Whole exome sequencing identifies genetic variants in Chinese Han pregnant women with venous thromboembolism

Objectives: Venous thromboembolism (VTE) is a common health problem, causing considerable morbidity and mortality. The incidence of VTE is higher in pregnant women than in those who are not pregnant. However, genetic factors for VTE in pregnant women are largely unknown. Methods: We performed a large-scale prospective cohort study of 65,138 pregnancies. 24 pregnant patients diagnosed with VTE and 24 matched pregnant women without VTE were enrolled and sequenced by whole exome sequencing. We investigated the occurrence of known VTE risk variants, damaging variants found in thrombophilia genes and rare damaging variants possibly related to VTE in pregnancies. An exome-wide association study was also performed using a case-control design. Results: Our findings suggest that VTE in pregnancies may be mainly related to (i) the presence of known pathogenic variants in affected individual like F2, (ii) possibly damaging variants found in major thrombophilia gene GCKR, and (iii) 1 pathogenic and 13 likely pathogenic rare damaging variants associated with genetic errors. In exome-wide association stage, 42 variants at 34 genes may show suggestive associations with VTE in pregnancies (the lowest P = 3.5 x 10(-7)). ZFP41 (rs6558339, P = 8.85 x 10(-5)) in 24 patients were the only exonic missense variant. Conclusion: The combined findings suggest that some genes may be involved in the mechanism of basement membranes, sterol accumulation and atherosclerosis, lipid metabolism and coagulation deficiency. These identified risk variants may improve the understanding of VTE pathogenesis in pregnancies and provide potential biomarker for development of clinical diagnosis.