nucleotide polymorphisms (SNPs) are variations in a single nucleotide that occur at a specific position in the genome[30, 31]. They are the most common type of genetic variation among people and can serve as biological markers, helping scientists locate genes associated with disease. Two SNPs of interest in the context of gastric cancer and depression are RS11739849 and RS11694231.
RS11739849 is a single nucleotide polymorphism (SNP) located in an intronic region upstream of the KCTD16 gene. The KCTD16 gene, also known as potassium channel tetramerization domain 16, is primarily predicted to be involved in protein homologous oligomerization and has a potential role in regulating upstream or internal signaling pathways of G protein-coupled receptors. It is also predicted to be located in cell projections and may be part of receptor complexes [32-34]. On the other hand, RS11694231 is a SNP located in an intronic region of a long non-coding RNA (lncRNA) called LINC01250. The relationship between LINC01250 and gastric cancer has been extensively studied. In a review on genetic polymorphisms associated with gastric cancer risk, LINC01250 was identified as one of the genes linked to this disease. Additionally, studies have suggested a potential genetic overlap between LINC01250 and depression, specifically in relation to Alzheimer's Disease (AD)[35, 36]. However, further research is needed to fully understand the mechanisms underlying these two SNPs and their potential role in the association between depression and gastric cancer.
The current research has several noteworthy limitations. Firstly, it is limited to individuals of European ancestry and may not be applicable to other racial groups. Secondly, while MR-Egger regression and MR-PRESSO were utilized to assess potential bias from heterogeneity and pleiotropy, there is no guarantee that the chosen genetic predictors for depression-related SNPs adhere to the assumptions of MR. Lastly, the study did not specifically focus on particular types of gastric cancer, such as gastric adenocarcinoma or gastric squamous cell carcinoma. It is possible that depression may have a more profound causal relationship with a specific type of gastric cancer, thus further extensive research is necessary in the future.
In summary, our study utilized publicly accessible epidemiological databases and GWAS data to examine the correlation between depression and gastric cancer. Our analysis revealed a significant link between the development of gastric cancer and the onset of depression. This highlights the importance of addressing the mental well-being of patients in future treatments for gastric cancer.