title: The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: aDepartment of Gynecology and Obstetrics, Haukeland University Hospital bDepartment of Clinical Science, University of Bergen, Bergen, Norway cCentre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Australia dDepartment of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim eDepartment of Heart Disease, Haukeland University Hospital, Bergen, Norway fSouth Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas, USA gDepartment of Obstetrics and Gynaecology, University of Melbourne, Parkville hPregnancy Research Centre, Department of Maternal-Fetal Medicine, Royal Women's Hospital, Parkville, Victoria iFaculty of Health Sciences, Curtin University, Perth, Western Australia, Australia.
authors.forename: Liv Cecilie V
authors.initials: LC
authors.lastname: Thomsen
authors.forename: Nina S
authors.initials: NS
authors.lastname: McCarthy
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Melton
authors.forename: Gemma
authors.initials: G
authors.lastname: Cadby
authors.forename: Rigmor
authors.initials: R
authors.lastname: Austgulen
authors.forename: Ottar K
authors.initials: OK
authors.lastname: Nygård
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Johnson
authors.forename: Shaun
authors.initials: S
authors.lastname: Brennecke
authors.forename: Eric K
authors.initials: EK
authors.lastname: Moses
authors.forename: Line
authors.initials: L
authors.lastname: Bjørge
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Iversen
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001315:Australia; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D058685:Genetic Pleiotropy; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics; D007249:Inflammation / Q000235:genetics; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D009664:Norway; D020641:Polymorphism, Single Nucleotide; D011225:Pre-Eclampsia / Q000235:genetics*; D011247:Pregnancy; D065840:Protective Factors; D055815:Young Adult
chemical_list: C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)