Functional investigation of a venous thromboembolism GWAS signal in a promoter region of coagulation factor XI gene

Coagulation factor XI (FXI) is essential for normal function of the intrinsic pathway of blood coagulation. A nucleotide variant (rs3756008) in the promoter region of the FXI gene was recently reported for association with venous thromboembolism. This study aimed to examine promoter activity of the rs3756008 or other variants linked with it. Luciferase assay was analyzed with minigenes including haplotypes (AA with frequency of 0.62 and TG with frequency of 0.38) of 2 completely linked nucleotide variants (rs3756008 and rs3756009) in 5'-upstream region of the FXI gene. While their expression did not differ in hepatic cell (P0.05), the major haplotype (AA) made a significantly more expression (P0.05) than the minor haplotype (TG) in human embryonic kidney 293 cells. Further luciferase analysis with additional haplotypes (artificial; TA, AG) revealed that the large expression was caused by the major allele of rs3756008 (P0.05), but not by that of rs3756009 (P0.05). We suggested that the minor allele of rs3756008 in the promoter of FXI gene could reduce its expression in kidney.