Absence of Pro475Ser polymorphism in ADAMTS-13 in Caucasians
Article first published online: 4 APR 2005
Journal of Thrombosis and Haemostasis
Volume 3, Issue 4, page 805, April 2005
How to Cite
BONGERS, T. N., DE MAAT, M. P. M., DIPPEL, D. W. J., UITTERLINDEN, A. G. and LEEBEEK, F. W. G. (2005), Absence of Pro475Ser polymorphism in ADAMTS-13 in Caucasians. Journal of Thrombosis and Haemostasis, 3: 805. doi: 10.1111/j.1538-7836.2005.01239.x
- Issue published online: 4 APR 2005
- Article first published online: 4 APR 2005
- Received 17 November 2004, accepted 20 December 2004
A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS-13) is a recently characterized metalloprotease that cleaves Ultra Large Von Willebrand Factor (ULVWF) . A deficiency of ADAMTS-13 results in an accumulation of ULVWF, and leads to microangiopathic thrombosis, which is characteristic of thrombotic thrombocytopenic purpura (TTP) . The microangiopathic arterial thrombotic complications of TTP occur predominantly in the brain.
It is hypothesized that low ADAMTS-13 levels may be a risk factor for arterial thrombosis, because less ULVWF cleavage may result in an excess of high VWF multimers, resulting in more adhesion and aggregation of platelets .
Recently, the proline (Pro) to serine (Ser) polymorphism in codon 475 of the ADAMTS-13 gene has been identified. This Pro475Ser polymorphism, caused by a base substitution of C1423 to T in exon 12, is reported to impair the activity of ADAMTS-13. In a Japanese study the frequency of the rare 475Ser allele of this single nucleotide polymorphism (SNP) was 5.1% in 364 healthy controls and it has been suggested that the 475Ser allele may increase the risk of arterial thrombosis because of the reduced activity of ADAMTS-13 [3,4].
To study whether this ADAMTS-13 polymorphism contributes to arterial thrombosis in Caucasians, we investigated the distribution of the Pro475Ser polymorphism in a Caucasian population of 125 patients suffering from ischemic stroke and 125 age- and gender-matched healthy controls.
The genotype was determined by polymerase chain reaction, digestion with RsaI and separation on a 2% agarose gel. We found that none of the 250 individuals carried the rare 475Ser allele.
We also investigated the Pro475Ser polymorphism in other populations, including 110 Chinese (HD02 and HD100 of the Human Variation Panel, Coriell Institute for Medical Research, Camden, NJ, USA) where we found one heterozygous subject, giving a frequency for the 475Ser allele of 0.5%[95% confidence interval (CI) 0–2.9]. This confirms the results of Ruan et al. who reported a frequency of 1.7% (95% CI 0.6–4.2) in healthy Chinese and 1.9% (95%CI 0.2–3.8) in Chinese patients who had had a myocardial infarction . Also in Afro-Americans (HD50), the 475Ser allele was not present.
Since no 475Ser carrier for the polymorphism was identified in our study (95% CI 0–1.5%) we conclude that the Pro475Ser polymorphism, which is associated with a reduced ADAMTS-13 activity, is not an important contributor to the risk of ischemic stroke in Caucasians. Our data suggest that outside the Japanese population, the 475Ser allele is very rare.