A COMMON GENETIC-POLYMORPHISM (46-C-SUBSTITUTION TO T-SUBSTITUTION) IN THE 5'-UNTRANSLATED REGION OF THE COAGULATION-FACTOR XII GENE IS ASSOCIATED WITH LOW TRANSLATION EFFICIENCY AND DECREASE IN PLASMA FACTOR-XII LEVEL

We studied the Hga I polymorphism (46 C/T) in the 5'-untranslated regi on of the coagulation factor XII (FXII) gene corresponding to four bas es upstream from the ATG translation initiation codon. By using allele -specific restriction analysis with restriction endonuclease Hga I, th e allele frequency of 46C/T was estimated to be 0.27/0.73 in Orientals (allele number = 152), and conversely, 0.8/0.2 in Caucasians (allele number = 40). Because it has been reported that plasma levels of FXII were lower in Orientals than in Caucasians, we investigated the relati onship between this polymorphism and plasma levels of FXII, As a resul t, there were significant differences in plasma FXII levels between th ese three allele types: C/C,170+/-38% (178+/-27%); C/T, 141+/-29% (123 +/-34%); and T/T, 82+/-19% (61+/-11%) [FXII activity (FXII antigen lev els)]. In heterozygotes of 46 C/T both alleles were equally transcribe d in hepatocytes, as determined by reverse transcription polymerase ch ain reaction (RT-PCR), suggesting little influence of the polymorphism at the level of transcription or on the stability of mRNA. In in vitr o transcription/translation analysis, less FXII was produced from cDNA containing 46 T than from that containing 46 C. Therefore, it is high ly likely that the 46 T polymorphism in the FXII gene decreased the tr anslation efficiency and led to low plasma levels of FXII activity and antigen, probably due to the creation of another ATG codon and/or imp airment of the consensus sequence for the translation initiation scann ing model. (C) 1998 by The American Society of Hematology.