title: Candidate-gene association study of mothers with pre-eclampsia, and their infants, analyzing 775 SNPs in 190 genes.
abstract: Pre-eclampsia (PE) affects 5-7% of pregnancies in the US, and is a leading cause of maternal death and perinatal morbidity and mortality worldwide. To identify genes with a role in PE, we conducted a large-scale association study evaluating 775 SNPs in 190 candidate genes selected for a potential role in obstetrical complications. SNP discovery was performed by DNA sequencing, and genotyping was carried out in a high-throughput facility using the MassARRAY(TM) System. Women with PE (n = 394) and their offspring (n = 324) were compared with control women (n = 602) and their offspring (n = 631) from the same hospital-based population. Haplotypes were estimated for each gene using the EM algorithm, and empirical p values were obtained for a logistic regression-based score test, adjusted for significant covariates. An interaction model between maternal and offspring genotypes was also evaluated. The most significant findings for association with PE were COL1A1 (p = 0.0011) and IL1A (p = 0.0014) for the maternal genotype, and PLAUR (p = 0.0008) for the offspring genotype. Common candidate genes for PE, including MTHFR and NOS3, were not significantly associated with PE. For the interaction model, SNPs within IGF1 (p = 0.0035) and IL4R (p = 0.0036) gave the most significant results. This study is one of the most comprehensive genetic association studies of PE to date, including an evaluation of offspring genotypes that have rarely been considered in previous studies. Although we did not identify statistically significant evidence of association for any of the candidate loci evaluated here after adjusting for multiple testing using the false discovery rate, additional compelling evidence exists, including multiple SNPs with nominally significant p values in COL1A1 and the IL1A region, and previous reports of association for IL1A, to support continued interest in these genes as candidates for PE. Identification of the genetic regulators of PE may have broader implications, since women with PE are at increased risk of death from cardiovascular diseases later in life.
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Katrina A B
authors.initials: KA
authors.lastname: Goddard
authors.forename: Gerard
authors.initials: G
authors.lastname: Tromp
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Jane M
authors.initials: JM
authors.lastname: Olson
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Xu
authors.forename: Neeta
authors.initials: N
authors.lastname: Parimi
authors.forename: Jyh Kae
authors.initials: JK
authors.lastname: Nien
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gomez
authors.forename: Ernesto
authors.initials: E
authors.lastname: Behnke
authors.forename: Margarita
authors.initials: M
authors.lastname: Solari
authors.forename: Jimmy
authors.initials: J
authors.lastname: Espinoza
authors.forename: Joaquin
authors.initials: J
authors.lastname: Santolaya
authors.forename: Tinnakorn
authors.initials: T
authors.lastname: Chaiworapongsa
authors.forename: Guy M
authors.initials: GM
authors.lastname: Lenk
authors.forename: Kimberly
authors.initials: K
authors.lastname: Volkenant
authors.forename: Madan Kumar
authors.initials: MK
authors.lastname: Anant
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Salisbury
authors.forename: Janet
authors.initials: J
authors.lastname: Carr
authors.forename: Min Soeb
authors.initials: MS
authors.lastname: Lee
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Vovis
authors.forename: Helena
authors.initials: H
authors.lastname: Kuivaniemi
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002677:Chile; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D053582:Interleukin-1alpha / Q000235:genetics; D008297:Male; D008431:Maternal-Fetal Exchange / Q000235:genetics; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D011225:Pre-Eclampsia / Q000235:genetics*; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C508584:IL1A protein, human; D053582:Interleukin-1alpha; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator