One gene affects ratio of boys and girls born

A joint research study involving Estonian scientists has been published which describes in detail the delicate balance between the paternal and maternal genes during pregnancy. Due to the paternal contribution, the embryo is genetically foreign to the mother’s body, but is nevertheless perfectly capable of developing in the womb and normally does not suffer from any maternal immune attacks. However, this balance is not always ideal and may prove fatal for both the embryo and the mother.

Most expectant mothers are healthy but may still experience miscarriage, premature labour or pre-eclampsia. Pre-eclampsia is an increase in blood pressure (hypertension) during pregnancy which affects 2–8% of expectant mothers. It significantly increases the health risks and complications associated with pregnancy, such as damage to the kidneys, liver or other organs. The researchers sought to find a correlation between pregnancy hypertension and foetal histocompatibility complex gene (HLA-G) variants. The task of HLA-G is to protect the developing foetus, which is essentially a foreign organism, from attacks by maternal immune cells.

The research study, which was published in the journal EBiomedicine, initially examined Finnish birth statistics based on 1.79 million children and found that hypertension was considerably more common in mothers expecting a girl compared to those expecting a boy. In addition, it was found that pregnancy hypertension was far more common in mothers expecting a girl compared to those expecting a boy if the infant was born prematurely or with a low birth weight. Subsequent laboratory analysis involving a smaller group of patients revealed that some HLA-G variants contribute to foetal death and pre-eclampsia. This means that in the event of a genetic conflict causing pregnancy hypertension, male foetuses perish in the early stage of pregnancy. Female foetuses are more resistant, but this leads to maternal pre-eclampsia.

On the other hand, it was noted with interest that although the oldest HLA-G variant in evolutionary terms does increase the risk of pre-eclampsia and stillbirth, it also provides protection for the foetus from infections during pregnancy such as malaria, which may have been an aspect of crucial importance in earlier times.

The researcher responsible for the laboratory analysis was Kaarel Krjutškov, senior researcher in molecular medicine at the University of Tartu and the head of the Precision Medicine Laboratory of the Competence Centre on Health Technologies. “This is the first known study in the world which not only identifies the genetic cause of pre-eclampsia, but also proves the fact that the ratio of girls and boys born is regulated not just by sex chromosomes, but also by the histocompatibility complex HLA-G gene,” he said, explaining the relevance of the study.

Laboratory DNA analysis covered 163 patients, some of whom were healthy and constituted the control group. The key genes were discovered with the help of bioinformatics software developed by University of Tartu PhD student Hindrek Teder and the TAC-seq DNA analysis method, which was used to identify the HLA-G variants and their rate of expression in placental tissue in the patients under study.

“The medical value of the study lies in the information we have obtained, which encourages us to test whether medicines for autoimmune disorders would be suitable in pre-eclampsia treatment by controlling the maternal immune response and preventing pregnancy hypertension,” Krjutškov explained. “The expression of HLA-G is low in pre-eclamptic placentas, which in turn leads to a higher expression of the IFNA1 gene, a marker for autoimmune disease and rejection reaction. If we could keep the IFNA1 level down, pre-eclampsia should not develop.”

Further information: Kaarel Krjutškov, Senior Research Fellow in Molecular Medicine, University of Tartu; Head of the Precision Medicine Laboratory, Competence Centre on Health Technologies, +372 512 6416, kaarel.krjutshkov@ut.ee