A common C-->T polymorphism at nt 46 in the promoter region of coagulation factor XII is associated with decreased factor XII activity.
Coagulation factor XII (FXII) deficiency is rarely found to be associated with bleeding, but single reports demonstrated thromboembolic events in FXII-deficient patients. Currently, the biological role of FXII is still discussed controversially. It is well known that plasma levels of FXII show great interindividual variability. Recently, it has been demonstrated that a frequently occurring C-->T polymorphism in the FXII promoter region at nucleotide (nt) 46 is associated with lower plasma FXII activity levels in Orientals. In our study, we evaluated the frequency of this polymorphism in a randomly selected sample of newborns and investigated whether this C-->T polymorphism also contributes to the frequently observed moderate FXII deficiency in Europeans. We developed a new mutagenically separated polymerase chain reaction assay (MS PCR), which allows mutation detection without the use of restriction enzymes. Among 100 healthy newborns, we found 64% homozygous carriers of the wildtype FXII 46C allele, 29% were heterozygous for FXII C46T, and 7% homozygous for FXII 46T. Evaluation of plasma FXII activity and genotype in 80 randomly selected and unrelated individuals revealed a highly statistically significant (P<.001) association of the FXII 46T allele with reduced FXII plasma activity. Individuals carrying the homozygous FXII 46C genotype had a mean of 1.17 U/ml (+/-0.31 U/ml), individuals heterozygous for FXII C46T showed a mean of 0.70 U/ml (+/-0.31 U/ml), and subjects homozygous for FXII 46T had only 0.44 U/ml (+/-0.10 U/ml) plasma FXII activity.
Endler
G
G
Department of Laboratory Medicine, University of Vienna Medical School, Vienna, Austria.
Exner
M
M
Mannhalter
C
C
Meier
S
S
Ruzicka
K
K
Handler
S
S
Panzer
S
S
Wagner
O
O
Quehenberger
P
P
D000483:Alleles; D001317:Austria; D001483:Base Sequence; D004252:DNA Mutational Analysis / Q000379:methods; D017931:DNA Primers / Q000235:genetics; D005174:Factor XII / Q000235:genetics* / Q000378:metabolism*; D005175:Factor XII Deficiency / Q000097:blood* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic
D017931:DNA Primers; D005174:Factor XII