Predominant mutations in a hotspot of SERPINC1 associated with venous thromboembolism in the Chinese population: a case-control study.

BACKGROUND: Antithrombin plays a key anticoagulant role. The prevalence of antithrombin deficiency is thought to be very low in patients with thromboembolism. However, increasing evidence suggests that antithrombin deficiency may be underestimated. We aimed to uncover predominant mutations in SERPINC1 in the Chinese population.

METHODS: In this case-control study, we selected individuals with venous thromboembolism from the biobank of Hubei Clinical Research Center of Thrombosis and Haemostasis in China and controls from the same area and the same time period. The controls had no history of thrombotic diseases. We included 1304 individuals with venous thromboembolism and 1334 controls from China. We also enrolled a cohort of white individuals from Spain, including 165 patients with antithrombin deficiency, 86 patients with venous thromboembolism, and 100 controls. Re-sequencing of SERPINC1 was performed in 190 Chinese patients with venous thromboembolism. Genotyping of predominant mutations was performed in the whole study population with a PCR-RFLP method using BstUI. Plasma antithrombin antigen concentrations, activity, and thrombin generation potential were measured. We obtained odds ratios (ORs) using logistic regression controlling for other risk factors for venous thromboembolism. This study was approved by the Ethics Committee of the Union Hospital affiliated with Huazhong University of Science and Technology. Written informed consent for research was obtained from each individual included in the study.

FINDINGS: We found no hotspot-mutations in any of the individuals of the white Spanish cohort. A hotspot-mutation involving residues 294 and 295 of antithrombin was revealed in the Chinese cohort. We identified the c.883G>A (p.Val295Met) mutation in 11 patients but in one control. We found the c.881G>T (p.Arg294Leu) mutation in six patients and the c.880C>T (p.Arg294Cys) mutation in two patients, whereas we identified the c.881G>A (p.Arg294His) mutation in one healthy control. Overall, these mutations significantly increased the risk of venous thromboembolism (OR=11·4, 95% CI 2·6-49·4; p=0·001). Carriers of these mutations had normal antithrombin antigen (79·1-116·0 U/dL) and functional activity (75·3-136·3 U/dL), but had a significantly increased endogenous thrombin potential (2·0-2·7 fold).

INTERPRETATION: Our results support the existence in the Chinese population of a hotspot in SERPINC1 that significantly increases the risk of venous thromboembolism without affecting functional assays of antithrombin.

FUNDING: National Natural Science Foundation of China (81370622 and 81400099).