Chronic infections with different pathogens are responsible for 13% of total cancer globally (an estimated 2.2 million new cancer cases annually), with more than a third in China. Based on existing evidence, chronic infections are also estimated to account for approximately10% of all disability-adjusted life-years due to non-communicable diseases (NCDs) worldwide, including cardiometabolic, autoimmune, neurodegenerative and psychiatric disorders.
Based on the HBsAg seropositity measured at baseline among entire 0.5 million CKB cohort participants, we found that chronic hepatitis B virus infection is associated with multiple NCDs, including chronic liver diseases, certain cancers and chronic kidney diseases (BMJ Open 2019; JAMA Netw Open 2019). Moreover, we found HBV also significantly increased risk of intracerebral hemorrhage (ICH) but not other stroke subtypes. In further analyses among participants with biochemistry data available, we found this increased risk of ICH may be mediated through liver dysfunction and altered lipid metabolism (Stroke 2023).
Gastric cancer is the second leading cause of cancer death globally, with particularly high rates in China. Although previous studies have demonstrated a clear causal link between H. pylori infection and non-cardia gastric cancer (NCGC), the estimated relative risks vary considerably between different studies and conflicting evidence about the role of H. pylori in the aetiology of cardia gastric cancer (CGC). Using a highly-sensitive assay to detect H. pylori infection of the stored blood samples in a large, nested case-cohort study, we found individuals who tested positive with H. pylori were six times more likely than those who were H. pylori negative to develop NCGC and three times more likely to develop CGC. These risk estimates were twice as strong as those reported in previous Chinese studies which used less sensitive assays. We estimated that H. pylori accounted for approximately 340,000 new gastric cancers each year in China, including about 80% of the NCGC and 60% of the CGC cases (Lancet Public Health 2021).
These updated risk estimates should help refine global disease burden estimation and inform the development of mass H. pylori screening and eradication programmes for primary prevention of gastric cancer in high risk populations.
Chronic infections with other pathogens such as human papillomavirus (HPV), human herpes viruses and fluke worms also play an important roles in cancer and other NCDs development and progression. To overcome the limitations of previous studies that tended to focus on a single pathogen with a single cancer, we have developed, in close collaboration with the German Cancer Research Center (DKFZ) and UK Biobank, a custom-designed multiplex serological panel that can measure multiple pathogens simultaneously. Our pilot study involving 2000 randomly selected participants confirmed high prevalence of most chronic infections, and demonstrated significant regional, gender and intergenerational variations of sero-prevalence for certain pathogens in Chinese adults. Co-infection with multiple pathogens was common: 25% of participants were sero-positive for more than 10 pathogens (BMJ Open 2022). Our first case-cohort study of gastrointestinal cancers showed, in combination with previous published studies, that H. pylori was associated with significantly increased risk of cardia gastric cancer in Asian populations, contrary to findings in Western populations, while for non-cardia gastric cancer the relative risks associated with H. pylori infection appeared more extreme (2-fold) in European than in Asian populations (Int J Epidemiol 2023). A few other pathogens (e.g. HBV, HHV-7) were also associated with risks of gastrointestinal cancers (Int J Cancer 2024). Our second case-cohort study of EBV (16 antigens) and nasopharyngeal cancer showed that use of only two anti-EBV-markers (i.e. LF2/BGLF2 IgG) yielded C-statistics of 0.85 for risk prediction of nasopharyngeal cancer, which persisted for more than five years after sample collection (Int J Epidemiol 2024). These study findings should improve the understanding of roles of various chronic infections in cancers development and also inform cost-effective cancer early detection/screening strategies. They also helped to optimise assay development for large-scale application.
Our ongoing large-scale assays of 47 antigens from 20 pathogens in 40,000 CKB participants (10,000 randomly selected sub-cohort participants and 30,000 site-specific cancer cases, with the serology data available in Q4/2024) will comprehensively assess the roles of chronic infections with multiple pathogens in the aetiology of multiple cancers and other NCDs. We will use integrative multi-omics approaches (e.g. genomics, proteomics) to investigate the potential biological mechanisms/pathways through which host immunity, chronic inflammation and host-pathogen-environmental interactions may influence the infection-associated NCDs risks.
Impact of research
CKB’s updated risk estimates should help refine global disease burden estimation. The comprehensive investigations between multiple infectious pathogens and risk of multiple chronic diseases and the potential biological mechanisms involved will inform infection-related NCDs prevention and control policy making, which will be of benefit to people in low-middle income countries and across the world.