The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia

Abstract

Objective: Preeclampsia is a complex heterogeneous disease commonly defined by newonset hypertension and proteinuria in pregnancy. Women experiencing preeclampsia have increased risk for cardiovascular diseases (CVD) later in life. Preeclampsia and CVD share risk factors and pathophysiologic mechanisms, including dysregulated inflammation and raised blood pressure. Despite commonalities, little is known about the contribution of shared genes (pleiotropy) to these diseases. This study aimed to reveal novel genetic links between preeclampsia and chronic hypertension and inflammation. Methods: We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n=1,006) and non-preeclamptic controls (n=816) from the Norwegian HUNT Study. SNPs were chosen based on previously reported associations with either nongestational hypertension or inflammation in genome-wide association studies. The SNPs were tested for association with preeclampsia in a multiple logistic regression model. Results: The minor (G) allele of the intronic SNP rs17367504 in the gene methylenetetrahydrofolate reductase (MTHFR) was associated with a protective effect on preeclampsia (OR 0.65, 95% CI 0.53-0.80). Conclusions: MTHFR is important for regulating transmethylation processes and is involved in regulation of folate metabolism. The G allele of rs17367504 has previously been shown to protect against non-gestational hypertension. We have demonstrated a novel association between this allele and reduced risk for preeclampsia. This is the first study associating a variant within the MTHFR gene with a protective effect on preeclampsia, and in doing so identifying its pleiotropic protective effects on preeclampsia and hypertension.