Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Polymorphism 663 C>T Affects Clotting Factor VIII Activity and Increases the Risk of Venous Thromboembolism.
Authors: Vormittag Rainer , Bencur Peter , Ay Cihan , Tengler Theres , Vukovich Thomas , Quehenberger Peter , Pabinger Ingrid , Mannhalter Christine 
Published: October 2019

Abstract
Clotting factor VIII (FVIII) is an independent risk factor for primary and recurrent venous thromboembolism (VTE). Various causes for high plasma FVIII levels have been identified and an involvement of genetic factors has been demonstrated. Currently, the underlying genetic components have not been fully elucidated. A multifunctional endocytic receptor, low-density lipoprotein receptor-related protein 1 (LRP1), mediates cellular uptake and subsequent degradation of factor VIII, and seems to contribute to variations in FVIII levels. We assessed the effect of a genetic variation in the coding region of the LRP1 gene (LRP1 663C>T) on basal FVIII levels and the risk of venous thrombosis in a high risk group of patients and healthy controls. One-hundred-fifty-two patients with a history of recurrent VTE (median age = 56 years, 25th – 75th percentile: 44 – 63, 47% women) were compared with 198 age- and sex-matched healthy controls (median age = 53 years, 25th – 75th percentile: 44–59, 50% women) in a case-control study. All patients had at least one spontaneous VTE. The LRP1 663C>T genotype was analysed by mutagenic separated polymerase chain reaction assay. Heterozygosity was confirmed by sequence analysis in all cases. The LRP1 663CC genotype was found in 138 patients and 190 controls, LRP1 663CT in 14 patients and 8 controls, respectively. No homozygous individuals were identified. Genotype distributions did not significantly deviate from Hardy-Weinberg-equilibrium in patients (p=0.6) and controls (p=0.8). Heterozygous individuals were approximately twice as frequent among patients as controls (9% versus 4%, p=0.048). LRP1 663CT was associated with increased odds for VTE in multivariate analysis adjusted for blood group 0, factor V Leiden and the prothrombin variation 20210G>A (OR=3.3, 95% CI [1.3–8.5]). In all study participants (n=350) LRP1 663CT carriers (n=22) had significantly higher factor VIII activity (median=193%, 25th − 75th percentile: 158 – 222) than LRP1 663CC carriers (n=328, median=160%, 25th – 75th percentile: 125 – 195, p=0.01). Blood group 0 was significantly less frequent among patients (18 %) than controls (32 %, p = 0.002) and was associated with significantly lower factor VIII activity levels (n=91, median: 118%, 25th – 75th percentile: 95 – 155) compared to blood group non-0 (n=259, median: 175%, 25th – 75th percentile: 143 – 212, p < 0.001). Particularly high factor VIII activity levels were found in persons with a combination of LRP1 663CT and an AB0 blood group non-0 (n=16, median: 209%, 25th – 75th percentile: 192 – 231). In conclusion, we present evidence that the LRP1 663C>T polymorphism is associated with higher factor VIII plasma levels. Our study is the first report of a significantly increased thrombosis risk in heterozygous carriers of the LRP1 663C>T polymorphism. Prospective studies will have to prove, whether this parameter could serve as predictive marker for risk of venous thrombosis.