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- ÍtemAcceso Abierto
Creating and validating a warfarin pharmacogenetic dosing algorithm for colombian patients(2018) Galvez, Jubby Marcela; Restrepo Fernández, Carlos Martín; Contreras Bravo, Nora Constanza; Alvarado, Clara; Calderón Ospina, Carlos Alberto; Peña, Nidia; Cifuentes, Ricardo A; Duarte, Daniela; Laissue, Paul; Fonseca Mendoza, Dora JanethPurpose: Warfarin is an oral anticoagulant associated with adverse reaction to drugs due to wide inter-and intra-individual dosage variability. Warfarin dosage has been related to non-genetic and genetic factors. CYP2C9 and VKORC1 gene polymorphisms affect warfarin metabolism and dosage. Due to the central role of populations’ ethnical and genetic origin on warfarin dosage variability, novel algorithms for Latin American subgroups are necessary to establish safe anticoagulation therapy. Patients and methods: We genotyped CYP2C9*2 (c.430C and gt; T), CYP2C9*3 (c.1075A and gt; C), CYP4F2 (c.1297G and gt; A), and VKORC1 (-1639 G and gt; A) polymorphisms in 152 Colombian patients who received warfarin. We evaluated the impact on the variability of patients’ warfarin dose requirements. Multiple linear regression analysis, using genetic and non-genetic variables, was used for creating an algorithm for optimal warfarin maintenance dose. Results: Median weekly prescribed warfarin dosage was significantly lower in patients having the VKORC1-1639 AA genotype and poor CYP2C9*2/*2,*2/*3 metabolizers than their wild-type counterparts. We found a 2.3-fold increase in mean dose for normal sensitivity patients (wild-type VKORC1/CYP2C9 genotypes) compared to the other groups (moderate and high sensitivity); 31.5% of the patients in our study group had warfarin sensitivity-related genotypes. The estimated regression equation accounted for 44.4% of overall variability in regard to warfarin maintenance dose. The algorithm was validated, giving 45.9% correlation (R 2 =0.459). Conclusion: Our results describe and validate the first algorithm for predicting warfarin maintenance in a Colombian mestizo population and have contributed toward the understanding of pharmacogenetics in a Latin American population subgroup. © 2018 Galvez et al. - ÍtemAcceso AbiertoCITED2 mutations potentially cause idiopathic premature ovarian failure(2012) Fonseca Mendoza, Dora Janeth; Ojeda, Diego; Lakhal, Besma; Braham, Rim; Eggers, Stefanie; Turbitt, Erin; White, Stefan; Grover, Sonia; Warne, Garry; Zacharin, Margaret; Lam, Alexandra Nevin; Landolsi, Hanène; Elghezal, Hatem; Saâd, Ali; Restrepo Fernández, Carlos Martín; Fellous, Marc; Sinclair, Andrew; Koopman, Peter; Laissue, PaulAnomalies in gonadal development in a mouse knockout model of Cited2 have been recently described. In Cited2 -/- female gonads, an ectopic cell migration was observed and the female program of sex determination was transiently delayed. We hypothesize that, in humans, this temporary inhibition of genes should be sufficient to provoke a developmental impairment of the female gonads, conducive to premature ovarian failure (POF). To establish whether CITED2 mutations are a common cause of the disease, we performed a mutational analysis of this gene in a panel of patients with POF and in a group of control women with normal fertility. We amplified and directly sequenced the complete open reading frame of CITED2 in 139 patients with POF and 290 controls. This study revealed 5 synonymous and 3 nonsynonymous variants. Among these, 7 are novel. The nonsynonymous variant c.604C and gt;A (p.Pro202Thr) was found uniquely in 1 woman from the POF group. In silico analysis of this mutation indicated a potential deleterious effect. We conclude that mutations in CITED2 may be involved in POF pathogenesis. © 2012 Mosby, Inc. All rights reserved.
- ÍtemAcceso AbiertoSequence analysis of the ADRA2A coding region in children affected by attention deficit hyperactivity disorder(2013) Castro, Taryn; Mateus, Heidi Eliana; Fonseca Mendoza, Dora Janeth; Forero, Diego; Restrepo Fernández, Carlos Martín; Talero Gutiérrez, Claudia; Vélez van Meerbeke, Alberto Francisco; Laissue, PaulAttention deficit hyperactivity disorder (ADHD) is a common neurobehavioral pathology characterized by distinct degrees of inattention, hyperactivity and impulsivity. Although ADHD etiology remains elusive, the ADRA2A candidate gene underlies a particular interest, since it participates in the prefrontal cortex regulation of executive function. Three SNPs located on 5? and 3?UTR regions of the gene have been extensively explored but none of them have been definitely validated as a predisposition or a causative sequence variation. In this study, in order to determine whether ADRA2A non-synonymous sequence variants, resulting in biochemical modifications of the protein, are a common cause of the disease we sequenced the complete ADRA2A coding region in a panel of ADHD children of Colombian origin. We identified the c.1138 C>A (p.Arg380Arg) silent substitution. We conclude that ADRA2A non-synonymous sequence variants do not cause ADHD in our sample population. We cannot formerly discard a potential role of this gene during ADHD pathogenesis since only the coding region was analysed. We hope that these results will encourage further researchers to sequence the promoter and coding regions of ADRA2A in large panels of ADHD patients from distinct ethnical origins. © 2013 Springer-Verlag Italia.
- ÍtemAcceso AbiertoCarrier frequency of F508del mutation of cystic fibrosis in medical students from Universidad del Rosario, Bogotá, Colombia(2007) Mateus H.E.; Fonseca Mendoza, Dora Janeth; Sanchez L.S.; Peñaloza I.F.; Forero D.V.; Perdomo P.A.; Quiasua D.C.; Ramírez A.; Montoya L.C.; Pérez L.A.; Amado H.P.; Molano J.A.; Amaya S.A.; Duran M.H.; Cárdenas V.C.; Guevara K.; Parga D.A.; Esparrogosa C.L.Introduction: Cystic fibrosis (CF) is the most frequent autosomical recessive disorder in Caucasian population with an incidence of in 2000 newborns. The disease is caused by mutations in the cfr gene, but the most common mutation is F508del, which accounts for 66% of CF chromosomes worldwide and a carrier frequency for Caucasian population of 1 in 25. Objective: To determine the carrier frequency of the F508del mutation in 110 unrelated, healthy students from the Facultad de Medicina, Universidad del Rosario. Methods. The presence of F508del mutation using PCR and heteroduplex analysis was determined. Results: Only four heterozygotes for F508del mutation were discovered. This represents a carrier frequency of 1 in 27 students. Conclusions: This estimated frequency of F508del carriers is higher than expected, encouraging further'screening in normal control individuals from different regions of Colombia. © 2007 Corporación Editora Médica del Valle.
ÍtemSolo MetadatosTranscriptomic analysis of FUCA1 knock-down in keratinocytes reveals new insights into the pathogenesis of fucosidosis skin lesions(2018) Valero-Rubio D.; Jiménez K.M.; Fonseca Mendoza, Dora Janeth; Payan-Gomez, Cesar; Laissue P.Fucosidosis is a rare lysosomal storage disease which has been classified into two subtypes, depending on the severity of clinical signs and symptoms. Fucosidosis patients’ skin abnormalities include angiokeratoma corporis diffusum, widespread telangiectasia, thick skin, hyperhidrosis and hypohidrosis, acrocyanosis and distal transverse nail bands. It has been described that >50% of fucosidosis patients have angiokeratoma. At molecular level, fucosidosis is caused by lysosomal alpha-L-fucosidase (FUCA1) gene mutations. Obtaining samples for functional studies has been challenging due to the inherent difficulty in finding affected individuals. The effect of FUCA1 dysfunction on gene expression is unknown. The aim of this study was to analyse, in keratinocytes, the transcriptomic effect of FUCA1 knock-down for a better understanding of skin lesions’ pathogenesis affecting fucosidosis patients. FUCA1 knock-down (siRNA) was performed in human HaCaT immortalised keratinocytes. Affymetrix arrays and qPCR were used for analysing gene expression. Bioinformatics was used for functional clustering of modified genes. In total, 387 genes showed differential expression between FUCA1 silenced and non-silenced cells (222 up-regulated and 165 down-regulated). Up-regulated genes belonged to two major groups: keratinocyte differentiation/epidermal development (n = 17) and immune response (n = 61). Several transcription factors were up-regulated in FUCA1-siRNA transfected cells. This effect might partly have been produced by abnormal transcription factor expression, that is FOXN1. We thus propose that fucosidosis-related skin lesions (eg angiokeratoma) and those of other diseases (eg psoriasis) might be caused by dysfunctions in common aetiological overlapping molecular cascades. © 2018 John Wiley and Sons A/S. Published by John Wiley and Sons Ltd- ÍtemSolo MetadatosEvidence of association between SNAP25 gene and attention deficit hyperactivity disorder in a Latin American sample(2014) Gálvez, Jubby M.; Garzon-Forero, Diego A; Fonseca Mendoza, Dora Janeth; Mateus, Heidi E.; Talero Gutiérrez, Claudia; Vélez van Meerbeke, Alberto FranciscoAttention deficit hyperactivity disorder (ADHD) is one of the most highly heritable behavioral disorders in childhood, with heritability estimates between 60 and 90 %. Family, twin and adoption studies have indicated a strong genetic component in the susceptibility to ADHD. The synaptosomal-associated protein of molecular weight 25 kDa (SNAP25) is a plasma membrane protein known to be involved in synaptic and neural plasticity. Animal model studies have shown that SNAP25 gene is responsible for hyperkinetic behavior in the coloboma mouse. In recent studies, several authors reported an association between SNAP25 and ADHD. In this study, we used a case-control approach to analyze the possible association of two polymorphisms of SNAP25 for possible association with ADHD in a sample of 73 cases and 152 controls in a Colombian children population. Polymorphisms are located in 3? untranslated region of SNAP25, positions T1065G and T1069C. We found a significant association with the GT haplotype (rs3746554{pipe}rs1051312) of SNAP25 (p = 0.001). Evidence of association was also found for the G/G genotype of rs3746554 (p = 0.002) and C/C genotype of rs1051312 (p = 0.009). This is the first study in a Latin American population. Similar to other studies, we found evidence of the association of SNAP25 and ADHD. © 2013 Springer-Verlag Wien.
- ÍtemAcceso AbiertoLack of association of polymorphisms in six candidate genes in Colombian adhd patients(2015) Fonseca Mendoza, Dora Janeth; Mateus, Heidi E; Gálvez, Jubby M; Forero, Diego A; Talero Gutiérrez, Claudia; Vélez van Meerbeke, Alberto FranciscoBackground: Attention Deficit and Hyperactivity Disorder (ADHD) is a common childhood neuropsychiatric condition. The disorder has a multifactorial background, with heritability estimates of around 76%, suggesting an important role of genetic factors. Candidate genes include those related to dopaminergic (e.g. DRD4, DRD5, SLC6A3 and DBH)and serotoninergic (e.g.HTR1B and SLC6A4) pathways. Purpose: To explore the association of common polymorphisms in six genes (DRD4, DRD5, SLC6A3, DBH, HTR1B and SLC6A4) and the susceptibility to ADHD in a Colombian sample population. Methods: Eighty-six ADHD trios and 152 healthy controls were recruited. Genotyping of the six polymorphisms was performed using described PCR-based protocols. A TDT analysis was used to test if there was preferential allelic transmission for any of the six polymorphisms. Additionally, a case-control analysis was performed to test for association of the serotoninergic (HTR1B and SLC6A4) polymorphisms with ADHD. Results: Through the TDT analysis there was no preferential allelic transmission for any of the studied variants. Case-control analysis did not show association. Conclusion: This is the first study in Latin America to describe six polymorphisms in a group of patients with ADHD. There was no evidence of association for any of the studied polymorphic variants in this Colombian ADHD sample. Further research, with larger sample sizes and study of endophenotypes, is needed in this population to confirm and extend the results. © 2015, Indian Academy of Neurosciences. All rights reserved.
- ÍtemAcceso AbiertoSequence analysis of the CDKN1B gene in patients with premature ovarian failure reveals a novel mutation potentially related to the phenotype(2011) Ojeda D.; Lakhal B.; Fonseca Mendoza, Dora Janeth; Braham R.; Landolsi H.; Mateus H.E.; Restrepo Fernández, Carlos Martín; Elghezal H.; Saâd A.; Laissue P.Earlier reports demonstrated a key role of Cdkn1b during mouse ovarian development. In this study, the sequencing analysis of the complete coding region of this gene in a panel of premature ovarian failure patients and control subjects reveals a novel mutation potentially related to the phenotype. © 2011 by American Society for Reproductive Medicine.
- ÍtemSolo MetadatosProstaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis(2012) Diggle, Christine P.; Parry, David A.; Logan, Clare V.; Laissue, Paul; Rivera, Carolina; Restrepo Fernández, Carlos Martín; Fonseca Mendoza, Dora Janeth; Morgan, Joanne E.; Allanore, Yannick; Fontenay, Michaela; Wipff, Julien; Varret, Mathilde; Gibault, Laure; Dalantaeva, Nadezhda; Korbonits, Márta; Zhou, Bowen; Yuan, Gang; Harifi, Ghita; Cefle, Kivanc; Palanduz, Sukru; Akoglu, Hadim; Zwijnenburg, Petra J.; Lichtenbelt, Klaske D.; Aubry?Rozier, Bérengère; Superti?Furga, Andrea; Dallapiccola, Bruno; Accadia, Maria; Brancati, Francesco; Sheridan, Eamonn G.; Taylor, Graham R.; Carr, Ian M.; Johnson, Colin A.; Markham, Alexander F.; Bonthron, David T.Pachydermoperiostosis, or primary hypertrophic osteoarthropathy (PHO), is an inherited multisystem disorder, whose features closely mimic the reactive osteoarthropathy that commonly accompanies neoplastic and inflammatory pathologies. We previously described deficiency of the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD) as a cause of this condition, implicating elevated circulating prostaglandin E2 (PGE2) as causative of PHO, and perhaps also as the principal mediator of secondary HO. However, PHO is genetically heterogeneous. Here, we use whole-exome sequencing to identify recessive mutations of the prostaglandin transporter SLCO2A1, in individuals lacking HPGD mutations. We performed exome sequencing of four probands with severe PHO, followed by conventional mutation analysis of SLCO2A1 in nine others. Biallelic SLCO2A1 mutations were identified in 12 of the 13 families. Affected individuals had elevated urinary PGE2, but unlike HPGD-deficient patients, also excreted considerable quantities of the PGE2 metabolite, PGE-M. Clinical differences between the two groups were also identified, notably that SLCO2A1-deficient individuals have a high frequency of severe anemia due to myelofibrosis. These findings reinforce the key role of systemic or local prostaglandin excess as the stimulus to HO. They also suggest that the induction or maintenance of hematopoietic stem cells by prostaglandin may depend upon transporter activity. © 2012 Wiley Periodicals, Inc.
- ÍtemSolo MetadatosFOXD1 mutations are related to repeated implantation failure, intra-uterine growth restriction and preeclampsia(2019) Quintero-Ronderos, Paula; Jiménez, Karen Marcela; Esteban-Pérez, Clara; Ojeda, Diego A.; Bello, Sandra; Fonseca Mendoza, Dora Janeth; Coronel, María Alejandra; Moreno-Ortiz, Harold; Sierra-Díaz, Diana Carolina; Lucena, Elkin; Barbaux, Sandrine; Vaiman, Daniel; Laissue, PaulBackground: Human reproductive disorders consist of frequently occurring dysfunctions including a broad range of phenotypes affecting fertility and women's health during pregnancy. Several female-related diseases have been associated with hypofertility/infertility phenotypes, such as recurrent pregnancy loss (RPL). Other occurring diseases may be life-threatening for the mother and foetus, such as preeclampsia (PE) and intra-uterine growth restriction (IUGR). FOXD1 was defined as a major molecule involved in embryo implantation in mice and humans by regulating endometrial/placental genes. FOXD1 mutations in human species have been functionally linked to RPL's origin. Methods: FOXD1 gene mutation screening, in 158 patients affected by PE, IUGR, RPL and repeated implantation failure (RIF), by direct sequencing and bioinformatics analysis. Plasmid constructs including FOXD1 mutations were used to perform in vitro gene reporter assays. Results: Nine non-synonymous sequence variants were identified. Functional experiments revealed that p.His267Tyr and p.Arg57del led to disturbances of promoter transcriptional activity (C3 and PlGF genes). The FOXD1 p.Ala356Gly and p.Ile364Met deleterious mutations (previously found in RPL patients) have been identified in the present work in women suffering PE and IUGR. Conclusions: Our results argue in favour of FOXD1 mutations' central role in RPL, RIF, IUGR and PE pathogenesis via C3 and PlGF regulation and they describe, for the first time, a functional link between FOXD1 and implantation/placental diseases. FOXD1 could therefore be used in clinical environments as a molecular biomarker for these diseases in the near future. Recurrent pregnancy loss, Preeclampsia, Intra-uterine growth restriction, FOXD1. © 2019 The Author(s).
