Abstract
Several conditions apparent at birth, e.g., neural tube defects (NTDs) and cardiac anomalies, are associated with polymorphisms in folate-related genes, such as the 677C → T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. Similar associations have been established for several constitutional chronic diseases in adulthood, such as schizophrenia, cardiovascular diseases, dementia, and even neoplasias in different organ systems. This spectrum of developmental anomalies and constitutional diseases may be linked to high-risk conceptions related to preovulatory overripeness ovopathy (PrOO). Some developmental anomalies, such as NTDs, are to a large extent prevented by supplementation of folic acid before conception, but supplementation does not seem to prevent cardiovascular disease or cognitive decline. These diverging results can be elucidated by introduction of the PrOO concept, as MTHFR polymorphisms and inherent low folate levels induce both non-optimal maturation of the oocyte and unsuccessful DNA methylation and demethylation, i.e. epigenetic mutations. The PrOO concept is testable and predicts in a random population the following: (1) female carriers of specific genetic MTHFR variants exhibit more ovulatory disturbances and inherent subfecundity traits, (2) descendents from a carrier mother, when compared with those from a wild-type mother, are more frequently conceived in PrOO high-risk conditions and, thus, (3) disadvantaged in life expectancy. If so, some MTHFR polymorphisms represent a novel, genetically determined, PrOO high-risk conception category comparable to those which are environmentally and behaviorly influenced. These high-risk conditions may cause developmental anomalies and defective epigenetic reprogramming in progeny. The interaction between genetic and environmental factors is a plausible mechanism of multifactorial inheritance.
Highlights
Most theories related to the origin of adult diseases focus on genetic causes and direct environmental effects preceding disease onset by several years at most
We proposed non-optimal oocyte ripening or impaired oocyte maturation can be an important cause of developmental anomaly and disease later in adult life [1,2,3,4]
The broad spectrum of diseases possibly related to suboptimal oocyte ripening strikingly appears to correspond with diseases that have been associated with the methylenetetrahydrofolate reductase (MTHFR) 677C o T polymorphism
Summary
Most theories related to the origin of adult diseases focus on genetic causes and direct environmental effects preceding disease onset by several years at most. This genetically conditioned high-risk for PrOO explains several unexplained phenomena related to MTHFR variants as well as to low dietary folate Both conditions are associated with increased fetal loss, intrauterine growth retardation, and heart defects in female mice [35], as well as with women experiencing fetal aneuploidy, recurrent pregnancy loss, early and late pregnancy loss, preeclampsia, preterm premature rupture of membranes, and of particular interest, congenital anomalies [36,37,38,39]. MTHFR polymorphisms and resulting low folate levels warrant consideration as factors inducing non-optimally matured oocytes before conception They represent a novel, genetically determined, high-risk PrOO condition comparable to the endocrine disturbances elicited by environmental and behavioral conditions. Further study of the interaction between genetic and environmental factors may indentify mechanisms of multifactorial inheritance and explain many commonly associated enigmata in chronic constitutional diseases
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