Identifying the genes for pre-eclampsia

Pre-eclampsia, characterised by high blood pressure and significant levels of protein in the urine, claims the lives of 50 000 mothers and almost 1 million babies annually. The only cure to date is the early delivery of the baby, a major cause of neonatal mortality.

Inherited factors have long been known to trigger pre-eclampsia, and may contribute to the pronounced differences in incidence between populations. The project INTERPREGGEN (Genetic studies of pre-eclampsia in central Asian and European populations) is studying genetic variation in a total of 7 600 mothers with the disease and their 4 000 affected babies, to be compared with a control group of 45 000 individuals.

Genome-wide (GWAS) analysis has been completed on over 6 000 affected mothers and 2 000 babies from Iceland and the UK, as well as 3 000 Kazakh cases and controls. Genotyping has commenced on 1 000 pre-eclamptic mothers, 1 000 babies and 1 000 controls from Uzbekistan.

Results revealed several regions of the maternal genome that may harbour genetic variations associated with pre-eclampsia. Nine low frequency variants found in the Icelandic population under investigation will be further tested.

A process called imputation makes use of the genotype of nearby single nucleotide polymorphisms even though they have not been directly genotyped. Literally millions of these results were combined in a meta-analysis and the most promising found in mothers and babies with pre-eclampsia were reserved for repeat testing.

An effective predictive tool for pre-eclampsia would almost certainly involve a combination of clinical, biochemical and genetic data. The Clinical Translation Working Group is currently assembling key clinical data from all sample collections used in INTERPREGEN for incorporation into a single database. Combined with genetic information generated during the project, BCGene software will develop predictive algorithms for the tool.

The INTERPREGGEN study is the largest of its kind undertaken. Discovery of variants that increase the risk of the disease promises to provide insights into defective biological pathways. Together, this should also pave the way for a rational basis for pre-eclampsia prevention and treatment.