The Combined Impact of Serum Albumin and Genetic Risk on VTE: Implications for Early Prevention

Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common vascular disease after coronary and cerebrovascular conditions, with approximately 10 million cases reported annually [1,2].

The pathogenesis of VTE involves various genetic, clinical, and environmental risk factors [3]. Among clinical factors, some studies suggest that low serum albumin levels (ALB), typically ranging from 35 to 50 g/L, may increase the risk of VTE [4,5,6], although this association has not been consistently confirmed [7-9].

Genetic factors also significantly contribute to VTE risk, with an estimated heritability of around 50-60% [10,11]. Polygenic risk scores (PRS) have proven effective in stratifying individuals’ VTE risk [12]. Although low ALB levels and genetic predisposition have been suggested to influence VTE risk, how these specific factors and their combined effects contribute remains unclear. A large prospective, population-based longitudinal cohort study was conducted to examine the individual and combined effects of ALB levels and PRS on VTE risk [13].

The study design

To clarify the individual and combined associations of ALB levels and PRS on VTE risk and to determine whether serum ALB levels and genetic risk interact in a multiplicative or additive manner, this cohort study utilized data from the UK Biobank (UKB), which included 500,000 participants recruited in the United Kingdom between 2006 and 2010 [14]. Based on the available data, ALB levels were analyzed in 417,113 participants, while the genetic susceptibility analysis involved 345,200 individuals. [13]

Diagnostic data were obtained through linkage to primary care records, hospital admissions, death registers, and self-reported medical conditions. At the same time, blood samples were collected, stored at −80°C, and serum ALB concentrations (g/L) were measured using a colorimetric assay, with the levels subsequently divided into quartiles [13].

The PRS model, on the other hand, was constructed using weights derived from a meta-analysis of four independent VTE Genome-Wide Association Studies (GWAS) datasets [15], and participants were divided into three groups: low, medium, and high genetic risk [13].

The extensive data collection by the UK Biobank allowed for comprehensive measurement of covariates, significantly improving the ability to control for confounding factors. The baseline measurements included related covariates, such as demographic factors, socioeconomic status, lifestyle habits, and other potential confounders. These covariates encompassed age, sex, ethnicity, body mass index (BMI), smoking and drinking status, physical activity, total cholesterol (TC), systolic blood pressure (SBP), white blood cell (WBC) count, C-reactive protein (CRP), alanine aminotransferase (ALT), and serum creatinine (SCR) [13].

How do serum albumin and genetic risk influence VTE risk?

In this study, over a median follow-up period of 13.4 years, VTE cases were reported in 11,502 participants, predominantly among older, overweight or obese males, as well as those who tended to engage in less physical activity and had higher levels of triglycerides, systolic blood pressure (SBP), white blood cell (WBC) count, C-reactive protein (CRP), serum creatinine (SCR), and poorer socioeconomic conditions [13]. Notably, a strong association was observed between lower ALB levels and an increased risk of VTE, with hazard ratios of 1.65 (95% CI, 1.56-1.74), 1.29 (95% CI, 1.21-1.36), 1.17 (95% CI, 1.10-1.24), and 1.00 from the lowest to the highest quartile of ALB [13].

Moreover, above an ALB concentration of 45 g/L, a gradual reduction in VTE risk was observed. However, the risk increased significantly below this threshold, highlighting a linear association and a dose-response relationship between ALB levels and VTE risk. Importantly, it was ruled out that inflammatory processes could explain the relationship between ALB and VTE. Even after accounting for WBC count and CRP, key markers of inflammation, in a multivariate model, the association between ALB and VTE remained significant [13].

Regarding genetic risk for VTE, the study demonstrated a positive correlation between PRS and VTE incidence, with hazard ratios of 2.61 (95% CI, 2.46-2.77) and 1.55 (95% CI, 1.46-1.64) for the high- and medium-risk genetic groups, respectively, compared to the low-risk group. This highlights the potential of the PRS model as an effective tool for identifying individuals at high risk of developing VTE [13].

This study’s most significant finding is that when the entire cohort was stratified based on genetic risk and ALB levels, the hazard ratio for VTE increased substantially with lower ALB levels and higher genetic risk. Participants with both high genetic risk and lower ALB levels experienced a markedly greater relative risk of VTE events compared to those with low genetic risk and higher ALB levels (HR 3.89; 95% CI, 3.41-4.43). This finding underscores a positive additive interaction between low ALB and high genetic risk and their combined effect in increasing VTE risk while ruling out the possibility of reverse causality. Specifically, the combined effect of low ALB levels and high genetic risk on VTE risk was found to exceed the impact of each factor individually or their sum, with 21% of VTE cases potentially attributable to this additive interaction [13].

The association between low ALB levels and increased VTE risk, as highlighted by this study, may be influenced by several factors: ALB’s role in inhibiting platelet activation and aggregation through its interaction with arachidonic acid or its ability to induce inducible nitric oxide synthesis in macrophages; the fact that low ALB levels are commonly linked to established VTE risk factors, such as nephrotic syndrome, chronic kidney disease, or cancer; and the association between low ALB levels and inflammation, which may be implicated in the development of VTE [16-19].

Conclusions

The findings of this study have important public health implications, as the observed additive interaction between genetic risk and ALB levels may allow for identifying individuals who could benefit most from targeted interventions aimed at modulating ALB levels. The combination of ALB as a laboratory parameter with PRS could serve as a valuable tool for the early identification of individuals at high risk of VTE.

Consequently, future research could explore the potential use of ALB levels as a foundation for developing strategies to prevent and treat VTE cases.

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