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Fetal inheritance of chromosomally integrated human herpesvirus 6 predisposes the mother to pre-eclampsia.

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Gaccioli, Francesca 
de Goffau, Marcus C 
Dopierala, Justyna 


Pre-eclampsia (typically characterized by new-onset hypertension and proteinuria in the second half of pregnancy) represents a major determinant of the global burden of disease1,2. 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 unknown3. We addressed this using RNA sequencing metagenomics4-6 of placental samples from normal and complicated pregnancies. Here, we show that human herpesvirus 6 (HHV-6, A or B) RNA was detected in 6.1% of cases of pre-eclampsia 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 pre-eclampsia cases and 3,854 controls and found an excess of iciHHV-6 in the cases (odds ratio of 2.8, 95% confidence intervals of 1.4-5.6, P = 0.008). We validated this finding by comparing iciHHV-6 in a further 740 cases with controls from large-scale population studies (odds ratio of 2.5, 95% confidence intervals of 1.4-4.4, P = 0.0013). We conclude that iciHHV-6 results in the transcription of viral RNA in the human placenta and predisposes the mother to pre-eclampsia.



Case-Control Studies, DNA, Viral, Disease Susceptibility, Female, Herpesvirus 6, Human, Humans, Infant, Infant, Newborn, Male, Maternal Inheritance, Polymorphism, Single Nucleotide, Pre-Eclampsia, Pregnancy, RNA, Viral, Roseolovirus Infections, Sequence Analysis, DNA, Virus Integration

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Nat Microbiol

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Springer Science and Business Media LLC


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Medical Research Council (G1100221)
Medical Research Council (MR/K021133/1)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Medical Research Council (MR/P001092/1)
Medical Research Council (G1100221/1)
This work was supported by the Women’s Health theme of the NIHR 446 Cambridge Biomedical Research Centre, the Medical Research Council (MR/K021133/1 to GCSS, 447 DSCJ, JP & SP and G1100221 to GCSS and DSC-J) and the UCL/UCLH NIHR Biomedical Research 448 Centre (to JB and CV)