Maternal and fetal genes in pre-eclampsia

18 May 2005

Pre-eclampsia is a serious complication of pregnancy, affecting around 1 in 10 pregnancies. It is a hypertensive disorder that affects multiple systems and causes significant morbidity and mortality among affected women and neonates. When pregnancies are established, fetal trophoblast cells (which give rise to the placenta) invade the uterus and remodel the maternal arteries to create blood vessels to sustain blood supply to the fetus. In pre-eclampsia the fetus receives an inadequate placental blood supply due to failing trophoblast invasion, which causes growth retardation. The only cure for pre-eclampsia is delivery, making it a major cause of premature birth. Between 3-5 mothers and 500-600 babies die annually in the UK as a result of pre-eclampsia, but a much greater number will suffer from long-term health problems, with a concomitant burden on the NHS.

The causes of pre-eclampsia remain poorly understood, although immunological responses against the invading trophoblast tissue have been proposed to play a role. There is a genetic component to the disease, which frequently runs in families, but the nature of this genetic aspect remains unclear. It has been suggested that pre-eclampsia may be a multigenic disease, influenced by environmental factors. It is also thought that a combination of maternal and fetal genetic factors may cause the condition. A new study has looked at genetic polymorphisms affecting fetal trophoblast cells and maternal uterine natural killer (NK) immune cells as risk factors for pre eclampsia. [Hiby SE et al (2004). J. Exp. Med. advance online publication 10.1084/jem.20041214]. The researchers reasoned that the only immune recognition components (histocompatibility antigens) on fetal trophoblast cells known to be polymorphic are HLA-C molecules, which are recognised by killer immunoglobulin receptors (KIRs) on maternal NK cells. These cells play a key role in establishing placental blood vessels. They postulated that this interaction could be a key factor in the development of pre-eclampsia.

Two key KIR genotypes (A and B) can be distinguished, such that all individuals can be classed as AA, AB or BB with respect to the KIR genes; the A genotype lacks activating KIR receptors. HLA-C genes fall into two major groups, C1 and C2. The study looked at maternal and fetal genotypes with respect to KIR and HLC-A in 200 women with pre-eclampsia and 201 matched controls. It was established that the frequencies of HLA-C alleles did not differ significantly among the test and control groups. However, a statistically significant increase in the frequency of the AA genotype (from 25% to 35%) was observed among pre-eclamptic pregnancies compared with controls. Analysis of combinations of maternal KIR genotypes with fetal HLA-C subgroups C1 and C2 revealed that the increased frequency of the AA genotype in mothers with pre eclampsia was present only where the fetal C2 HLA-C subgroup was also present (ie. where the fetus was heterozygous or homozygous for C2).

It was concluded that mothers with an AA genotype (lacking all or most activating KIR) were at a greatly increased risk of pre-eclampsia where the fetus possessed HLA-C2 group genes, even if the mother herself possessed such genes. The researchers postulate that in this situation, fetal trophoblast HLA-C2 molecules only interact with inhibitory killer immunoglobulin receptors, resulting in excessive inhibition of maternal uterine NK cells and poor trophosblast invasion. An examination of the relative frequencies of HLA-C2 and the KIR AA genotype in a range of ethnic populations revealed an inverse relationship between HLA-C2 and AA frequencies, suggesting evolutionary selection against this genetic combination.

Comment: This report is only one further contribution to the studies on possible genetic factors involved in the development of pre eclampsia, and the authors themselves concede that further research is required (see BBC news report); a much larger study size would be desirable. Although they cannot represent the sole genetic interaction important in the disorder, if validated these results could have potential application in the development of a screening test to identify pregnant women at high risk for pre-eclampsia. Presently the condition cannot be diagnosed until overt symptoms develop, but if it could be identified earlier in pregnancy then careful clinical management would be likely to improve outcomes for both mothers and babies.

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