A common polymorphism in NR1H2 (LXRbeta) is associated with preeclampsia
- Kevin Mouzat1Email author,
- Eric Mercier2,
- Anne Polge1,
- Alexandre Evrard1,
- Silvère Baron3,
- Jean-Pierre Balducchi4,
- Jean-Paul Brouillet1,
- Serge Lumbroso†1 and
- Jean-Christophe Gris†2
© Mouzat et al; licensee BioMed Central Ltd. 2011
Received: 24 May 2011
Accepted: 26 October 2011
Published: 26 October 2011
Preeclampsia is a frequent complication of pregnancy and a leading cause of perinatal mortality. Both genetic and environmental risk factors have been identified. Lipid metabolism, particularly cholesterol metabolism, is associated with this disease. Liver X receptors alpha (NR1H3, also known as LXRalpha) and beta (NR1H2, also known as LXRbeta) play a key role in lipid metabolism. They belong to the nuclear receptor superfamily and are activated by cholesterol derivatives. They have been implicated in preeclampsia because they modulate trophoblast invasion and regulate the expression of the endoglin (CD105) gene, a marker of preeclampsia. The aim of this study was to investigate associations between the NR1H3 and NR1H2 genes and preeclampsia.
We assessed associations between single nucleotide polymorphisms of NR1H3 (rs2279238 and rs7120118) and NR1H2 (rs35463555 and rs2695121) and the disease in 155 individuals with preeclampsia and 305 controls. Genotypes were determined by high-resolution melting analysis. We then used a logistic regression model to analyze the different alleles and genotypes for those polymorphisms as a function of case/control status.
We found no association between NR1H3 SNPs and the disease, but the NR1H2 polymorphism rs2695121 was found to be strongly associated with preeclampsia (genotype C/C: adjusted odds ratio, 2.05; 95% CI, 1.04-4.05; p = 0.039 and genotype T/C: adjusted odds ratio, 1.85; 95% CI, 1.01-3.42; p = 0.049).
This study provides the first evidence of an association between the NR1H2 gene and preeclampsia, adding to our understanding of the links between cholesterol metabolism and this disease.
Preeclampsia (PE) is a frequent complication of the second half of pregnancy and is one of the leading causes of maternal perinatal mortality and morbidity . This condition, affecting 2.5 to 3% of pregnant women is defined by gestational hypertension accompanied by proteinuria [2, 3]. Many risk factors have been described, including, in particular, cardiovascular risks, such as diabetes mellitus and high body mass index [4, 5]. Cholesterol metabolism may also contribute to the pathogenesis of preeclampsia. Indeed, high total cholesterol and LDL (low density lipoprotein)-cholesterol levels are significantly associated with this disease . Moreover, it has been shown that a familial history of PE almost triples the risk of a woman developing this disease, consistent with the involvement of genetic factors . Many risk factors have been described, but the molecular mechanisms underlying this disease remain unclear. Liver X receptors (LXRs) NR1H3 and NR1H2, more commonly known as LXRalpha and LXRbeta, play a key role in cholesterol metabolism [7, 8]. They belong to a subclass of nuclear receptors that form obligate heterodimers with 9-cis retinoic acid receptors (RXR). They also bind to and are activated by naturally occurring oxidized forms of cholesterol, known as oxysterols, the intracellular concentrations of which are directly correlated with cholesterol concentration . Knockout mice deficient in oxysterol synthesis pathways are unable to induce LXR-target genes in response to dietary cholesterol, demonstrating that these nuclear receptors are endogenous receptors for oxysterols . Upon ligand binding, they activate the transcription of many genes involved essentially in lipid metabolism, cholesterol metabolism in particular. Thus, by stimulating the cellular efflux and hepatic reverse transport of cholesterol and inhibiting its endogenous synthesis, they act as hypocholesterolemic factors . LXRs may therefore be considered endogenous cholesterol sensors.
LXRs are promising candidates in investigations of the molecular causes of PE. It is now widely accepted that PE results from placentation defects. Indeed, any defect in trophoblast development or differentiation can result in PE . LXRs are expressed in human placenta at various stages of pregnancy, right until term , and their expression increases during pregnancy . In addition to their potential role in regulating placental lipid metabolism, LXRbeta has recently been shown to control trophoblast invasion in vitro . Furthermore, we have also shown that ENG, encoding endoglin (CD105), a protein controlling placental angiogenesis , is a direct target of LXRalpha . Soluble ENG is a marker of PE, and its serum concentration is tightly correlated with disease severity.
Single nucleotide polymorphisms (SNP) of the NR1H3 (LXRalpha) and NR1H2 (LXRbeta) genes have recently been associated with many metabolic indicators and conditions, including circulating total, LDL and HDL (High Density Lipoprotein)-cholesterol levels for NR1H3 [18–20], and type 2 diabetes mellitus and obesity for both NR1H3 and NR1H2 [21–24]. Based on these previous studies, we selected two SNPs (rs2279238 and rs7120118) in the NR1H3 gene, mapping to chromosome 11p11.2 and two SNPs (rs2695121 and rs35463555) in the NR1H2 gene, mapping to chromosome 19q13.3 for study. Rs2279238, rs2695121 and rs35463555 have been reported to be associated with obesity ; rs2279238 is also associated with risk factors for type 2 diabetes mellitus . Finally, rs7120118 was chosen for study because it has been shown to be associated with HDL-cholesterol levels .
In a case-control study of 155 preeclamptic and 305 normal pregnancies based on a powerful high-resolution melting curve analysis technique, we showed that the NR1H2 polymorphism rs2695121 was strongly associated with PE. These findings suggest that further studies of the role of LXRbeta in the pathogenesis of this disease will be of interest. By contrast, we found no significant association between the NR1H3 SNPs (rs2279238 and rs7120118) and PE.
This study was approved by the local ethics committee (CPP: Comité de Protection des Personnes Sud Méditerranée III). We recruited 155 patients between December 1997 and July 2002. Both cases and controls gave written informed consent for participation in the study. The clinical investigation was performed in accordance with the Helsinki Declaration and its amendments.
Patients and controls
All the patients and controls were primiparous.
Patients were referred to the outpatient clinic of the Gynecology and Obstetrics Department or to the Hematology Laboratory, University Hospital of Nîmes, between December 1997 and July 2002, for thrombophilia screening and relevant investigations.
The inclusion criterion for the patients was preeclampsia during a natural pregnancy, defined as gravidic hypertension (systolic blood pressure [BP] > 140 mm Hg, diastolic BP > 90 mm Hg, a rise in systolic BP > 30 mm, or a rise in diastolic BP > 15 mm Hg on at least two measurements 6 hours apart) after 20 weeks, associated with significant proteinuria (> 300 mg/24 h). Thirty-six of the 155 preeclampsia patients had developed a severe form according to current definitions, before 34 weeks of gestation in nine cases. There were 11 cases of HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and two cases of eclampsia. We were unable to analyze severity subgroups, due to the small number and heterogeneity of the severe preeclampsia cases.
The 305 controls were women from the NOHA First Cohort, with uneventful pregnancies .
Data were collected for putative clinical predictors of preeclampsia: age, body mass index (BMI), smoking (defined as at least one cigarette per day), gravidity (evaluating the number of previous miscarriages), ethnicity, diabetes mellitus, pre-existing arterial hypertension (defined as the use of hypertensive medication, a systolic blood pressure of at least 140 mm Hg or a diastolic blood pressure of at least 90 mm Hg on two readings taken in a supine position 5 min apart, and on two separate occasions) and maternal history of preeclampsia.
Sequence primers used for high-resolution melting curve analyses
Size of the amplicon (bp)
Deviation from Hardy-Weinberg equilibrium (HWE) was assessed with DeFinetti software (T.F. Wienker and T.M. Strom, unpublished data, http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). The frequencies of particular alleles and genotypes in cases and controls were assessed by χ2 analysis (Statview software 5.0, SAS Institute). Analyses of the pairwise linkage disequilibrium (D' and r2) between the markers in each genomic region and haplotype analysis were carried out with Haploview 4.2 Software .
The putative predictors of preeclampsia -- the clinical factors listed above and the four polymorphisms studied -- were evaluated in women, initially by univariate analysis and then by multivariate logistic regression analysis. We calculated the corresponding crude odds ratio (cOR) and its 95% confidence interval (95% CI) and then the adjusted odds ratio (aOR) and its 95% CI. Variables for multivariate models were selected in a stepwise manner, beginning with all the variables for which p < 0.25 in univariate models as potential predictors, with final adjustment for all variables for which p < 0.25 in the univariate models.
Characteristics of the participants
Clinical characteristics of controls and patients
Controls (N = 305)
Patients (N = 155)
cOR (95% CI)
29 ± 7 (23-36)
30 ± 7 (23-37)
22.46 ± 2.60
22.80 ± 2.45
Pre-existing arterial hypertension
Maternal PE antecedent
Polymorphisms and risk of preeclampsia
Allelic counts and frequencies of studied polymorphisms
Genotypic counts and frequencies of the studied polymorphisms
Logistic regression analysis of the associations between LXRalpha or LXRbeta SNPs and preeclampsia (univariate analysis)
Logistic regression model of risk factors for PE (multivariate analysis)
Pre-existing arterial hypertension
Maternal history of PE
Haplotypic prevalence of genotyped NR1H3 and NR1H2 in both groups
This is the first study to investigate the association of the NR1H2 (LXRbeta) gene with preeclampsia. We report here a new genetic association between the SNP rs2695121, in the NR1H2 gene, and preeclampsia. By contrast, the two SNPs within the NR1H3 (LXRalpha) gene studied, rs2279238 and rs7120118, were not identified as independent risk factors for this disease.
Despite the demonstration of an interesting association between the r2695121 polymorphism in NR1H2 (LXRbeta) and preeclampsia, this study was subject to several limitations. Univariate logistic regression analysis showed that both the SNPs within the NR1H2 gene tested were associated with preeclampsia. However, in a multivariate model including all the clinical cofactors and these two polymorphisms, only rs2695121 remained associated with PE. This association was strengthened by a significant adjusted link between the mutated homozygous but also heterozygous SNP and preeclampsia, but the lack of association between rs35463555 and the diseases warrants further investigation. It may result from there being too few samples in our study, but it could also reflect genetic linkage between the two polymorphisms. We calculated the linkage disequilibrium between the two polymorphisms in our genotyped population and we found evidence of genetic linkage between the two polymorphisms (D' = 0.85; r2 = 0.21; Additional file 1, Figure S1), likely to account, at least in part, for the apparent lack of statistical power in our study.
Many risk factors for preeclampsia have been described. High body mass index, obesity and cholesterolemia are among the most frequently studied and are tightly linked to this disease [6, 31]. High total and LDL-cholesterol levels have been identified as risk factors for preeclampsia. Our discovery of an association between a polymorphism of NR1H2 (LXRbeta) and PE is therefore of particular interest. Indeed, both LXRs are now widely considered to be major regulators of lipid homeostasis. In recent years, many studies in animals and in vitro models have demonstrated that these nuclear receptors modulate the expression of genes involved in various aspects of the control of cholesterol metabolism (For a review, see ). They may act on various pathways: inhibiting de novo cholesterol synthesis by downregulating key enzymes involved in its synthesis, stimulating the cellular efflux of cholesterol by upregulating ATP-binding cassette A1, G1 and G5/G8 (ABCA1, ABCG1 and ABCG5/G8) transporters and inducing the reverse transport of cholesterol by regulating apolipoprotein-encoding genes, such as APOE (apolipoprotein E). Circulating cholesterol has been widely described as a risk factor for preeclampsia, and some APOE alleles have been associated with PE . Our work is thus consistent with recent findings of associations between polymorphisms in the genes encoding LXRalpha and LXRbeta and circulating total, LDL- and HDL-cholesterol concentrations [18–20] and obesity [22, 24].
The physiopathological features of preeclampsia seem to result principally from placental ischemia and/or a maternal inflammatory response . Many factors are involved in the development of this disease. In particular, the gene encoding cyclooxygenase-2 (COX-2) has been shown to be overexpressed in the vessels of women with PE , and circulating levels of proinflammatory cytokines, such as inteleukin-6 (IL-6), are higher in patients than in controls . In addition to their well known cholesterolemia-lowering effects, LXRs have been implicated in immune processes. Their anti-inflammatory action was first described in 2003 in a study showing that their activation decreased the expression of many proinflammatory factors, including COX-2, iNOS (inducible nitric oxide synthase), IL-1beta (interleukin-1 beta) and IL-6 . Thus, further studies on the role of LXRs in the immune processes associated with preeclampsia will be of particular interest.
Placental angiogenesis also makes a major contribution to preeclampsia. Indeed, defects in the development, differentiation and angiogenesis of the placenta may lead to PE . Defects in signaling by angiogenic factors, such as vascular endothelial growth factor (VEGF), are also frequently observed. Circulating levels of sFLT-1 (soluble VEGF receptor 1) and sENG (soluble endoglin) are high in patients suffering from PE, and may contribute to the pathogenesis of the disease [16, 32]. Interestingly, VEGF is a direct target gene of both LXRs . We have also previously reported that ENG is a direct target of LXRalpha in human placental cell cultures . Direct effects of liver X receptors on the placenta, such as trophoblast invasion [15, 37] and syncytialization , have recently been suggested. One recent study revealed that the expression of NR1H3, NR1H2 and their target gene ABCA1 in JAR cells is stimulated under conditions of low oxygen concentration, mimicking the conditions occurring in preeclampsia . The authors hypothesized that these deregulations might affect cholesterol transport between the mother and the fetus. Overall, these data provide evidence for a functional role for LXRs in the maintenance of placental homeostasis.
Human genetic studies have recently demonstrated associations between polymorphisms of the NR1H3 (LXRalpha) gene and circulating total, LDL- and HDL-cholesterol [18–20]. A role for LXRalpha in the pathogenesis of preeclampsia is also supported by our previous work showing that LXRalpha but not LXRbeta induced the promoter of ENG gene . Our work reveals that the NR1H2 (LXRbeta) SNP rs2695121 is a risk factor for preeclampsia. The lack of association between the two tested NR1H3 SNPs and preeclampsia in our work is quite surprising. However, we limited our study to only two polymorphisms of NR1H3 gene, which had already been reported to be associated with physiological and/or pathological conditions. We cannot, on the basis of our results, exclude the possibility that NR1H3 is involved in the pathogenesis of preeclampsia, for two major reasons: the statistical power of this study may simply have been too low to pick up a significant association. Moreover, other SNPs, located within the same gene and not in strong linkage disequilibrium with rs2279238 and rs7120118, may be associated with the disease. Indeed, using Tagger implemented in Haploview software with an aggressive tagging method (r2 threshold = 0.8) , we showed that our two SNPs covered 91% of the haplotypic variability of the NR1H3 gene (including 2 kb on either side of the gene; mean max r2 = 0.97). However, as they did not account for all the variability, it is possible that the absence of association was due to missed haplotypes. Additional studies including more NR1H3 SNPs and/or more samples are therefore required to rule out definitively the existence of an association between this gene and the disease. The two polymorphisms of the NR1H2 gene studied (rs2695121 and rs35463555) have not yet been genotyped in the CEU+TSI populations of the Hapmap project. However, only three SNPs within this gene region have been described in the Hapmap project. These three SNPs are in strong linkage disequilibrium, defining a unique haploblock. As the two TagSNPs proposed by Tagger have never been associated with any physiological or physiopathological condition, we preferred to investigate two potentially functional SNPs described in previous studies, despite the possible lack of haplotypic variability coverage. A deeper replication study, including a larger number of polymorphisms, may facilitate definition of the contribution of NR1H2 to the pathogenesis of preeclampsia. In parallel, it will be interesting to determine the concentration of circulating endoglin in our cohort of patients, to identify possible associations with NR1H2 genotypes.
In conclusion, we demonstrate here, for the first time, an association between a polymorphism of the NR1H2 (LXRbeta) gene and preeclampsia. However, caution is required in the clinical interpretation of risk factors . The results of this retrospective pilot study will therefore require confirmation in a secondary prospective study on a set of patients, in which it should be possible to assess the association between the SNPs and disease severity. In addition to improving our understanding of the molecular physiopathological features of preeclampsia, this study opens up new possibilities for investigation. In particular, it will be particularly interesting to determine whether LXRbeta could serve as a new marker of the disease. Moreover, as this nuclear receptor is an inducible transcription factor, an understanding of its role in preeclampsia could guide the development of new ligands for the treatment of this disease.
List of abbreviations used
- 95% CI:
95% confidence interval
chicken ovalbumin upstream promoter transcription factor
hemolysis: elevated liver enzymes: low platelets
inducible nitric oxide synthase
liver X receptor
retinoid × receptor
soluble VEGF receptor 1
single nucleotide polymorphism
vascular endothelial growth factor.
We thank all the participants, patients and controls who agreed to participate in this study. We thank R. Guirard and E. Douard for excellent technical assistance, Prof. J-M.A. Lobaccaro and Dr. Françoise Caira (UMR CNRS 6247 - Clermont University - INSERM U931) for critically reading the manuscript and for helpful discussions.
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