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 new-onset 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 investigate whether genetic risk factors for hypertension or inflammation are pleiotropic by also being associated with preeclampsia.Methods:We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n = 1006) and nonpreeclamptic controls (n = 816) from the Norwegian HUNT Study. SNPs were chosen on the basis of 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 (odds ratio 0.65, 95% confidence interval 0.53–0.80) in the Norwegian cohort. This association did not replicate in an Australian preeclampsia case–control cohort (P = 0.68, odds ratio 1.05, 95% confidence interval 0.83–1.32, minor allele frequency = 0.15).Conclusion: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 nongestational hypertension. Our study suggests a novel association between this allele and reduced risk for preeclampsia. This is the first study associating the minor (G) allele of a SNP within the MTHFR gene with a protective effect on preeclampsia, and in doing so identifying a possible pleiotropic protective effect on preeclampsia and hypertension.

Ordered multinomial regression for genetic association analysis of ordinal phenotypes at Biobank scale

“…It is thus not surprising that our results differ from previous BP trait GWAS with UK Biobank. Still, even with all the caveats, a large number of the loci, notably CACNB2, MTHFR, and PLCD3, have been reported to be linked to hypertension in previous studies (Levy et al, ; Newton‐Cheh et al, ; Thomsen et al, ).…”

Arterial Hypertension and Methylenetetrahydrofolate Reductase C677T Gene Polymorphism

“…Ген MTHFR кодирует аминокислотную последовательность фермента, играющего ключевую роль в метаболизме фолиевой кислоты, который преобразует 5,10-метилентетрагидрофолат в 5-метилтетрагидрофолат, активную форму фолатов, и участвует в превращении гомоцистеина в метионин. Плейотропное влияние гена MTHFR описано более чем в 2 900 научных публикациях, полиморфизмы ассоциируются с сердечно-сосудистыми заболеваниями (ССЗ), ишемическими инсультами, болезнью Паркинсона, дефектами развития нервной трубки плода, онкологическими заболеваниями, осложнениями беременности и офтальмологической патологией (глаукома, катаракта, диабетическая ретинопатия) [1][2][3]. Одним из наиболее изученных полиморфизмов гена MTHFR, влияющим на активность фермента, является вариант, в котором нуклеотид цитозин (C) в позиции 677 заменен тимином (T).…”

Homocysteine During the Third Trimester is a Risk Factor for Preeclampsia: A Prospective Study

“…At the same time, we also found that the G mutation of MTHFR rs17367504 had had a protective effect on Hcy during pregnancy, and the G mutation might cause Hcy decline. This might explain Thomsen's ndings [12]. Thomsen [12] rst found that the G mutation at MTHFR rs17367504 was a protective factor for PE (OR=0.65, 95% CI 0.53-0.80).…”

“…This might explain Thomsen's ndings [12]. Thomsen [12] rst found that the G mutation at MTHFR rs17367504 was a protective factor for PE (OR=0.65, 95% CI 0.53-0.80). In addition to the MTHFR gene, creatinine and protein levels in pregnancy were also possible factors that in uence Hcy in pregnancy.…”