Analgesic effect of paracetamol monotherapy vs. the combination of paracetamol/parecoxib vs. the combination of pethidine/paracetamol in patients undergoing thyroidectomy.

INTRODUCTION: The purpose of this study was to investigate the analgesic effect of 3 different regimens of combination analgesics administered to patients undergoing thyroidectomy. MATERIAL AND METHODS: A total of 152 patients undergoing total or subtotal thyroidectomy were enrolled. Patients allocated to group A received a combination of intravenous (IV) paracetamol and intramuscular (IM) pethidine, patients in group B received a combination of IV paracetamol and IV parecoxib, while patients in group C received IV paracetamol monotherapy. RESULTS: The analgesic regimens of groups A and B were found to be of equivalent efficacy (p-value = 1.000). In contrast, patients in group C (paracetamol monotherapy) had higher numerical rating scale scores, compared to both patients in groups A (p-value < 0.001) and B (p-value < 0.001). CONCLUSIONS: The combinations of IV paracetamol with either IM pethidine or IV parecoxib are superior to IV paracetamol monotherapy in achieving pain control in patients undergoing thyroid surgery.

LRF/ZBTB7A conservation accentuates its potential as a therapeutic target for the hematopoietic disorders.

Conserved sequences across species have always provided valuable insights to improve our understanding on the human genome's entity and the interplay among different loci. Lymphoma/leukemia related factor (LRF) is encoded by ZBTB7A gene and belongs to an evolutionarily conserved family of transcription factors, implicated in vital cellular functions. The present data, demonstrating the wide-spread and the high overlap of the LRF/ZBTB7A recognition sites with genomic segments identified as CpG islands in the human genome, suggest that its binding capacity strongly depends on a specific sequence-encoded feature within CpGs. We have previously shown that de-methylation of the CpG island 326 lying in the ZBTB7A gene promoter is associated with impaired pharmacological induction of fetal hemoglobin in ß-type hemoglobinopathies patients. Within this context we aimed to investigate the extent of the LRF/ZBTB7A conservation among primates and mouse genome, focusing our interest also on the CpG island flanking the gene's promoter region, in an effort to further establish its epigenetic regulatory role in human hematopoiesis and pharmacological involvement in hematopoietic disorders. Comparative analysis of the human ZBTB7A nucleotide and amino acid sequences and orthologous sequences among non-human primates and mouse, exhibited high conservation scores. Pathway analysis, clearly indicated that LRF/ZBTB7A influences conserved cellular processes. These data in conjunction with the high levels of expression foremost in hematopoietic tissues, highlighted LRF/ZBTB7A as an essential factor operating indisputably during hematopoiesis.

The multi-faceted functioning portrait of LRF/ZBTB7A.

Transcription factors (TFs) consisting of zinc fingers combined with BTB (for broad-complex, tram-track, and bric-a-brac) domain (ZBTB) are a highly conserved protein family that comprises a multifunctional and heterogeneous group of TFs, mainly modulating cell developmental events and cell fate. LRF/ZBTB7A, in particular, is reported to be implicated in a wide variety of physiological and cancer-related cell events. These physiological processes include regulation of erythrocyte maturation, B/T cell differentiation, adipogenesis, and thymic insulin expression affecting consequently insulin self-tolerance. In cancer, LRF/ZBTB7A has been reported to act either as oncogenic or as oncosuppressive factor by affecting specific cell processes (proliferation, apoptosis, invasion, migration, metastasis, etc) in opposed ways, depending on cancer type and molecular interactions. The molecular mechanisms via which LRF/ZBTB7A is known to exert either physiological or cancer-related cellular effects include chromatin organization and remodeling, regulation of the Notch signaling axis, cellular response to DNA damage stimulus, epigenetic-dependent regulation of transcription, regulation of the expression and activity of NF-κB and p53, and regulation of aerobic glycolysis and oxidative phosphorylation (Warburg effect). It is a pleiotropic TF, and thus, alterations to its expression status become detrimental for cell survival. This review summarizes its implication in different cellular activities and the commonly invoked molecular mechanisms triggered by LRF/ZBTB7A's orchestrated action.

Genomic variants in members of the Krüppel-like factor gene family are associated with disease severity and hydroxyurea treatment efficacy in ß-hemoglobinopathies patients.

Aim: ß-Type hemoglobinopathies are characterized by vast phenotypic diversity as far as disease severity is concerned, while differences have also been observed in hydroxyurea (HU) treatment efficacy. These differences are partly attributed to the residual expression of fetal hemoglobin (HbF) in adulthood. The Krüppel-like family of transcription factors (KLFs) are a set of zinc finger DNA-binding proteins which play a major role in HbF regulation. Here, we explored the possible association of variants in KLF gene family members with response to HU treatment efficacy and disease severity in ß-hemoglobinopathies patients. Materials & methods: Six tag single nucleotide polymorphisms, located in four KLF genes, namely KLF3, KLF4, KLF9 and KLF10, were analyzed in 110 ß-thalassemia major patients (TDT), 18 nontransfusion dependent ß-thalassemia patients (NTDT), 82 sickle cell disease/ß-thalassemia compound heterozygous patients and 85 healthy individuals as controls. Results: Our findings show that a KLF4 genomic variant (rs2236599) is associated with HU treatment efficacy in sickle cell disease/ß-thalassemia compound heterozygous patients and two KLF10 genomic variants (rs980112, rs3191333) are associated with persistent HbF levels in NTDT patients. Conclusion: Our findings provide evidence that genomic variants located in KLF10 gene may be considered as potential prognostic biomarkers of ß-thalassemia clinical severity and an additional variant in KLF4 gene as a pharmacogenomic biomarker, predicting response to HU treatment.

Role of Genomic Biomarkers in Increasing Fetal Hemoglobin Levels Upon Hydroxyurea Therapy and in ß-Thalassemia Intermedia: A Validation Cohort Study.

Hemoglobinopathies exhibit a remarkable phenotypic diversity in terms of disease severity, while individual genetic background plays a key role in differential response to drug treatment. In the last decade, genomic variants in genes located within, as well as outside the human ß-globin cluster have been shown to be significantly associated with Hb F increase, in relation to hydroxyurea (HU) therapy in patients with these diseases. Here, we aim to determine the effect of genomic variants located in genes, such as MAP3K5, ASS1, NOS2A, TOX, PDE7B, NOS1, FLT1 and ARG2, previously shown to modulate fetal hemoglobin (Hb F) levels in patients with ß type hemoglobinopathies and reflecting disease severity and response to HU therapy in an independent cohort of Greek patients with these diseases. We recruited and genotyped 45 ß-thalassemia patients (ß-thal), either transfusion-dependent (TDT) or non transfusion-dependent (NTDT), 42 Hb S (HBB: c.20A>T)-ß-thal compound heterozygotes, who were treated with HU, as well as 53 healthy individuals, all of Hellenic origin. Our study showed that genomic variants of the MAP3K5, NOS2A and ARG2 gene are associated with HU therapy efficacy in Hb S-ß-thal compound heterozygotes. We have also shown that FLT1 and ARG2 genomic variants are associated with the mild phenotype of NTDT patients. Our findings provide evidence that MAP3K5, NOS2A, ARG2 and FLT1 genomic variants could be considered as genomic biomarkers to predict HU therapy efficacy in Hb S-ß-thal compound heterozygotes and also to describe disease severity in patients with ß type hemoglobinopathies.

Impact of ZBTB7A hypomethylation and expression patterns on treatment response to hydroxyurea.

BACKGROUND: We aimed to clarify the emerging epigenetic landscape in a group of genes classified as "modifier genes" of the ß-type globin genes (HBB cluster), known to operate in trans to accomplish the two natural developmental switches in globin expression, from embryonic to fetal during the first trimester of conception and from fetal to adult around the time of birth. The epigenetic alterations were determined in adult sickle cell anemia (SCA) homozygotes and SCA/ß-thalassemia compound heterozygotes of Greek origin, who are under hydroxyurea (HU) treatment. Patients were distinguished in HU responders and HU non-responders (those not benefited from the HU) and both, and in vivo and in vitro approaches were implemented. RESULTS: We examined the CpG islands' DNA methylation profile of BCL11A, KLF1, MYB, MAP3K5, SIN3A, ZBTB7A, and GATA2, along with γ-globin and LRF/ZBTB7A expression levels. In vitro treatment of hematopoietic stem cells (HSCs) with HU induced a significant DNA hypomethylation pattern in ZBTB7A (p*, 0.04) and GATA2 (p*, 0.03) CpGs exclusively in the HU non-responders. Also, this group of patients exhibited significantly elevated baseline methylation patterns in ZBTB7A, before the HU treatment, compared to HU responders (p*, 0.019) and to control group of healthy individuals (p*, 0.021), which resembles a potential epigenetic barrier for the γ-globin expression. γ-Globin expression in vitro matched with detected HbF levels during patients' monitoring tests (in vivo) under HU treatment, implying a good reproducibility of the in vitro HU epigenetic effect. LRF/ZBTB7A expression was elevated only in the HU non-responders under the influence of HU. CONCLUSIONS: This is one of the very first pharmacoepigenomic studies indicating that the hypomethylation of ZBTB7A during HU treatment enhances the LRF expression, which by its turn suppresses the HbF resumption in the HU non-responders. Its role as an epigenetic regulator of hemoglobin switching is also supported by the wide distribution of ZBTB7A-binding sites within the 5' CpG sequences of all studied human HBB cluster "modifier genes." Also, the baseline methylation level of selective CpGs in ZBTB7A and GATA2 could be an indicator of the negative HU response among the ß-type hemoglobinopathy patients.

Whole transcriptome analysis of human erythropoietic cells during ontogenesis suggests a role of VEGFA gene as modulator of fetal hemoglobin and pharmacogenomic biomarker of treatment response to hydroxyurea in ß-type hemoglobinopathy patients.

BACKGROUND: Human erythropoiesis is characterized by distinct gene expression profiles at various developmental stages. Previous studies suggest that fetal-to-adult hemoglobin switch is regulated by a complex mechanism, in which many key players still remain unknown. Here, we report our findings from whole transcriptome analysis of erythroid cells, isolated from erythroid tissues at various developmental stages in an effort to identify distinct molecular signatures of each erythroid tissue. RESULTS: From our in-depth data analysis, pathway analysis, and text mining, we opted to focus on the VEGFA gene, given its gene expression characteristics. Selected VEGFA genomic variants, identified through linkage disequilibrium analysis, were explored further for their association with elevated fetal hemoglobin levels in ß-type hemoglobinopathy patients. Our downstream analysis of non-transfusion-dependent ß-thalassemia patients, ß-thalassemia major patients, compound heterozygous sickle cell disease/ß-thalassemia patients receiving hydroxyurea as fetal hemoglobin augmentation treatment, and non-thalassemic individuals indicated that VEGFA genomic variants were associated with disease severity in ß-thalassemia patients and hydroxyurea treatment efficacy in SCD/ß-thalassemia compound heterozygous patients. CONCLUSIONS: Our findings suggest that VEGFA may act as a modifier gene of human globin gene expression and, at the same time, serve as a genomic biomarker in ß-type hemoglobinopathy disease severity and hydroxyurea treatment efficacy.

Key Pharmacogenomic Considerations for Sickle Cell Disease Patients.

Sickle cell disease (SCD), although a monogenic disease, exhibits a complex clinical phenotype that hampers optimum patient stratification and disease management, especially on hydroxyurea treatment. Moreover, theranostics, the combination of diagnostics to individualize and optimize therapeutic interventions, has not been firmly on the forefront of SCD research and clinical management to date. We suggest that if tailor-made theranostics in SCD is envisaged, pharmacogenomics is anticipated to be the way forward. Herein, we present the current key pharmacogenomic opportunities and challenges in SCD, considering population variation, ethics, and socioeconomic aspects. We focus on pharmacogenomics and pain management, genethics, and cost-effectiveness in SCD. We searched for and synthesized data from PubMed and Google Scholar, and the references from relevant articles, using the keywords "pharmacogenomics," "sickle cell disease," "hydroxyurea," "ethics," "pain management," "morphine metabolism," "opioids," "pharmacogenomics and chronic pain," "cost-effectiveness," and "economic evaluation." Only articles published in English were included. So far, when pharmacogenomics in SCD has been considered, interindividual variability in hydroxyurea response/toxicity has been of primary interest. We underscore the need to extend pharmacogenomic considerations on other therapeutic interventions currently present using a holistic patient-centric approach, and taking disease complications into account as well. Furthermore, we raise awareness toward socioeconomic, ethical, and population differences in the way sickle cell pharmacogenomics might unfold in the future. If pharmacogenomics in SCD is to be used in the clinic in an evidence-based manner, cost-effectiveness and population-specific empirical ethics data are urgently needed.

Correlation of SIN3A genomic variants with ß-hemoglobinopathies disease severity and hydroxyurea treatment efficacy.

AIMS: Hemoglobinopathies, particularly ß-thalassemia and sickle cell disease, are characterized by great phenotypic variability in terms of disease severity, while notable differences have been observed in hydroxyurea treatment efficacy. In both cases, the observed phenotypic diversity is mostly dependent on the elevated fetal hemoglobin levels, resulting from the persistent fetal globin gene expression in the adult erythroid stage orchestrated by intricate mechanisms that still remain only partly understood. We have previously shown that several protein factors act as modifiers of fetal hemoglobin production, exerting their effect via different pathways. MATERIALS & METHODS: Here, we explored whether SIN3A could act as a modifier of fetal globin gene expression, as it interacts with KLF10, a known modifier of fetal hemoglobin production. RESULTS: We show that SIN3A genomic variants are associated both with ß-thalassemia disease severity (rs11072544) as well as hydroxyurea treatment response (rs7166737) in ß-hemoglobinopathies patients. CONCLUSION: Our findings further underline that fetal hemoglobin production is the result of a complex interplay in which several human globin gene cluster variants interact with protein factors encoded by modifier genes to produce the observed clinical outcome.

Genomic variants in the ASS1 gene, involved in the nitric oxide biosynthesis and signaling pathway, predict hydroxyurea treatment efficacy in compound sickle cell disease/ß-thalassemia patients.

AIM: Hemoglobinopathies exhibit a remarkable phenotypic diversity that restricts any safe association between molecular pathology and clinical outcomes. PATIENTS & METHODS: Herein, we explored the role of genes involved in the nitric oxide biosynthesis and signaling pathway, implicated in the increase of fetal hemoglobin levels and response to hydroxyurea treatment, in 119 Hellenic patients with ß-type hemoglobinopathies. RESULTS: We show that two ASS1 genomic variants (namely, rs10901080 and rs10793902) can serve as pharmacogenomic biomarkers to predict hydroxyurea treatment efficacy in sickle cell disease/ß-thalassemia compound heterozygous patients. CONCLUSION: These markers may exert their effect by inducing nitric oxide biosynthesis, either via altering splicing and/or miRNA binding, as predicted by in silico analysis, and ultimately, increase γ-globin levels, via guanylyl cyclase targeting.

Individualizing fetal hemoglobin augmenting therapy for ß-type hemoglobinopathies patients.

Individual genetic composition is an important cause of variations in the response and tolerance to drug treatment. Pharmacogenomics is a modern discipline aiming to delineate individual genomic profiles and drug response. To date, there are several medical disciplines where pharmacogenomics is readily applicable, while in others its usefulness is yet to be demonstrated. Recent experimental evidence suggest that besides genomic variation within the human ß-globin gene cluster, other variants in modifier genes residing outside the human ß-globin gene cluster are significantly associated with response to hydroxyurea treatment in ß-type hemoglobinopathies patients, deducted from the increase in fetal hemoglobin levels. This article aims to provide an update and to discuss future challenges on the application of pharmacogenomics for ß-type hemoglobinopathies therapeutics in relation to the current pharmacological treatment modalities for those disorders.

Genomic variation in the MAP3K5 gene is associated with ß-thalassemia disease severity and hydroxyurea treatment efficacy.

AIM: In this study we explored the association between genetic variations in MAP3K5 and PDE7B genes, residing on chromosome 6q23, and disease severity in ß-hemoglobinopathy patients, as well as the association between these variants with response to hydroxyurea (HU) treatment. Furthermore, we examined MAP3K5 expression in the context of high fetal hemoglobin (HbF) and upon HU treatment in erythroid progenitor cells from healthy and KLF1 haploinsufficient individuals. MATERIALS & METHODS: For this purpose, we genotyped ß-thalassemia intermedia and major patients and healthy controls, as well as a cohort of compound heterozygous sickle cell disease/ß-thalassemia patients receiving HU as HbF augmentation treatment. Furthermore, we examined MAP3K5 expression in the context of high HbF and upon HU treatment in erythroid progenitor cells from healthy and KLF1 haploinsufficient individuals. RESULTS: A short tandem repeat in the MAP3K5 promoter and two intronic MAP3K5 gene variants, as well as a PDE7B variant, are associated with low HbF levels and a severe disease phenotype. Moreover, MAP3K5 mRNA expression levels are altered in the context of high HbF and are affected by the presence of HU. Lastly, the abovementioned MAP3K5 variants are associated with HU treatment efficacy. CONCLUSION: Our data suggest that these MAP3K5 variants are indicative of ß-thalassemia disease severity and response to HU treatment.

Association of genome variations in the renin-angiotensin system with physical performance.

BACKGROUND: The aim of this study was to determine the genotype distribution and allelic frequencies of ACE (I/D), AGTR1 (A +1166 C), BDKRB2 (+9/-9) and LEP (G-2548A) genomic variations in 175 Greek athletes who excelled at a national and/or international level and 169 healthy Greek adults to identify whether some particular combinations of these loci might serve as predictive markers for superior physical condition. RESULTS: The D/D genotype of the ACE gene (p = 0.034) combined with the simultaneous existence of BDKRB2 (+9/-9) (p = 0.001) or LEP (G/A) (p = 0.021) genotypes was the most prevalent among female athletes compared to female controls. A statistical trend was also observed in BDKRB2 (+9/-9) and LEP (G-2548A) heterozygous genotypes among male and female Greek athletes, and in ACE (I/D) only in male athletes. Finally, both male and female athletes showed the highest rates in the AGTR1 (A/A) genotype. CONCLUSIONS: Our results suggest that the co-existence of ACE (D/D), BDKRB2 (+9/-9) or LEP (G/A) genotypes in female athletes might be correlated with a superior level of physical performance.

KLF10 gene expression is associated with high fetal hemoglobin levels and with response to hydroxyurea treatment in ß-hemoglobinopathy patients.

AIM: In humans, fetal hemoglobin (HbF) production is controlled by many intricate mechanisms that, to date, remain only partly understood. PATIENTS & METHODS: Pharmacogenomic analysis of the effects of hydroxyurea (HU) on HbF production was undertaken in a collection of Hellenic ß-thalassemia and sickle cell disease (SCD) compound heterozygotes and a collection of healthy and KLF1-haploinsufficient Maltese adults, to identify genomic signatures that follow high HbF patterns. RESULTS: KLF10 emerged as a top candidate. Moreover, genotype analysis of ß-thalassemia major and intermedia patients and an independent cohort of ß-thalassemia/SCD compound heterozygous patients that do or do not respond to HU treatment showed that the homozygous mutant state of a tagSNP in the KLF10 3'UTR is not present in ß-thalassemia intermedia patients and is underrepresented in ß-thalassemia/SCD compound heterozygous patients that respond well to HU treatment. CONCLUSION: These data suggest that KLF10 may constitute a pharmacogenomic marker to discriminate between response and nonresponse to HU treatment.

A single nucleotide polymorphism in the HBBP1 gene in the human ß-globin locus is associated with a mild ß-thalassemia disease phenotype.

The rs2071348 (g.5264146A>C) polymorphism on the HBB pseudogene, namely HBBP1, previously emerged as a variant significantly associated with a milder disease phenotype in Asian ß(0)-thalassemia/hemoglobin (Hb) E (ß(0)-thal/Hb E [ß26(B8)Glu→Lys, GAG>AAG]) patients. In this study, we aimed to explore the possible association of rs2071348 with ß-thalassemia (ß-thal) disease severity in a group of ß-thal major (ß-TM) patients (severe phenotype) and ß-thal intermedia (ß-TI) patients (mild phenotype) of Hellenic origin and compare the results with normal (non thalassemic) individuals of the same origin. In addition, we explored whether this single nucleotide polymorphism (SNP) can be exploited as a pharmacogenomic marker to predict the outcome of Hb F-augmenting therapy in ß-thal patients receiving hydroxyurea (HU). Our data suggest that the rs2071348 polymorphism is associated with higher Hb F levels and a milder ß-thal disease phenotype. However, the rs2071348 polymorphism in the HBBP1 gene does not correlate with response to HU treatment.

Identical mutations in the paralogous human γ-globin genes leading to hemoglobin variants and nondeletional hereditary persistence of fetal hemoglobin.

The human fetal globin genes are highly similar at the DNA sequence level, resulting in a single amino acid difference between the (G)γ- and (A)γ-globin chains. A large proportion of hemoglobin (Hb) variants of the (G)γ- and (A)γ-globin chains result from an identical mutation in the HBG2 and HBG1 genes, respectively, while the same is true for a fraction of mutations leading to nondeletional hereditary persistence of fetal Hb (HPFH). In particular, 11 different Hb variants result from identical mutations on either one of the two human γ-globin paralogous genes, while seven other promoter substitutions result either in nondeletional HPFH or are benign polymorphisms. In the former case, the percentage of the Hb variants due to an HBG2 gene mutation was significantly higher than the percentage of Hb variants due to the same HBG1 gene mutation, following the (G)γ/(A)γ-globin chain ratio seen in wild-type individuals. These γ-globin chain variants have most likely occurred via recurrent mutations, gene conversion events or both and, contrary to the situation observed in the human α-globin genes, these mutations lead to distinct variant Hb molecules.

Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach.

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases.

First report of Hb A2-NYU (HBD:c.39T>A) in the Hellenic population.

We report the first heterozygous case of Hb A(2)-NYU (HBD:c.39T>A) in the Hellenic population. The proband, an adult female from the island of Crete, Greece, was identified during routine family screening. DEAE chromatography of the index case revealed a minor hemoglobin (Hb) fraction preceding the elution of the wild-type Hb A(2). DNA sequencing of the entire HBD gene coding regions indicated that the index case was heterozygous for the rare variant Hb A(2)-NYU. Family studies indicated that this Hb variant was inherited from the mother. This finding underlines the vast genetic heterogeneity of the HBD gene in the Hellenic population.

Region-specific genetic heterogeneity of HBB mutation distribution in South-Western Greece.

beta-Thalassemia (beta-thal), is caused by reduced or absent synthesis of beta-globin chains resulting in impaired erythropoiesis. It is the most common single gene defect disease in Greece, with heterozygous rates reaching, on average, 8% in the general population. Here, we performed molecular analyses on 199 unrelated beta-thal and compound beta-thal/sickle cell disease patients, of whom 157 originated from three prefectures of South-Western Greece, namely Achaia, Ilia and Etoloakarnania. Our results indicate that the frequency of specific HBB gene mutations, namely the HBB:c.118C>T (codon 39, C>T), HBB:c.92+6T>C (IVS-I-6, T>C), and HBB:c.20A>T [Hb S, beta6(A3)Glu-->Val, GAG>GTG], present distinct distribution patterns in the Achaia and Ilia prefectures (p < 0.001, p < 0.003 and p < 0.002, respectively). This detailed analysis of the distribution of the HBB gene mutations is useful for genetic counseling in the region, and illustrates that the identification of the HBB gene mutation spectrum in this region is necessary for population carrier screening and for efficient provision of prenatal diagnosis.

Allelic imbalance of expression and epigenetic regulation within the alpha-synuclein wild-type and p.Ala53Thr alleles in Parkinson disease.

Genetic alterations in the alpha-synuclein (SNCA) gene have been implicated in Parkinson Disease (PD), including point mutations, gene multiplications, and sequence variations within the promoter. Such alterations may be involved in pathology through structural changes or overexpression of the protein leading to protein aggregation, as well as through impaired gene expression. It is, therefore, of importance to specify the parameters that regulate SNCA expression in its normal and mutated state. We studied the expression of SNCA alleles in a lymphoblastoid cell line and in the blood cells of a patient heterozygous for p.Ala53Thr, the first mutation to be implicated in PD pathogenesis. Here, we provide evidence that: (1) SNCA shows monoallelic expression in this patient, (2) epigenetic silencing of the mutated allele involves histone modifications but not DNA methylation, and (3) steady-state mRNA levels deriving from the normal SNCA allele in this patient exceed those of the two normal SNCA alleles combined, in matching, control individuals. An imbalanced SNCA expression in this patient is thus documented, with silencing of the p.Ala53Thr allele and upregulation of the wild-type-allele. This phenomenon is demonstrated for a first time in the SNCA gene, and may have important implications for PD pathogenesis.