Objective prioritization of positional candidate genes at a quantitative trait locus for pre-eclampsia on 2q22

Abstract

Pre-eclampsia/eclampsia (PE/E) is a common, serious medical disorder of human pregnancy. Familial association of PE/E has been recognized for decades, but the genetics are complex and poorly understood. In an attempt to identify PE/E susceptibility genes, we embarked on a positional cloning strategy using 34 Australian and New Zealand PE/E pedigrees. An initial 10-cM resolution genome scan revealed a putative susceptibility locus spanning a broad region on chromosome 2 that overlaps an independently determined linkage signal seen in Icelandic PE pedigrees. Subsequent fine mapping using 25 additional short tandem repeat (STR) markers in this region and non-parametric multipoint linkage analysis did not change the overall position. Under a strict diagnosis of PE, we obtained significant evidence of linkage on 2q with a peak log-of-odds ratio score (LOD) of 3.43 near marker D2S151 at 155 cM. To prioritize positional candidate genes at the 2q locus for detailed analysis, we applied an objective prioritization strategy that integrates quantitative bioinformatics, assessment of differential gene expression and association analysis of single-nucleotide polymorphisms (SNPs). Highest priority was assigned to the activin receptor gene ACVR2. This gene also showed >10-fold differential gene expression in human decidual tissue from normotensive and PE individuals. We genotyped five known SNPs in this gene in our pedigrees and performed tests for association and linkage disequilibrium. One SNP (rs1424954) showed strong preliminary evidence of association with PE (P = 0.007), whereas two others (rs1364658 and rs1895694) exhibited nominal evidence (P < 0.05). Haplotype analysis revealed no additional association information. There was evidence of weak linkage disequilibrium among these SNPs. The highest observed LD occurred between the two strongest associated SNPs, suggesting that the observed signals may be the signature of an observed functional variant.

Nodal Signals through Activin Receptor-Like Kinase 7 to Inhibit Trophoblast Migration and Invasion

“…20 -23 Interestingly, a type II receptor (activin receptor IIA) and two type I receptors (ALK2 and ALK7) are located on chromosome 2q22, which contains a preeclampsia susceptibility locus, and the potential association of these receptors, particularly activin receptor IIA, with preeclampsia has been suggested. 24,25 To further elucidate the role of Nodal/ALK7 signaling in human placenta, we performed immunohistochemical (IHC) analysis to determine Nodal and ALK7 expression in normal and preeclamptic placentae. We also investigated the role and mechanism of Nodal in trophoblast cell migration and invasion.…”

Genetische Faktoren beim HELLP-Syndrom – eine kritische Übersicht

“…Dazu gehören u. a. die Gene für den Activin-Rezeptor Typ II (ACVR2), für plazentare Aminopeptidasen und Peptidhormone [56,57]. Bisher gibt es zwar nur wenige Untersuchungen zu Plazentagenen und Präeklampsie, die vorliegenden Ergebnisse sind aber vielversprechend, sodass weitergehende Analysen auf diesem Gebiet durchgeführt werden sollten.…”

Selection of Genes and Single Nucleotide Polymorphisms for Fine Mapping Starting From a Broad Linkage Region

“…Other approaches described in the present literature propose genotyping of all the coding SNPs (Bergholdt et al, 2005) or a selection of (validated) intragenic SNPs (Curran et al, 2006;Moses et al, 2006), sequencing the gene and comparing discordant subjects (Dash et al, 2006;Lowe et al, 2007), using evenly spaced SNPs throughout the gene (Lou et al, 2007;Palmer et al, 2006), or combinations of the previous methods (Hinks et al, 2006;Nicolae et al, 2005;Wang et al, 2007;Wilson et al, 2006;Yang et al, 2005). This field is clearly evolving rapidly, but it is beyond the scope of this manuscript to go into detail on each of these methods.…”