A functional polymorphism at the transcriptional initiation site in beta2-glycoprotein I (apolipoprotein H) associated with reduced gene expression and lower plasma levels of beta2-glycoprotein I.

Human beta2-glycoprotein I (beta2GPI), also known as apolipoprotein H, has been implicated in haemostasis and the production of anti-phospholipid antibodies. There is a wide range of interindividual variation in beta2GPI plasma levels that is thought to be under genetic control, but its molecular basis remains unknown. To understand the genetic basis of beta2GPI variation, we analyzed the 5' flanking region of the beta2GPI gene for mutation detection by DHPLC and identified a point mutation at the transcriptional initiation site (-1C-->A) with a carrier frequency of 12.1%. The mutation was associated with significantly lower beta2GPI plasma levels (P < 0.0001) and low occurrence of anti-phospholipid antibodies in lupus patients (4.8% antibody-positive group vs. 16.6% in the antibody-negative group; P = 0.019). Northern blot analysis confirmed that the -1C-->A mutation was associated with lower mRNA levels and it reduced the reporter (luciferase) gene expression by twofold. Electrophoretic gel mobility shift assay (EMSA) revealed that the -1C-->A mutation disrupts the binding for crude hepatic nuclear extracts and purified TFIID. These results suggest that the substitution of C with A at the beta2GPI transcriptional initiation site is a causative mutation that affects its gene expression at the transcriptional level and ultimately beta2GPI plasma levels and the occurrence of anti-phospholipid antibodies.