Association between an AMH promoter polymorphism and serum AMH levels in PCOS patients.
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ABSTRACT:
SUBMITTER: Moolhuijsen LME
PROVIDER: S-EPMC9247424 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
Publications
Association between an AMH promoter polymorphism and serum AMH levels in PCOS patients.
Moolhuijsen Loes M E LME Louwers Yvonne V YV McLuskey Anke A Broer Linda L Uitterlinden Andre G AG Verdiesen Renée M G RMG Sisk Ryan K RK Dunaif Andrea A Laven Joop S E JSE Visser Jenny A JA
Human reproduction (Oxford, England) 20220601 7
<h4>Study question</h4>Do polymorphisms in the anti-Müllerian hormone (AMH) promoter have an effect on AMH levels in patients with polycystic ovary syndrome (PCOS)?<h4>Summary answer</h4>We have identified a novel AMH promoter polymorphism rs10406324 that is associated with lower serum AMH levels and is suggested to play a role in the mechanism of regulation of AMH gene expression in women.<h4>What is known already</h4>Follicle number is positively correlated with serum AMH levels, reflected by ...[more]
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Project description:Abstract Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women, is diagnosed based on three criteria, including a polycystic ovarian morphology (PCOM). Although the etiology of PCOS is not fully understood, a genetic component has been demonstrated. Women with PCOS have elevated serum Anti-Müllerian Hormone (AMH) levels, a hormone known to reflect the ovarian reserve. Furthermore, the AMH production per follicle is suggested to be higher in PCOS patients and this combined implies an aberrant regulation of ovarian AMH expression. Currently, some transcription factors, such as FOXL2 and SF1, have been demonstrated to play a role in the ovarian regulation of AMH promoter activity. However, still little is known about AMH gene regulation, particularly in women with PCOS. Hence, the aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) in the AMH promoter on serum AMH levels in a cohort of PCOS patients. A candidate gene association study was conducted. All two-allelic SNPs located in or nearby the AMH promoter (Chr19:2,245,353 – 2,250,827bp) with a minor allele frequency > 1% and an imputation quality r2 threshold above 0.75 were included. We included Caucasian PCOS women, diagnosed based on the Rotterdam criteria. AMH levels were measured with the picoAMH assay (Ansh Labs®, Houston, Texas, USA). The association between SNPs and serum AMH levels was assessed by linear regression with Wald test of significance, allele carrier model analysis with one-way analysis of covariance (ANCOVA). All statistical models were adjusted for age, BMI and total follicle count (TFC). AMH levels were natural log transformed to obtain a normal distribution. A p-value below 8.51e-03 was considered as statistically significant, based on Matrix Spectral Decomposition with an effective number of independent variables (VeffLi) of 6. All analyses were performed using R studio. We assessed 11 SNPs in 700 Caucasian PCOS women. Human AMH promoter polymorphism rs10406324 (-220 A/G) was associated with serum levels of AMH in the linear regression analysis (β = 0.52, p=6.08e-07). This association was also present in the dominant carrier model (AA: 9.85 ng/ml ± 0.27 (n=645) vs AG/GG: 7.60ng/ml ± 0.84 (n=54/n=1), p=6.48e-05, F = 16.2). The association of TFC and the polymorphism rs10406324, corrected for Age, BMI and AMH, showed an inverse trend compared to serum AMH levels (β=-8.00, p=3.75e-03), however this result was not significant in the carrier model (AA: 42.2 ± 0.88 (n=645) vs AG/GG: 43.6 ± 2.41 (n=54/n=1), p=0.60, F = 0.281). Moreover, this SNP was not in LD with any other SNP in the selected region. The human AMH promoter polymorphism rs10406324 is associated with serum AMH levels in Caucasian PCOS women. Replication and functional analyses are necessary to further elucidate the mechanisms by which this SNP affects the AMH promoter activity.
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Project description:ObjectiveTo retrospectively analyze the association of serum estradiol (E2) levels on human chorionic gonadotropin (hCG) trigger day and live birth rates (LBRs) in women undergoing fresh embryo transfer and not exhibiting polycystic ovary syndrome.DesignRetrospective cohort study.MethodsAnalysis of 13,950 patients who had fresh embryo transfer between December 2013 and December 2019. The main outcome measurement was LBRs. Multivariable regression analysis was performed to investigate associations between E2 levels on the hCG trigger day and LBRs. Stratification analysis was performed to test for effect modification in subgroups. Furthermore, a two-piecewise linear regression model was established to find nonlinear relationships.ResultsMultivariable regression analysis showed a significant association between serum E2 levels on the hCG trigger day and LBRs, adjusting for covariates [relative risk (RR) 1.027, 95% confidence interval (CI) 1.007, 1.049]. Stratification analysis showed that the LBRs were positively associated (RR 1.052, 95% CI 1.004, 1.102) with every 1 ng/ml increase of serum E2 on the hCG trigger day for the subgroup with low antral follicle counts on the trigger day. Specifically, a two-piecewise linear regression model showed that there was a positive association (RR 1.188, 95% CI 1.057, 1.334) between serum E2 and LBR for every increase of 1 ng/ml E2 when the concentration of serum E2 was lower than 2.1 ng/ml. However, there was no significant association (RR 1.002, 95% CI 0.971, 1.032) between E2 levels and LBRs when the concentration of E2 was higher than the 2.1ng/ml inflection point.ConclusionsSerum E2 levels on the hCG trigger day were segmentally connected with LBRs.
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Project description:Anti-Müllerian hormone (AMH) is an essential messenger of sexual differentiation in the foetus and is an emerging biomarker of postnatal reproductive function in females. Due to a paucity of adequately sized studies, the genetic determinants of circulating AMH levels are poorly characterized. In samples from 2815 adolescents aged 15 from the ALSPAC study, we performed the first genome-wide association study of serum AMH levels across a set of ∼9 m '1000 Genomes Reference Panel' imputed genetic variants. Genetic variants at the AMH protein-coding gene showed considerable allelic heterogeneity, with both common variants [rs4807216 (P(Male) = 2 × 10(-49), Beta: ∼0.9 SDs per allele), rs8112524 (P(Male) = 3 × 10(-8), Beta: ∼0.25)] and low-frequency variants [rs2385821 (P(Male) = 6 × 10(-31), Beta: ∼1.2, frequency 3.6%)] independently associated with apparently large effect sizes in males, but not females. For all three SNPs, we highlight mechanistic links to AMH gene function and demonstrate highly significant sex interactions (P(Het) 0.0003-6.3 × 10(-12)), culminating in contrasting estimates of trait variance explained (24.5% in males versus 0.8% in females). Using these SNPs as a genetic proxy for AMH levels, we found no evidence in additional datasets to support a biological role for AMH in complex traits and diseases in men.
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