Genetic Susceptibility as an Effect Modifier for the Association of Chronic Kidney Disease with Risks of Venous Thromboembolism and Pulmonary Embolism

BackgroundThe association between chronic kidney disease (CKD) and the risk of developing venous thromboembolism (VTE) or pulmonary embolism (PE) is still controversial. Further, it is unknown if genetic predisposition modifies these relationships. This work aimed to investigate plausible effect modification of genetic factors on the association between CKD and incident VTE, as well as incident PE. MethodsPopulation-based cohort study of the UK Biobank, including participants of European ancestry that were free of VTE (397,658 participants) or PE (406,486 participants) at recruitment. We used cystatin C combining creatinine estimated glomerular filtration rate and albuminuria to classify the participants as the low, intermediate, and high or very high-risk groups suggested by KDIGO. Cox proportional hazards model was applied to evaluate the associations of CKD with incident VTE and PE. In addition, we used an externally validated polygenic risk score (PRS) for VTE to evaluate whether the genetic predisposition modified the associations of interest. ResultsDuring median follow-up of 12.7 years, 11,372 participants developed VTE, and 6,518 participants developed PE. As compared with the low KDIGO risk category, covariate-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for VTE risk with the intermediate KDIGO risk category and high or very high KDIGO risk category at baseline were 1.278 (1.191-1.372) and 1.892 (1.658-2.159), respectively. Participants at high or very high KDIGO risk category and in the highest tertile of PRS had the highest risk of developing VTE (HR, 4.397; 95% CI, 3.639-5.313), and this group showed the most conspicuous additive interaction between CKD and the genetic predisposition, which was responsible for 1.389-fold relative excess risk and 31.6% of the VTE risk. Also, when either estimated glomerular filtration rate or urine albumin-creatinine ratio was treated as the exposure, consistent associations were observed. Analyses for PE yielded similar associations and supra-additive interactions. ConclusionsCKD is associated with future VTE and PE, especially in those with high genetic risk. CLINICAL PERSPECTIVE What is new?O_LIWe observed that chronic kidney disease is associated with future venous thromboembolism and pulmonary embolism independently, irrespective of genetic predisposition. C_LIO_LIWe found considerable additive interaction between chronic kidney disease and genetic predisposition for future venous thromboembolism or pulmonary embolism risk. C_LI What are the clinical implications?O_LIIt is essential to evaluate kidney condition in primary prevention of venous thromboembolism and pulmonary embolism. C_LIO_LIIndividuals with high genetic risk of venous thromboembolism might be the most relevant population to implement a personalized program of chronic kidney disease prevention, screening, and management. C_LI