K J Gray1,2, V P Kovacheva3, H Mirzakhani4, A C Bjonnes2, B Almoguera5, M L Wilson6, S A Ingles6, C J Lockwood7, H Hakonarson5,8, T F McElrath1, J C Murray9, E R Norwitz10, S A Karumanchi11,12, B T Bateman4, B J Keating13, R Saxena2,4. 1. Division of Maternal-Fetal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. 2. Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. 3. Department of Anesthesiology, Brigham and Women's Hospital, Boston, Massachusetts, USA. 4. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. 5. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 6. Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. 7. Morsani College of Medicine, University of South Florida, Tampa, Florida, USA. 8. Department of Pediatrics, Divisions of Human Genetics and Pulmonary Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 9. Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. 10. Department of Obstetrics & Gynecology, Tufts Medical Center, Boston, Massachusetts, USA. 11. Center for Vascular Biology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 12. Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA. 13. Department of Surgery and Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Abstract
OBJECTIVE: To assess whether women with a genetic predisposition to medical conditions known to increase pre-eclampsia risk have an increased risk of pre-eclampsia in pregnancy. DESIGN: Case-control study. SETTING AND POPULATION: Pre-eclampsia cases (n = 498) and controls (n = 1864) in women of European ancestry from five US sites genotyped on a cardiovascular gene-centric array. METHODS: Significant single-nucleotide polymorphisms (SNPs) from 21 traits in seven disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal and thrombophilia) with published genome-wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous scaled genetic instrument with pre-eclampsia. Odds of pre-eclampsia were compared across quartiles of the genetic instrument and evaluated for significance. MAIN OUTCOME MEASURES: Genetic predisposition to medical conditions and relationship with pre-eclampsia. RESULTS: An increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of pre-eclampsia (DBP, overall OR 1.11, 95% CI 1.01-1.21, P = 0.025; BMI, OR 1.10, 95% CI 1.00-1.20, P = 0.042), whereas alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89, 95% CI 0.82-0.97, P = 0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early-onset pre-eclampsia cases (at <34 weeks of gestation, OR 1.30, 95% CI 1.08-1.56, P = 0.005). For other traits, there was no evidence of an association. CONCLUSIONS: These results suggest that the underlying genetic architecture of pre-eclampsia may be shared with other disorders, specifically hypertension and obesity. TWEETABLE ABSTRACT: A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre-eclampsia.
OBJECTIVE: To assess whether women with a genetic predisposition to medical conditions known to increase pre-eclampsia risk have an increased risk of pre-eclampsia in pregnancy. DESIGN: Case-control study. SETTING AND POPULATION: Pre-eclampsia cases (n = 498) and controls (n = 1864) in women of European ancestry from five US sites genotyped on a cardiovascular gene-centric array. METHODS: Significant single-nucleotide polymorphisms (SNPs) from 21 traits in seven disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal and thrombophilia) with published genome-wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous scaled genetic instrument with pre-eclampsia. Odds of pre-eclampsia were compared across quartiles of the genetic instrument and evaluated for significance. MAIN OUTCOME MEASURES: Genetic predisposition to medical conditions and relationship with pre-eclampsia. RESULTS: An increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of pre-eclampsia (DBP, overall OR 1.11, 95% CI 1.01-1.21, P = 0.025; BMI, OR 1.10, 95% CI 1.00-1.20, P = 0.042), whereas alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89, 95% CI 0.82-0.97, P = 0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early-onset pre-eclampsia cases (at <34 weeks of gestation, OR 1.30, 95% CI 1.08-1.56, P = 0.005). For other traits, there was no evidence of an association. CONCLUSIONS: These results suggest that the underlying genetic architecture of pre-eclampsia may be shared with other disorders, specifically hypertension and obesity. TWEETABLE ABSTRACT: A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre-eclampsia.
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