Pre-eclampsia Protectors and Promoters

Abstract

A new study identifies genes linked to the risk for preeclampsia in a population from sub-Saharan Africa. These genes encode for human leukocyte antigen (HLA) ligands on trophoblasts and receptors that recognize these ligands, which are present on maternal Natural Killer (NK) cells [1]. Trophoblast invasion of the uterine tissue leads to the remodeling of uterine arteries into large vessels, thereby tapping the mother’s blood supply. This is a carefully equilibrated event. Too aggressive of an invasion can result in outsized babies, exposure to excess nutrients and oxygen in utero, and placental overgrowth conditions that can lead to hemorrhage. Poor invasion can result in such conditions as fetal growth restriction and pre-eclampsia. Maternal NK cells modulate the activity of trophoblasts, determining the extent of invasion in humans. This modulation occurs via HLA-C ligands on trophoblast cells, which recognize a key family of receptors on NK cells: killer-cell immunoglobulin-like receptors (KIRs). In previous studies, Ashley Moffett and colleagues found that genetic risk for pre-eclampsia, and some related conditions such as fetal growth restriction, is linked to various genetic variants at the KIR and HLA-C loci. But their studies, conducted primarily in European populations, limit their analysis. In the new study, the researchers turned to women of sub-Saharan African ancestry, who have elevated rates of pre-eclampsia and also a high diversity of KIR genotypes, and found some parallels and some differences with European women. Moffett and colleagues studied pregnant women at a hospital in Kampala, Uganda: 251 with pre-eclampsia and 483 without the condition. As with Europeans, they found elevated risk for pre-eclampsia in women homozygous for one of two major haplotypes, the KIR A haplotype. This risk was even higher if the fetus also had particular HLA-C alleles, which encode C2 epitopes (all HLA-C alleles encode either a C1 or C2 epitope). The researchers also identified three KIR genes that seemed to protect against pre-eclampsia in the women in Kampala—alleles that are rare in Europeans. A KIR gene known to be protective in Europeans was found at only low frequency in the women from Kampala. The study highlights the need for global genetic studies to assess pre-eclampsia risk—curiously, distinct human populations seem to have evolved to have distinct mixes of favorable KIR-HLA-C combinations. Future research should flesh out the biological mechanisms. One study, for instance, showed that favorable KIR-HLA-C combinations result in increased production of soluble factors that promote trophoblast invasion.