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Methylation allelic polymorphism (MAP) in chorionic gonadotropin beta5 (CGB5) and its association with pregnancy success.

ABSTRACT: Increased epigenetic variability in the placenta may have evolved in response to its role in mediating the conflicting demands of the mother and fetus. One essential guardian of early pregnancy maintenance is the placental hormone human chorionic gonadotropin (HCG).Among the four primate-specific duplicate HCG?-coding genes, chorionic gonadotropin-?8 (CGB8) and chorionic gonadotropin-?5 (CGB5) jointly contribute 62-82% of the total HCG? transcript pool. Because these genes share common features with known imprinted placenta-expressed loci, we addressed the role of epigenetic mechanisms affecting their action.Parental origin of CGB5 and CGB8 transcripts and promoter methylation patterns were addressed in trophoblastic tissues from 23 mother-offspring duos and nine mother-father-offspring trios including the following: 1) third-trimester normal delivery at term (n = 14), 2) first-trimester elective termination of uncomplicated pregnancy (n = 10), and 3) first-trimester recurrent (?3) miscarriage (n = 8).A normal uncomplicated pregnancy was characterized by balanced, biallelic expression of CGB5 and CGB8. However, in three (two recurrent miscarriage and one early elective termination of uncomplicated pregnancy) of nine genetically informative cases of CGB5, monoallelic expression of maternal alleles and hemimethylated gene promoters were identified.Our finding may represent a novel methylation allelic polymorphism or gain of imprinting in CGB5 promoter leading to expressional silencing of paternal alleles and increasing susceptibility to pregnancy loss. Aberrant methylation patterns in placenta may result from random reprogramming defects affecting normal implantation process. Alternatively, methylation allelic polymorphism in the placenta favoring the failure of pregnancy may arise as a response to cellular stress caused by, in general, aneuploidy or conditions in placental-maternal interface.

SUBMITTER: Uuskula L

PROVIDER: S-EPMC3046612 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Methylation allelic polymorphism (MAP) in chorionic gonadotropin beta5 (CGB5) and its association with pregnancy success.

Uusküla Liis L Rull Kristiina K Nagirnaja Liina L Laan Maris M

The Journal of clinical endocrinology and metabolism 20101020 1

<h4>Context</h4>Increased epigenetic variability in the placenta may have evolved in response to its role in mediating the conflicting demands of the mother and fetus. One essential guardian of early pregnancy maintenance is the placental hormone human chorionic gonadotropin (HCG).<h4>Objective</h4>Among the four primate-specific duplicate HCGβ-coding genes, chorionic gonadotropin-β8 (CGB8) and chorionic gonadotropin-β5 (CGB5) jointly contribute 62-82% of the total HCGβ transcript pool. Because ...[more]

PMID: 20962020

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Project description:BACKGROUND:A positive pregnancy test in acute or chronically ill patients has implications for the use of potentially mutagenic or teratogenic products in urgent medical therapies such as the use of chemotherapies or therapies with immunosuppressants, for anesthesia, and for time-sensitive indications like urgent surgery or organ Transplantation. Despite a lack of evidence, it is currently believed that human chorionic gonadotropin serum concentrations are always elevated in female dialysis patients even without pregnancy. It is also believed that human chorionic gonadotropin cannot be used to confirm or exclude pregnancy. METHODS:Human chorionic gonadotropin was examined in female dialysis patients (18-50?years of age), and was classified as positive above 5 mlU/ml. In addition, fertility status was determined. For an enhanced index test, the cut-off of 5 mIU/ml was used for potentially fertile patients and 14 mIU/ml for infertile patients to calculate diagnostic test accuracy. The ideal cut-off for human chorionic gonadotropin was estimated using Liu's method with bootstrapped 95% confidence intervals. Predictors of human chorionic gonadotropin increase were analyzed using multivariable linear regression. RESULTS:Among 71 women, two (2.8%) were pregnant, 46 (64.8%) potentially fertile, and 23 (32.4%) infertile. We observed human chorionic gonadotropin concentrations >?5 mIU/ml in 10 patients, which had a sensitivity of 100% (95% confidence interval: 100 to 100), a specificity of 86% (95% confidence interval: 77 to 94), a positive predictive value of 17% (95% confidence interval: 8 to 25) and a negative predictive value of 100% (95% confidence interval: 100 to 100) for the diagnosis of pregnancy. Using a cut-off >?14 mIU/ml for infertile patients or the exclusion of infertile patients increased specificity to 93% or 98%, respectively. The ideal cut-off was 25 mIU/ml (95% confidence interval: 17 to 33). Pregnancy and potential fertility, but not age, were independent predictors of human chorionic gonadotropin. CONCLUSION:Human chorionic gonadotropin is elevated >?5mIU/ml in 14.5% of non-pregnant dialysis patients of child-bearing age. In potentially fertile women, this cut-off can be used to exclude pregnancy. In case of an unknown fertility status, the ideal human chorionic gonadotropin cut-off was 25 mIU/ml.

Project description:Immunopathological outcomes in Systemic Lupus Erythematosus (SLE; or lupus) are believed to be autoantibody-mediated. Conditions which promote a Th2 skew (such as pregnancy) should encourage antibody production, worsening antibody-mediated diseases while ameliorating Th1/Th17-mediated diseases. Although an increased propensity toward autoreactivity can be observed in pregnant lupus patients and in pregnant lupus-prone mice, whether a unique human pregnancy-specific factor can contribute to such effects is unknown. This study assessed whether human chorionic gonadotropin (hCG, a pregnancy-specific hormone of diverse function) at physiological concentrations could mediate stimulatory influences on immune parameters in non-pregnant, lupus-prone mice, in light of the hormone's ameliorating effects on Th1-mediated autoimmunity in murine models. Results demonstrate that administration of hCG heightened global autoreactivity in such mice; antibodies to dsDNA, RNP68, Protein S, Protein C, β2-glycoprotein 1, and several phospholipids were enhanced, and hormone administration had adverse effects on animal survival. Specifically in splenic cell cultures containing cells derived from lupus-prone mice, hCG demonstrated synergistic effects with TLR ligands (up-modulation of costimulatory markers on B cells) as well as with TCR stimuli (enhanced proliferative responses, enhanced levels of cytokines, and the phosphorylation of p38). In both instances, enhanced synthesis of lupus-associated cytokines was observed, in addition to the heightened generation of autoantibodies reactive toward apoptotic blebs. These results suggest that selective transducive, proliferative, and differentiative effects of hCG on adaptive immune cells may drive autoreactive responses in a lupus environment, and may also potentially provide insights into the association between the presence of higher hCG levels (or the administration of hCG) with the presence (or appearance) of humoral autoimmunity.

Dataset Information

Methylation allelic polymorphism (MAP) in chorionic gonadotropin beta5 (CGB5) and its association with pregnancy success.

Publications

Methylation allelic polymorphism (MAP) in chorionic gonadotropin beta5 (CGB5) and its association with pregnancy success.

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