The Roles of Diaminoxidase Activity and Concentration and Associated Variations in the DAO-Promotor in Women with Abortus Habitualis
Habitual abortion (HA), also known as recurrent miscarriage, is defined as three or more consecutive abortions with the same partner and concerns about 1% of women in reproductive age. Known causes for a habitual abortion are anatomic anomalies, coagulation disorders, chronic infections, endocrinologic malfunctions and autoimmunity, but in about 40-50% of all cases, the underlying reason or mechanism is not known. Evidence suggests that pathological changes in histamine- or polyamine-metabolism are associated with the occurrence of habitual abortion. Several studies showed that not only elevated level of histamine but also a decrease in Diamineoxidase (DAO) activity correlate with otherwise unexplained miscarriages.
The enzyme DAO plays an important role in the degradation-process of histamine, putrescine, spermine and spermidine – signalling molecules critical in allergic reactions, cell proliferation, cell differentiation and tumor development. Within the placenta, DAO has a crucial role in female reproduction functions.
It is known, that polyamine levels are increased during pregnancy, as well as DAO. DAO increases in the first trimester up to 1000-fold compared to levels of not pregnant women and plateaus at this level along the pregnancy. If DAO levels remain low during pregnancy, women are at higher risk to develop preeclampsia, hyperemesis gravidarum and abortion.
Histamine is a biogenic amine involved in many processes within the body. Its plasma levels are tightly regulated (±1ng/ml) and already a low increase above normal levels can cause many pathological symptoms including itching, headache, vomiting, hypotension, tachycardia and cardiac arrest. During pregnancy, toleration of an increase in plasma-levels of histamine is probably even lower.
DAO uses both, histamine and polyamines as substrates. The increase of polyamine levels might triggers an increase in histamine levels if DAO is occupied by increasing amounts of polyamines and DAO activity does not increase properly. Another proposed underlying mechanism are the immunosuppressive properties of Diamineoxidase-oxidized polyamines and generated aldehydes within the placenta, thereby suppressing immune reactions against the foetus.
To date, the specific underlying pathological molecular mechanism between plasma histamine concentration, DAO-activity and increase risk for miscarriage/abortion are not identified. Moreover, the to date available data are not sufficient to assess the risk for miscarriage in connection with decreased levels of DAO.
Aim of this thesis project is, to identify SNPs or mutations within the DAO-coding gene (also known as amiloride-binding protein, ABP1), specifically within its promotor-region, in patients with decreased blood levels of DAO, who have been diagnosed with habitual abortion. Furthermore, this study aims to evaluate whether the same mutations can be found in the DAO-gene of the sexual partners of these patients.
Methods and Skills:
Clinical studies; DAO ELISA