Human Molecular Genetics Advance Access originally published online on March 5, 2007
Human Molecular Genetics 2007 16(5):573-578; doi:10.1093/hmg/ddm017
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A common haplotype of the annexin A5 (ANXA5) gene promoter is associated with recurrent pregnancy loss
1 Institut für Humangenetik and 2 Institute of Medical Biochemistry, ZMBE, Westfalian Wilhelms-University of Münster and University Clinic Münster, Münster, Germany, 3 Institute of Medical Informatics and Statistics and 4 Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Clinic Schleswig-Holstein, Kiel, Germany and 5 Laboratory of Molecular Pathology, University Hospital of Obstetrics and Gynecology, Medical University of Sofia, Sofia, Bulgaria
* To whom correspondence should be addressed at: Institute of Medical Biochemistry, ZMBE, Westfalian-Wilhelms University of Münster, Von-Esmarch-Str. 56, D-48149 Münster, Germany. Email: markoff{at}uni-muenster.de
We sought to verify whether variation in the promoter of the gene encoding placental anticoagulant protein annexin A5 (ANXA5) represents a risk factor for recurrent pregnancy loss (RPL). Sequence analysis of 70 German RPL patients, all known to carry neither factor V Leiden nor a prothrombin mutation, revealed four consecutive nucleotide substitutions in the ANXA5 promoter, which were transmitted as a joint haplotype (M2). Reporter gene assays revealed that M2 reduces the in vitro activity of the ANXA5 promoter to 37–42% of the normal level. The possible relationship between M2 and RPL was evaluated by comparing RPL patients with two independent control groups recruited from the registry of the Institut für Humangenetik in Münster and the PopGen biobank in Kiel, respectively. Carriers of M2 were found to exhibit a > 2-fold higher RPL risk than non-carriers (odds ratio, 2.42; 95% confidence interval, 1.27–4.58) when using unselected controls (PopGen) and an almost 4-fold higher risk when using the Münster ‘super-controls’, i.e. women with successful pregnancies and no previous history of pregnancy losses (odds ratio, 3.88; 95% confidence interval, 1.98–7.54). This statistically significant association should facilitate the development of improved prognostic algorithms for RPL, involving a more precise assessment of individual disease risks, and provide a guide to offering adequate therapies where relevant.