Fetal inheritance of chromosomally integrated HHV-6 predisposes to preeclampsia in the mother

Preeclampsia (typically characterised by new onset hypertension and proteinuria in the second half of pregnancy) represents a major determinant of the global burden of disease(1,2). Its pathophysiology involves placental dysfunction, but the mechanism is unclear. Viral infection can cause organ dysfunction but its role in placentally-related disorders of human pregnancy is unknown(3). We addressed this using RNA-seq metagenomics(4–6) of placental samples from normal and complicated pregnancies. Here we show that human herpes virus 6 (HHV-6, A or B) RNA was detected in 6.1% of cases of preeclampsia and 2.2% of other pregnancies. Fetal genotyping demonstrated that 70% of samples with HHV-6 RNA in the placenta exhibited inherited, chromosomally integrated HHV-6 (iciHHV-6). We genotyped 467 preeclampsia cases and 3,854 controls and found an excess of iciHHV-6 in cases (odds ratio (OR) 2.8, 95% CI: 1.4 to 5.6, P=0.008). We validated this finding, comparing iciHHV-6 in a further 740 cases with controls from large-scale population studies (OR=2.5, 95% CI: 1.4 to 4.4, P=0.0013). We conclude that iciHHV-6 results in transcription of viral RNA in the human placenta and predisposes to preeclampsia.