Abstract
This study determines whether genetic variability in the gene-encoding factor V contributes to differences in pre-eclampsia susceptibility. Allele and genotype frequencies of three single-nucleotide polymorphisms (SNPs) in the factor V gene leading to nonsynonymous changes (M385T in exon 8, and R485K and R506Q (Leiden mutation) in exon 10) were studied in 133 Caucasian women with pre-eclampsia and 112 healthy controls. Single-point analysis was expanded to haplotype analysis, and haplotype frequencies were estimated using an expectation-maximization algorithm. Comparison of single-point allele and genotype distributions of SNPs in exons 8 and 10 of the factor V gene revealed statistically significant differences in R485K allele (P=0.003) and genotype (P=0.03) frequencies between the patients and the control subjects. The A allele of SNP R485K was over-represented among the patients (12%) vs the control subjects (4%), at an odds ratio (OR) of 2.8 (95% confidence interval (CI) 1.2–6.2) for combined A genotypes (GA+AA vs GG). Allele and genotype differences between the patients and control subjects as regards M385T and Leiden mutation were not significant. In haplotype estimation analysis, there was a significantly elevated frequency of haplotype T-A-G encoding the M385-K485-R506 variant in the pre-eclamptic group vs the control group (P=0.01), at an OR of 2.6 (95% CI 1.2–5.5). We conclude that the T-A-G haplotype was more frequent among the patient group than in the control group, and genetic variations in the factor V gene other than the Leiden mutation may play a role in disease susceptibility.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Dahlback B, Hansson C, Islam MQ et al: Assignment of gene for coagulation factor V to chromosome 1 in man and to chromosome 13 in rat. Somat Cell Mol Genet 1988; 14: 509–514.
Kane WH, Davie EW : Blood coagulation factors V and VIII: structural and functional similarities and their relationship to hemorrhagic and thrombotic disorders. Blood 1988; 71: 539–555.
Dahlback B, Carlsson M, Svensson PJ : Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004–1008.
Bertina RM, Koeleman BP, Koster T et al: Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64–67.
Zoller B, Svensson PJ, He X, Dahlback B : Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 1994; 94: 2521–2524.
Graf LL, Welsh CH, Qamar Z, Marlar RA : Activated protein C resistance assay detects thrombotic risk factors other than factor V Leiden. Am J Clin Pathol 2003; 119: 52–60.
Hiyoshi M, Arnutti P, Prayoonwiwat W et al: A polymorphism nt 1628G–>A (R485K) in exon 10 of the coagulation factor V gene may be a risk factor for thrombosis in the indigenous Thai population. Thromb Haemost 1998; 80: 705–706.
Le W, Yu JD, Lu L et al: Association of the R485K polymorphism of the factor V gene with poor response to activated protein C and increased risk of coronary artery disease in the Chinese population. Clin Genet 2000; 57: 296–303.
Rey E, Kahn SR, David M, Shrier I : Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901–908.
Spina V, Aleandri V, Morini F : The impact of the factor V Leiden mutation on pregnancy. Hum Reprod Update 2000; 6: 301–306.
van Pampus MG, Dekker GA, Wolf H et al: High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia. Am J Obstet Gynecol 1999; 180: 1146–1150.
Watanade H, Hamada H, Yamada N et al: Association analysis of nine missense polymorphisms in the coagulation factor V gene with severe preeclampsia in pregnant Japanese women. J Hum Genet 2002; 47: 131–135.
Peltonen L, Jalanko A, Varilo T : Molecular genetics of the Finnish disease heritage. Hum Mol Genet 1999; 8: 1913–1923.
National High Blood Pressure Working Group: Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000; 183: S1–S22.
Arngrimsson R, Björnsson H, Geirsson R : Analysis of different inheritance patterns in preeclampsia/eclampsia syndrome. HypertensPregnancy 1995; 14: 27–38.
Grandone E, Margaglione M, Colaizzo D et al: Factor V Leiden, C>T MTHFR polymorphism and genetic susceptibility to preeclampsia. Thromb Haemost 1997; 77: 1052–1054.
Dizon-Townson DS, Nelson LM, Easton K, Ward K : The factor V Leiden mutation may predispose women to severe preeclampsia. Am J Obstet Gynecol 1996; 175: 902–905.
Lindoff C, Ingemarsson I, Martinsson G, Segelmark M, Thysell H, Astedt B : Preeclampsia is associated with a reduced response to activated protein C. Am J Obstet Gynecol 1997; 176: 457–460.
Rigo Jr J, Nagy B, Fintor L et al: Maternal and neonatal outcome of preeclamptic pregnancies: the potential roles of factor V Leiden mutation and 5,10 methylenetetrahydrofolate reductase. Hypertens Pregnancy 2000; 19: 163–172.
Pastinen T, Perola M, Ignatius J et al: Dissecting a population genome for targeted screening of disease mutations. Hum Mol Genet 2001; 10: 2961–2972.
Gandrille S, Greengard JS, Alhenc-Gelas M et al: Incidence of activated protein C resistance caused by the ARG 506 GLN mutation in factor V in 113 unrelated symptomatic protein C-deficient patients. The French Network on the behalf of INSERM. Blood 1995; 86: 219–224.
Helley D, Besmond C, Ducrocq R et al: Polymorphism in exon 10 of the human coagulation factor V gene in a population at risk for sickle cell disease. Hum Genet 1997; 100: 245–248.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Faisel, F., Romppanen, EL., Hiltunen, M. et al. Susceptibility to pre-eclampsia in Finnish women is associated with R485K polymorphism in the factor V gene, not with Leiden mutation. Eur J Hum Genet 12, 187–191 (2004). https://doi.org/10.1038/sj.ejhg.5201124
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5201124
