title: Epistasis between COMT and MTHFR in maternal-fetal dyads increases risk for preeclampsia.
abstract: Preeclampsia is a leading cause of perinatal morbidity and mortality. This disorder is thought to be multifactorial in origin, with multiple genes, environmental and social factors, contributing to disease. One proposed mechanism is placental hypoxia-driven imbalances in angiogenic and anti-angiogenic factors, causing endothelial cell dysfunction. Catechol-O-methyltransferase (Comt)-deficient pregnant mice have a preeclampsia phenotype that is reversed by exogenous 2-methoxyestradiol (2-ME), an estrogen metabolite generated by COMT. 2-ME inhibits Hypoxia Inducible Factor 1α, a transcription factor mediating hypoxic responses. COMT has been shown to interact with methylenetetrahydrofolate reductase (MTHFR), which modulates the availability of S-adenosylmethionine (SAM), a COMT cofactor. Variations in MTHFR have been associated with preeclampsia. By accounting for allelic variation in both genes, the role of COMT has been clarified. COMT allelic variation is linked to enzyme activity and four single nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4680, and rs4818) form haplotypes that characterize COMT activity. We tested for association between COMT haplotypes and the MTHFR 677 C → T polymorphism and preeclampsia risk in 1103 Chilean maternal-fetal dyads. The maternal ACCG COMT haplotype was associated with reduced risk for preeclampsia (P = 0.004), and that risk increased linearly from low to high activity haplotypes (P = 0.003). In fetal samples, we found that the fetal ATCA COMT haplotype and the fetal MTHFR minor "T" allele interact to increase preeclampsia risk (p = 0.022). We found a higher than expected number of patients with preeclampsia with both the fetal risk alleles alone (P = 0.052) and the fetal risk alleles in combination with a maternal balancing allele (P<0.001). This non-random distribution was not observed in controls (P = 0.341 and P = 0.219, respectively). Our findings demonstrate a role for both maternal and fetal COMT in preeclampsia and highlight the importance of including allelic variation in MTHFR.
authors.affiliation: Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America.
authors.forename: Lori D
authors.initials: LD
authors.lastname: Hill
authors.forename: Timothy P
authors.initials: TP
authors.lastname: York
authors.forename: Juan P
authors.initials: JP
authors.lastname: Kusanovic
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gomez
authors.forename: Lindon J
authors.initials: LJ
authors.lastname: Eaves
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Strauss
mesh_terms: D000483:Alleles; D000818:Animals; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D006239:Haplotypes; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D011225:Pre-Eclampsia / Q000235:genetics*; D011247:Pregnancy
chemical_list: D042965:Methylenetetrahydrofolate Reductase (NADPH2); D002394:Catechol O-Methyltransferase