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Polymorphism in exon 10 of the human coagulation factor V gene in a population at risk for sickle cell disease
D Helley1, C Besmond, R Ducrocq
1Laboratoire de Recherche sur l'Hémostase et la Thrombose, Faculté Xavier Bichat, Paris, France.
Insights
The Factor V Leiden (FV Leiden) mutation increases thrombosis risk in Caucasians but was absent in African populations. This FV gene mutation is not a risk factor for sickle cell disease in sub-Saharan Africa.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- The Factor V Leiden (FV Leiden) mutation (R506Q) in exon 10 of the factor V gene is a known risk factor for thromboembolism in Caucasian populations.
- Sickle cell disease (SCD) populations may have different genetic predispositions to thrombosis.
- Investigating genetic variations in the factor V gene in at-risk populations is crucial for understanding thrombosis risk.
Purpose of the Study:
- To screen exon 10 of the factor V gene for mutations in populations at risk for sickle cell disease (SCD).
- To determine the frequency of the FV Leiden (R506Q) mutation and other potential thrombosis-risk variants in sub-Saharan African and West Indian populations.
- To assess the relevance of FV gene mutations as additional risk factors for thrombosis in SCD.
Main Methods:
- Genomic DNA was analyzed from 450 subjects from populations at risk for SCD.
- The R506Q mutation (FV Leiden) and other substitutions in exon 10 of the factor V gene were screened.
- Allelic frequencies of identified mutations and polymorphisms were calculated.
Main Results:
- The R506Q mutation was absent in subjects from sub-Saharan Africa.
- The FV Leiden mutation had an allelic frequency of 2.5% in the West Indies.
- A substitution R485K, with no in vitro functional consequence, was found at a high allelic frequency (32.4%) in sub-Saharan Africa.
Conclusions:
- No mutations in exon 10 of the factor V gene, including FV Leiden, were found to be an additional risk factor for thrombosis in sub-Saharan African SCD populations.
- The absence of FV Leiden in sub-Saharan Africa suggests its selective advantage does not apply to these populations.
- The presence of FV Leiden in American Africans may be of Caucasian origin, and R485K exhibits significant ethnic variation.
Abstract:
In Caucasians, the R506Q mutation in exon 10 of the factor V gene (FV Leiden) confers an increased risk of thromboembolism. We have scanned this region of the gene for possible mutations in 450 subjects from populations at risk for sickle cell disease (SCD). The R506Q mutation was absent in subjects from sub-Saharan Africa, whereas its allelic frequency was 2.5% in the West Indies. Only one other substitution with no functional consequences in vitro (R485K) was found (32.4% allelic frequency) in sub-Saharan Africa. Thus, we found no mutations in exon 10 of the FV gene constituting an additional risk factor for thrombosis in SCD in sub-Saharan Africa. This suggests that the putative selective advantage conferred by R506Q does not exist in these populations, unless R485K has functional consequences in vivo. If further suggests that R506Q in American Africans is of Caucasian origin. Our data are the first to document ethnic variations in the frequency of the R485K polymorphism.