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Role of hypertension genetic factors in susceptibility to preeclampsia
Abstract Number: BP 1
Abstract Type: Original Research
Introduction: Hypertension is a diagnostic feature of preeclampsia. Preeclampsia is also associated with a substantially elevated risk for essential hypertension in later life.
Several large, genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that are associated with essential hypertension or blood pressure levels. In contrast, despite its strong heritable component, there are no genetic variants that have been robustly associated with preeclampsia.
In an effort to shed light on the genetic basis for preeclampsia and to better understand the shared liability to preeclampsia and essential hypertension, we sought to define the association between preeclampsia and SNPs implicated in essential hypertension or blood pressure levels in pregnant patients of European ancestry.
Methods: We employed a case-control design using samples from 315 preeclamptic patients and 470 control women with completed pregnancies that did not develop preeclampsia, drawn from sample collections from 7 U.S. academic medical centers. Subjects were genotyped on a cardiovascular gene-centric SNP array containing ~2,000 loci selected based on prior genetic studies of cardiovascular diseases and on pathways expected to be important in cardiovascular disease.
SNPs from 29 independent loci associated with hypertension or blood pressure levels at P<1x10-7 were identified from the National Human Genome Research Institute GWAS catalog; there were 25 SNPs with direct genotypes or proxies with r2>0.8 in HapMap CEU contained on our SNP array. These were analyzed for association with preeclampsia.
Single-SNP genetic association testing was completed using logistic regression, assuming additive effects for each risk allele present, and included principal components in the model to account for population structure. Statistical significance was judged as a Bonferroni-corrected P<0.002 to account for multiple testing.
Results: One of the 25 SNPs analyzed demonstrated a study-wide significant association with preeclampsia (rs1173743; P=0.00078, Padj=0.002). The hypertension risk allele at this locus was associated with an increased risk of preeclampsia (OR: 1.45, 95% confidence interval 1.16-1.76). The variant resides upstream of the gene NPR3, Natriuretic peptide receptor C/guanylate cyclase C, which is a receptor responsible for clearing circulating atrial natriuretic factor.
Conclusion: The association between preeclampsia and rs1173743 may provide insight into the shared predisposition to preeclampsia and essential hypertension. This finding needs to be replicated and its biological basis elucidated.