Antithrombin Cambridge II (A384S): an underestimated genetic risk factor for venous thrombosis.
The antithrombin A384S mutation has a relatively high frequency in the British population but has not been identified in other populations. This variant has been associated with cases of thrombotic disease, but its clinical relevance in venous thrombosis remained unclear. We have conducted a secondary analysis of the prevalence of the mutation in a large case-control study, including 1018 consecutive Spanish patients with venous thromboembolism. In addition, we evaluated its functional consequences in 20 carriers (4 homozygous). This mutation, even in the homozygous state, did not affect anti-Xa activity or antigen levels, and it only slightly impaired anti-IIa activity. Thus, routine clinical methods cannot detect this anomaly, and, accordingly, this alteration could have been underestimated. We identified this mutation in 0.2% of Spanish controls. Among patients, this variant represented the first cause of antithrombin anomalies. Indeed, 1.7% patients carried the A384S mutation, but 0.6% had any other antithrombin deficiency. The mutated allele was associated with an increased risk of venous thrombosis with an adjusted OR of 9.75 (95% CI, 2.2-42.5). This is the first study supporting that antithrombin A384S mutation is a prevalent genetic risk factor for venous thrombosis and is the most frequent cause of antithrombin deficiency in white populations.
Corral
Javier
J
Centro Regional de Hemodonación, Universidad de Murcia, Murcia, Spain. javier.corral@carm.es
Hernandez-Espinosa
David
D
Soria
Jose Manual
JM
Gonzalez-Conejero
Rocio
R
Ordonez
Adriana
A
Gonzalez-Porras
Jose Ramon
JR
Perez-Ceballos
Elena
E
Lecumberri
Ramon
R
Sanchez
Ignacio
I
Roldan
Vanessa
V
Mateo
Jose
J
Minano
Antonia
A
Gonzalez
Marcos
M
Alberca
Ignacio
I
Fontcuberta
Jordi
J
Vicente
Vicente
V
D000328:Adult; D000409:Alanine / Q000235:genetics; D000990:Antithrombin III / Q000032:analysis / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D012307:Risk Factors; D012694:Serine / Q000235:genetics; D020246:Venous Thrombosis / Q000235:genetics*
C069998:antithrombin Cambridge II; D012694:Serine; D000990:Antithrombin III; D000409:Alanine