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Hypertension. 2018 Aug;72(2):408-416. doi: 10.1161/HYPERTENSIONAHA.117.10688. Epub 2018 Jul 2.

Gene-Centric Analysis of Preeclampsia Identifies Maternal Association at PLEKHG1.

Author information

1
From the Division of Maternal-Fetal Medicine (K.J.G., T.F.M.) kgray6@bwh.harvard.edu.
2
Center for Genomic Medicine (K.J.G., A.C.B., R.S.).
3
Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.J.G., A.C.B., R.S.).
4
Department of Anesthesiology (V.P.K.).
5
Brigham and Women's Hospital, Boston, MA; Department of Anesthesia, Critical Care and Pain Medicine (H.M., B.T.B., R.S.).
6
Center for Applied Genomics, Children's Hospital of Philadelphia, PA (B.A., H.H.).
7
Department of Chronic Disease Epidemiology (A.T.D.).
8
Yale School of Public Health, New Haven, CT; Center for Outcomes Research and Evaluation, Yale School of Medicine, New Haven, CT (E.W.T.).
9
Department of Epidemiology, College of Public Health, University of Iowa (A.F.S.).
10
Department of Environmental Health Sciences (J.H.).
11
Inova Translational Medicine Institute, Inova Health System, Falls Church, VA (D.L.B., E.K., K.C.H.).
12
Department of Preventative Medicine, University of Southern California, Keck School of Medicine, Los Angeles (S.A.I., M.L.W.).
13
University of South Florida, Morsani College of Medicine, Tampa (C.J.L.).
14
Divisions of Human Genetics and Pulmonary Medicine, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (H.H.).
15
From the Division of Maternal-Fetal Medicine (K.J.G., T.F.M.).
16
Department of Pediatrics, Carver College of Medicine, University of Iowa (J.C.M.).
17
Department of Obstetrics and Gynecology, Tufts Medical Center, Boston, MA (E.R.N.).
18
Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA (S.A.K.).
19
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (S.A.K.).
20
Department of Surgery and Pediatrics, University of Pennsylvania, Philadelphia (B.J.K.).

Abstract

The genetic susceptibility to preeclampsia, a pregnancy-specific complication with significant maternal and fetal morbidity, has been poorly characterized. To identify maternal genes associated with preeclampsia risk, we assembled 498 cases and 1864 controls of European ancestry from preeclampsia case-control collections in 5 different US sites (with additional matched population controls), genotyped samples on a cardiovascular gene-centric array composed of variants from ≈2000 genes selected based on prior genetic studies of cardiovascular and metabolic diseases and performed case-control genetic association analysis on 27 429 variants passing quality control. In silico replication testing of 9 lead signals with P<10-4 was performed in independent European samples from the SOPHIA (Study of Pregnancy Hypertension in Iowa) and Inova cohorts (212 cases, 456 controls). Multiethnic assessment of lead signals was then performed in samples of black (26 cases, 136 controls), Hispanic (132 cases, 468 controls), and East Asian (9 cases, 80 controls) ancestry. Multiethnic meta-analysis (877 cases, 3004 controls) revealed a study-wide statistically significant association of the rs9478812 variant in the pleiotropic PLEKHG1 gene (odds ratio, 1.40 [1.23-1.60]; Pmeta=5.90×10-7). The rs9478812 effect was even stronger in the subset of European cases with known early-onset preeclampsia (236 cases diagnosed <37 weeks, 1864 controls; odds ratio, 1.59 [1.27-1.98]; P=4.01×10-5). PLEKHG1 variants have previously been implicated in genome-wide association studies of blood pressure, body weight, and neurological disorders. Although larger studies are required to further define maternal preeclampsia heritability, this study identifies a novel maternal risk locus for further investigation.

KEYWORDS:

genetic association studies; hypertension; population control; preeclampsia; pregnancy

PMID:
29967039
PMCID:
PMC6043396
[Available on 2019-08-01]
DOI:
10.1161/HYPERTENSIONAHA.117.10688
[Indexed for MEDLINE]

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