Epistasis between COMT and MTHFR in Maternal-Fetal Dyads Is Associated with Increased Risk for Preeclampsia

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dc.catalogadorpau
dc.contributor.authorHill, Lori D.
dc.contributor.authorYork, Timothy P.
dc.contributor.authorKusanovic Pivcevic, Juan Pedro
dc.contributor.authorGómez Mora, Ricardo Alberto
dc.contributor.authorEaves, Lindon J.
dc.contributor.authorRomero, Roberto
dc.contributor.authorStrauss, Jerome F.
dc.date.accessioned2023-07-21T17:46:03Z
dc.date.available2023-07-21T17:46:03Z
dc.date.issued2011
dc.description.abstractPreeclampsia 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.
dc.fechaingreso.objetodigital2024-06-05
dc.format.extent8 páginas
dc.fuente.origenORCID
dc.identifier.doi10.1371/journal.pone.0016681
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0016681
dc.identifier.urihttps://publons.com/wos-op/publon/28238183/
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/74224
dc.information.autorucEscuela de Medicina; Kusanovic Pivcevic, Juan Pedro; 0000-0003-0640-2070; 1008900
dc.information.autorucEscuela de Medicina; Gómez Mora, Ricardo Alberto; 0000-0001-9267-304X; 80926
dc.issue.numero1
dc.language.isoen
dc.nota.accesoContenido completo
dc.pagina.final8
dc.pagina.inicio1
dc.revistaPlos onees_ES
dc.rightsacceso abierto
dc.titleEpistasis between COMT and MTHFR in Maternal-Fetal Dyads Is Associated with Increased Risk for Preeclampsia
dc.typeartículo
dc.volumen6
sipa.codpersvinculados1008900
sipa.codpersvinculados80926
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