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The ERAP2 gene is associated with preeclampsia in Australian and Norwegian populations

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Abstract

Preeclampsia is a heritable pregnancy disorder that presents new onset hypertension and proteinuria. We have previously reported genetic linkage to preeclampsia on chromosomes 2q, 5q and 13q in an Australian/New Zealand (Aust/NZ) familial cohort. This current study centered on identifying the susceptibility gene(s) at the 5q locus. We first prioritized candidate genes using a bioinformatic tool designed for this purpose. We then selected a panel of known SNPs within ten prioritized genes and genotyped them in an extended set of the Aust/NZ families and in a very large, independent Norwegian case/control cohort (1,139 cases, 2,269 controls). In the Aust/NZ cohort we identified evidence of a genetic association for the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene (rs3734016, P uncorr = 0.009) and for the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene (rs2549782, P uncorr = 0.004). In the Norwegian cohort we identified evidence of a genetic association for ERAP1 (rs34750, P uncorr = 0.011) and for ERAP2 (rs17408150, P uncorr = 0.009). The ERAP2 SNPs in both cohorts remained statistically significant (rs2549782, P corr = 0.018; rs17408150, P corr = 0.039) after corrections at an experiment-wide level. The ERAP1 and ERAP2 genes encode enzymes that are reported to play a role in blood pressure regulation and essential hypertension in addition to innate immune and inflammatory responses. Perturbations within vascular, immunological and inflammatory pathways constitute important physiological mechanisms in preeclampsia pathogenesis. We herein report a novel preeclampsia risk locus, ERAP2, in a region of known genetic linkage to this pregnancy-specific disorder.

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Acknowledgments

This work was supported by National Institutes of Health grants HD049847 (to E.K.M., S.P.B. and J.B.) and MH059490 (to J.B.); a grant from the Semp Russ Foundation of the San Antonio Area Foundation (to M.P.J.); The Norwegian University of Science and Technology (NTNU) (R.A.); the Central Norway Regional Health Authority; and the Medical Faculty and Office of International Relations at NTNU (to L.T.R., Ph.D. scholar). M.P.J. is the recipient of a Cowles Postdoctoral Fellowship. This investigation was conducted in facilities constructed with support from Research Facilities Improvement Program grants RR13556 and RR017515 from the National Center for Research Resources, National Institutes of Health. The Nord-Trøndelag Health Study (the HUNT study) is a collaboration between the HUNT Research Centre, the Faculty of Medicine, NTNU, the Norwegian Institute of Public Health and the Nord-Trøndelag County Council. We thank Dr. Jeremy Jowett for bioinformatic analyses and Mr. Anthony Borg for technical assistance. We thank all the preeclampsia families and unrelated preeclamptic women whose participation made this work possible and the support of all the clinicians and research midwives who contributed to this study.

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Authors and Affiliations

  1. Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, 78227, USA

    Matthew P. Johnson, Thomas D. Dyer, John Blangero & Eric K. Moses

  2. Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, 7006, Trondheim, Norway

    Linda T. Roten & Rigmor Austgulen

  3. Department of Perinatal Medicine, Royal Women’s Hospital, Parkville, 3052, Australia

    Christine E. East & Shaun P. Brennecke

  4. Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, 3052, Australia

    Christine E. East & Shaun P. Brennecke

  5. Department of Public Health and General Practice, Norwegian University of Science and Technology, 7006, Trondheim, Norway

    Siri Forsmo

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  1. Matthew P. Johnson
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  2. Linda T. Roten
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  3. Thomas D. Dyer
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  4. Christine E. East
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  5. Siri Forsmo
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  6. John Blangero
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  7. Shaun P. Brennecke
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  8. Rigmor Austgulen
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  9. Eric K. Moses
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Correspondence to Matthew P. Johnson.

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M. P. Johnson and L. T. Roten contributed equally to this work.

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Johnson, M.P., Roten, L.T., Dyer, T.D. et al. The ERAP2 gene is associated with preeclampsia in Australian and Norwegian populations. Hum Genet 126, 655–666 (2009). https://doi.org/10.1007/s00439-009-0714-x

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