Beyond Cardiovascular Disease: Blood Pressure and Cancer Risk through a Genetic Lens

In 2023, cancer was the second leading cause of death globally after cardiovascular diseases [1]. Cancers of the digestive tract, including those of the esophagus, stomach, colon, rectum, pancreas, and small intestine, represent a major global health challenge. Together, they account for millions of new cancer cases and deaths each year, contributing substantially to overall cancer morbidity and mortality [1]. Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death worldwide [1]. Gastric and esophageal cancers, while geographically variable in incidence, are similarly responsible for high mortality rates due to late diagnosis and limited curative options [1]. Recent epidemiological data indicate a concerning rise in early-onset digestive tract cancers, particularly in individuals younger than 50 years [2, 3], underscoring the need for improved preventive and etiological insights.Parallel to the global cancer burden is the pandemic of hypertension – a condition affecting more than 1.4 billion people worldwide [4] and contributing to an estimated 10 million deaths annually [5]. Hypertension is a well-established risk factor for cardiovascular and renal diseases [6], yet its broader systemic effects, including potential links to cancer, are increasingly recognized. The biological plausibility of a hypertension-cancer link stems from shared mechanisms such as chronic inflammation, oxidative stress, endothelial dysfunction, and metabolic dysregulation. Both conditions are influenced by lifestyle and environmental factors, diet, obesity, physical inactivity, and alcohol consumption [7], creating overlapping risk pathways.Given that hypertension is highly prevalent and modifiable, understanding whether elevated blood pressure contributes causally to the development of digestive tract cancers has significant implications for public health and disease prevention strategies. Observational studies over the past 2 decades have explored the relationship between hypertension and digestive tract cancers, producing inconsistent and sometimes conflicting findings [8]. One of the most persistent challenges in epidemiologic studies of hypertension and cancer is confounding by metabolic and lifestyle factors. Physical inactivity, obesity, smoking, alcohol consumption, and insulin resistance are common to both hypertension and cancer risk [7], making it difficult to disentangle direct effects of blood pressure from these correlated exposures. Moreover, antihypertensive medications, diagnostic biases, and disease misclassification can introduce additional sources of bias. Several observational studies conducted in Asian populations have suggested stronger positive associations between hypertension and certain digestive tract cancers – particularly colorectal and esophageal cancers – than those typically reported in Western cohorts [9]. However, direct comparative evidence across ancestries remains limited, and such differences may reflect variation in genetic architecture, dietary sodium intake, salt sensitivity, or other environmental modifiers. Furthermore, most existing evidence has been derived from observational designs, which cannot establish causality.To address these limitations, Deng et al. [10] employed Mendelian randomization (MR), a genetic epidemiological approach that uses inherited genetic variants as instrumental variables to test causal relationships between risk factors and outcomes. By leveraging genome-wide association study (GWAS) data across European and Asian populations, the authors aimed to clarify whether genetically elevated blood pressure directly increases the risk of digestive tract cancers and whether these effects differ by ancestry.In this two-sample MR study, Deng et al. [10] investigated the causal associations between blood pressure traits (systolic blood pressure [SBP], diastolic blood pressure, and clinically defined hypertension) and a range of digestive tract cancers, including colorectal, gastric, esophageal, and small intestine cancers. The authors used large-scale GWAS summary statistics from European datasets (UK Biobank and FinnGen) and Asian datasets (Biobank Japan and the Korean Genome and Epidemiology Study). The inverse-variance weighted method served as the primary analytic approach, supported by sensitivity analyses (MR-Egger, weighted median, and MR-PRESSO) to test for pleiotropy and robustness. Key findings included no evidence of causality in Europeans and a potential causal association for CRC in Asians. Sensitivity analyses generally supported the robustness of the SBP-CRC relationship, though replication in independent Asian datasets was inconsistent [10].This work has several methodological and conceptual strengths, which the authors clearly acknowledge. It represents the first MR analysis to comprehensively assess the causal impact of blood pressure traits on digestive tract cancers across both European and Asian populations. The cross-ancestry comparison is particularly valuable as it provides novel insights into population differences in genetic architecture and environmental exposures that may shape cancer risk [10]. Several caveats merit acknowledgment. The number of single-nucleotide polymorphisms available for blood pressure instruments in Asian cohorts was smaller, resulting in weaker instrument strength and imprecise estimates. Findings derived primarily from Japanese and Korean populations may not extend to other Asian subgroups with different genetic and lifestyle backgrounds [10].This study adds to a growing body of literature exploring the systemic effects of blood pressure beyond cardiovascular outcomes [10]. If replicated, the findings suggest that elevated SBP may play a causal role in colorectal carcinogenesis among Asians. From a clinical and public-health perspective, the potential dual benefit of blood-pressure control – reducing both cardiovascular and CRC risks – deserves serious consideration. In populations with a high burden of hypertension and increasing CRC incidence, particularly in East Asia, integrated preventive strategies could yield substantial health gains. Encouraging adherence to dietary sodium reduction, weight control, and regular physical activity may simultaneously improve cardiovascular and oncologic outcomes. Furthermore, the study underscores the importance of population-specific prevention: the apparent ancestry-dependent effect suggests that precision public health approaches, informed by genetic and environmental data, may be more effective than one-size-fits-all strategies.However, the authors appropriately emphasize the need for replication. The observed association requires confirmation in additional large, ancestrally diverse MR analyses and in longitudinal cohorts with detailed phenotype and lifestyle data. Future studies should explore nonlinear dose-response relationships, sex-specific effects, and interactions with antihypertensive medications. Notably, emerging evidence suggests that some antihypertensive agents, such as β-blockers and angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), may exert anti-cancer effects, potentially through mechanisms involving inhibition of angiogenesis, reduction of oxidative stress, modulation of immune pathways, and attenuation of tumor-promoting neurohormonal signaling [11, 12]. These observations underscore the importance of considering medication class and duration of use in future analyses of hypertension-cancer relationships. Expanding GWAS coverage for digestive tract cancers, particularly in underrepresented populations, will be critical for refining causal inference and identifying underlying biological mechanisms. At the mechanistic level, integrative analyses combining MR with multi-omics, including metabolomics and microbiome profiling, could illuminate pathways linking vascular regulation and carcinogenesis. Understanding these mechanisms may ultimately reveal novel preventive or therapeutic targets.Deng et al. [10] provide compelling, genetically anchored evidence that elevated SBP may causally increase the risk of CRC in Asian populations but not in Europeans. Their work highlights how ancestry, environment, and biology converge to shape disease risk and illustrates the power of MR for disentangling complex epidemiologic relationships. If substantiated, these findings could transform how clinicians and policymakers view hypertension – not solely as a cardiovascular threat but also as a potential modifiable determinant of cancer risk. Integrating rigorous blood pressure management into broader cancer-prevention frameworks, especially in regions where hypertension and CRC are both rising, could represent a pragmatic step toward reducing the global burden of both diseases.The authors have no conflicts of interest to declare.This study was not supported by any sponsor or funder.Conceptualization, investigation, writing – original draft preparation, supervision, and project administration: S.K.K.; methodology: S.K.K. and J.A.L.; and writing – review and editing: S.K.K. and J.A.L.

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