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.

Meta-analysis of the methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to pre-eclampsia

“…However, some relevant articles in other languages were published in specific journals but were not found in the international journals. (3) In this study, we could not obtain information from some of the studies on folate and vitamin B12 levels, which may affect the associations between the MTHFR C677T polymorphism and PE. In conclusion, our meta-analysis suggests that the MTHFR C677T polymorphism may contribute to individual susceptibility to PE in the Asians; however, there is insufficient evidence to confirm this association in the Caucasians.…”

“…A genetic susceptibility to PE has been well established, and genes involved with endothelial dysfunction, oxidative stress, angiogenesis and thrombophilia have been associated with PE. [2][3][4] Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that catalyzes the conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for the transmethylation of homocysteine to methionine. Severe MTHFR deficiency is associated with hyperhomocysteinemia.…”

Epistasis among eNOS, MMP-9 and VEGF maternal genotypes in hypertensive disorders of pregnancy

“…Seven clinically relevant polymorphisms were studied in eNOS (T-786C, rs2070744 in the promoter region; the 27 bp variable number of tandem repeats in intron 4; and Glu298Asp, rs1799983 in exon 7), in the promoter region of MMP-9 (C-1562T, rs3918242 and -90(CA) [13][14][15][16][17][18][19][20][21][22][23][24][25] , rs2234681), and in the promoter region of VEGF (C-2578A, rs699947 and G-634C, rs2010963). Genotypes for eNOS rs2070744 and rs1799983 and for VEGF polymorphisms were determined by TaqMan allele discrimination assays using probes and primers designed by Applied Biosystems (Carlsbad, CA, USA), as previously described.…”

“…They have largely focused on maternal genotypes, and polymorphisms in genes involved in angiogenesis, endothelial function and oxidative stress have been associated with PE. [15][16][17] We previously studied clinically relevant polymorphisms of the eNOS (T-786C, 27 bp variable number of tandem repeats in intron 4 and Glu298Asp), MMP-9 (C-1562T and -90(CA) [13][14][15][16][17][18][19][20][21][22][23][24][25] ) and VEGF (C-2578A and G-634C) genes in HDP. We reported associations of some genotypes and haplotypes formed by these polymorphisms with PE and/or gestational hypertension (GH).…”

Gene-Centric Genomewide Association Study via Entropy

“…Eligible mothers were enrolled in a longitudinal cohort study designed to predict either the subsequent development of PE or the existence of PE at the time of admission to the hospital. For a detailed data description, please refer to Goddard et al (2007). After elimination of SNPs with minor allele TABLE 5 Power of the association test based on statistic T gene assuming one disease locus in a tested gene under different sample sizes and different simulation schemes.…”