Thrombomodulin ( THBD ) gene variants and thrombotic risk in a population‐based cohort study

Background The protein C anticoagulant system plays a key role in maintaining the hemostatic balance. Although several studies have identified thrombomodulin gene (THBD) variants among venous thromboembolism (VTE) patients, the role of THBD in relation to VTE in humans remains to be clarified. Objectives This study aimed to determine the thrombotic risk of rare and common THBD variants in a large population-based cohort of middle-aged and older adults. Patients/Methods The exome sequence of THBD was analyzed for qualifying variants in 28,794 subjects (born 1923-1950, 60% women), who participated in the Malmo Diet and Cancer study (1991-1996). Patients were followed from baseline until the first event of VTE, death, or 2018. Qualifying variants were defined as loss-of-function or non-benign (PolyPhen-2) missense variants with minor allele frequency <0.1%. Results The single common coding variant rs1042579 was not associated with incident VTE. Sixteen rare variants were classified as qualifying and included in collapsing analysis. Seven individuals with VTE compared to 24 individuals without VTE carried one qualifying variant. Cox multivariate regression analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking and alcohol consumption, rs6025, rs1799963, and the top two eigenvectors from a principal components analysis showed a hazard ratio of 3.0 (95% confidence interval 1.4-6.3) for the rare qualifying variants. The distributions of qualifying variants in THBD showed a difference for individuals with and without incident VTE indicating a possible position effect. Conclusions Rare qualifying THBD variants were associated with VTE, suggesting that rare variants in THBD contribute to development of VTE.