Association of CYP2C19*2 polymorphism with clopidogrel resistance among patients with high cardiovascular risk in Northeastern Mexico / Asociación del polimorfismo CYP2C19*2 con resistencia a clopidogrel en pacientes con alto riesgo cardiovascular en el noreste de México

abstract Objective: Oral antiplatelet drugs are a key to modern pharmacotherapy in cardiovascular atherothrombotic diseases. Clopidogrel (CLO) constitutes the main preventive treatment of atherothrombosis. However, a considerable inter-individual variation in CLO response has been documented, resulting in suboptimal therapy and an increased risk of recurrent adverse effects in some patients. The enzyme CYP2C19 has been reported to be the CYP isoform that activates CLO to its active metabolite. Several single nucleotide polymorphisms in the CYP2C19 gene have been identified as strong predictors of CLO-impaired pharmacological response. At least 16 variants have been associated with changes in CYP2C19 activity. Materials and Methods: The following research was composed of a total of 102 subjects with high cardiovascular risk in the northeast of Mexico, with a maintenance dose of 75 mg of CLO per day. The platelet reactivity was measured with VerifyNow P2Y12 assay, while the presence of CYP2C19*2 was identified by real-time polymerase chain reaction. Results: Patients were categorized by CYP2C19 metabolizer status based on *2 genotypes using the common consensus star allele nomenclature as normal metabolizer (G/G), intermediate metabolizer (G/A), and poor metabolizer (A/A), respectively. The phenotype frequency for CYP2C19*2 was 74.5% (G/G), 21.6% (G/A), and 3.9% (A/A). The subjects with the A allele presented ≥235 P2Y12 reaction unit levels, classifying them how poor metabolizer. The prevalence of reduced CLO effectiveness was associated with the presence of CYP2C19*2 polymorphism among Mexican patients. Conclusion: The presence of the CYP2C19*2 allele is related to resistance to the antiplatelet effect of CLO (p = 0.003).

Resumen Objetivo: Los antiplaquetarios orales son clave en la farmacoterapia moderna de las enfermedades aterotrombóticas cardiovasculares. Clopidogrel (CLO) constituye el principal tratamiento preventivo de aterotrombosis (AT). Sin embargo, se ha documentado una considerable variación interindividual en la respuesta a CLO, lo que da como resultado una terapia subóptima y mayor riesgo de efectos adversos en algunos pacientes. La enzima CYP2C19 es la isoforma CYP que activa CLO a su metabolito activo. Se han identificado varios polimorfismos de un solo nucleótido en el gen CYP2C19 como fuertes predictores de respuesta farmacológica alterada a CLO. Al menos 16 variantes se han asociado con cambios en la actividad de CYP2C19. Método: Se reclutaron un total de 102 sujetos con alto riesgo cardiovascular del noreste de México, con dosis de mantenimiento de 75 mg de CLO/día. La reactividad plaquetaria se midió con el ensayo Verify Now P2Y12, la presencia de CYP2C19*2 se identificó mediante polymerase chain reaction en tiempo real. Resultado: Los pacientes fueron clasificados por el estado metabolizador CYP2C19*2 utilizando nomenclatura consenso, como metabolizador normal (G/G), metabolizador intermedio (G/A) y metabolizador pobre (A/A), respectivamente. La frecuencia del fenotipo para CYP2C19*2 fue 74.5% (G/G), 21.6% (G/A) y 3.9% (A/A). Los sujetos con alelo A presentaron ≥235 niveles P2Y12 reaction unit, clasificándolos como metabolizadores deficientes. La prevalencia de eficacia reducida a CLO se asoció con la presencia del polimorfismo CYP2C19*2 en pacientes mexicanos. Conclusiones: La presencia del alelo CYP2C19*2 se relaciona con resistencia al efecto antiagregante plaquetario del CLO (p = 0.003).

Estructura genética poblacional del pez Brycon henni (Characiformes: Characidae) en la región andina de Colombia utilizando marcadores microsatélites

Las especies de peces en Colombia están sujetas a procesos de sobrepesca, introducción de especies exóticas, deterioro de hábitat y fragmentación de ecosistemas, con la consecuente pérdida de conectividad que limita el flujo genético y pudiera llevar a las poblaciones a la extinción. En el presente trabajo se analizó la estructura genética poblacional de Brycon henni, un pez de importancia económica y ecológica, en cuatro cuencas de la región Andina colombiana, mediante el uso de diez marcadores microsatélites en 60 muestras de los ríos Risaralda (RR), Campoalegre (RC), Riofrío (RRf) y Chinchiná (RCh). Se encontró un total de 136 alelos. Con excepción del marcador BoM12, todos fueron altamente informativos y polimórficos y en todos se presentó desviación significativa (P < 0.05) del equilibrio Hardy Weinberg. En RC se observó el mayor número de alelos (81), Número promedio de alelos (8) y alelos privados (34), además una HE de 0.689 ± 0.05. En general, hubo un marcado déficit de heterocigotos con respecto a la población total (FIT = 0.562), dentro de las subpoblaciones (FIS = 0.526) y moderada, pero altamente significativa estructura genética (FST = 0.07). Según la distancia estándar de Nei, la población más divergente fue la del RC con un k = 4, se encontró tendencia a cuatro poblaciones ancestrales. Los resultados sugieren que el flujo genético entre poblaciones naturales de B. henni es limitado, lo cual puede tener efectos negativos sobre su conservación. Los resultados sugieren que las poblaciones pueden estar alcanzando valores críticos de baja densidad, lo cual pone en riesgo su conservación.

Fish species in Colombian Andes are subject to processes of overfishing, exotic species invasions, habitat loss, ecosystems fragmentation and low connectivity that limits the genetic flow and leads populations to loss genetic variability and extinction. Genetic variation of B. henni from four basins of the Colombian Andean region (Risaralda, Campoalegre, Riofrío and Chinchiná) was analyzed using ten microsatellites in 60 samples. A total of 136 alleles were found. Except BoM12, all markers were highly informative and polymorphic and presented a significant deviation (P < 0.05) from Hardy Weinberg Equilibrium. There was a marked deficiency of heterozygotes (FIS = 0.526). In Campoalegre river basin, the largest allele number, average allele number and private alleles were observed (81, eight and 34 alleles, respectively) and HE 0.689 ± 0.05. Moderate and highly significant genetic structure was evidenced (FST = 0.07). According to the standard distance of Nei (1972), population from Campoalegre River basin was the most divergent. This results suggest that genetic variability of the B. henni in the studied basins may be affected by critical low population density, river pollution and overfishing.

C677t (rs1801133) MTFHR gene polymorphism frequency in a colombian population / Frecuencia del polimorfismo c677t (rs1801133) del gen MTFHR en individuos colombianos

Introduction: Abnormal levels of the enzyme methylenetetrahydrofolate reductase (MTHFR) are associated with an increased risk of both cardiovascular and cerebrovascular disease and higher concentrations of homocysteine. Abnormal levels are also related to birth defects, pregnancy complications, cancer and toxicity to methotrexate (MTX). Polymorphisms of MTHFR affect the activity of the enzyme. Genetic associations have been related to treatment efficacy. Objective: To establish the frequency of the C>T polymorphism at nucleotide 677 of the MTHFR gene in a group of Colombian individuals. Methods: Data from pharmacogenetic microarrays that include MTX sensibility-associated polymorphisms were retrospectively collected (Pathway Genomics©). The frequency of the C>T MTHFR rs1801133 marker polymorphism was analyzed. Results: Microarray data from 68 men and 84 women were analyzed. Comparisons of genotype C/C vs. C/T and T/T were statistically significantly different (p= 0.00, p= 0.026, respectively), as were C/T and T/T (p= 0.0001). Conclusions: Results for the C/C and C/T genotypes in a Colombian population are similar to other previously studied groups of healthy subjects. Subjects from our population might be at risk of developing diseases associated with MTHFR polymorphisms and might present toxicity and adverse effects if treated with MTX, which suggests the need to evaluate therapeutic alternatives based on individual pharmacogenetic studies.

Introducción: Las alteraciones de la enzima metilen-tetrahidrofolato reductasa (MTHFR) se asocian con riesgo cardiovascular y cerebrovascular y con presencia de concentraciones altas de homocisteína. Se relacionan también con defectos congénitos, complicaciones en embarazo, cáncer y toxicidad del Metotrexato (MTX). Los polimorfismos del gen MTHFR afectan la actividad de la enzima. Se han descrito asociaciones genéticas con la eficacia del tratamiento con MTX. Objetivo: Establecer la frecuencia del polimorfismo C>T en el nucleótido 677 del gen MTHFR en un grupo de individuos Colombianos. Métodos: Estudio descriptivo de corte transversal. Se recolectaron retrospectivamente resultados de microarreglos farmacogenéticos que incluyen polimorfismos asociados con la sensibilidad al MTX (PathwayGenomics©). Se analizó la frecuencia del polimorfismo C>T del polimorfismo rs1801133 del gen MTHFR. Resultados: Se analizaron microarreglos de 68 hombres y 84 mujeres. Las comparaciones del genotipo C/C frente a C/T y a T/T fueron estadísticamente significativas (p= 0.001 y p= 0.026 respectivamente) tanto como la comparación entre C/T y T/T (p= 0.0001). Conclusiones: Los genotipos C/C y C/T en Colombia son tan variables como en otros grupos sanos en otras poblaciones. Los sujetos de nuestra población podrían tener riesgo para el desarrollo de enfermedades asociadas al polimorfismo del gen MTHFR y con genotipos de riesgo de presentar toxicidad y efectos adversos del MTX, lo cual sugiere la necesidad de evaluar alternativas terapéuticas con estudios farmacogenéticos.

Variabilidad genética de la respuesta inflamatoria: I. Polimorfismo -511 C/T en el gen IL1β en diferentes subpoblaciones peruanas / Genetic variability of the inflammatory response: I. The -511 C/T IL1β polymorphism in different Peruvian subpopulations

El polimorfismo -511 citosina/timina (-511 C/T) en la región promotora del gen interleuquina 1 beta (IL1β) estα implicado en la producciσn diferencial de la citoquina y por tanto puede estar asociado a la respuesta inmuno-inflamatoria en obesidad, dislipidemias, cardiopatías, cáncer, infecciones, y el tratamiento con nutrientes y fármacos. Objetivos: Establecer la distribución de frecuencias de los genotipos y alelos del polimorfismo -511 C/T del gen IL1β en diferentes subpoblaciones peruanas. Diseño: Estudio descriptivo, observacional, transversal. Instituciones: Centro de Investigación de Bioquímica y Nutrición e Instituto de Medicina Tropical D.A. Carrión, Facultad de Medicina, UNMSM y Centro de Genética y Biología Molecular, Facultad de Medicina, USMP, Lima, Perú. Participantes: Pobladores peruanos. Intervenciones: Extracción de ADN genómico a partir de muestras sanguíneas o epitelio bucal según metodología estándar, de 168 individuos de 9 grupos subpoblacionales: 23 mestizos de Lima, 33 amazónicos (20 de Pucallpa y 13 de Amazonas) y 112 andinos (12 de Ancash, 10 de Cajamarca, 18 de Huarochirí-Lima, 25 de Puno-Taquile, 25 de Puno-Uros y 22 de Puno-Anapia). Análisis del polimorfismo -511 C/T mediante la técnica de PCR/RFLP, con primers específicos y digestión con la enzima de restricción AvaI, detectándose los fragmentos por electroforesis en geles de agarosa al 2% y tinción con bromuro de etidio. Principales medidas de resultados: Frecuencias genotípicas y alélicas del gen IL1β. Resultados: Se encontró las siguientes frecuencias genotípicas CC=0,024; CT=0,369 y TT=0,607, consistentes con el equilibrio de Hardy-Weinberg; y las frecuencias alélicas fueron alelo C=0,208 y aleloT= 0,792. La frecuencia del alelo T, considerado el mutante, fue muy alta en los Uros de Puno (0.940) y más baja en los mestizos de Lima (0.609). La comparación de las frecuencias genotípicas (TT versus CT+CC) y alélicas (T versus C) mostraron diferencias significativas (p<0,01) entre los pares Lima mestizos y las de Puno-Taquile y Puno-Uros. Existieron diferencias significativas (p<0,001) cuando se las comparó con otras poblaciones del mundo. Conclusiones: El alelo T mutante del polimorfismo -511 C/T en el gen IL1β, asociado a mayor producciσn de la citoquina, fue frecuente en las subpoblaciones estudiadas. Debido a las diferencias encontradas, es importante considerar la etnicidad en los estudios de asociaciσn y de riesgo de este gen, como factor de respuesta inflamatoria, en obesidad, dislipidemias, cardiopatías, cáncer, infecciones, y el tratamiento con nutrientes y fármacos.

The -511 citosyne/thymine (-511 C/T) polymorphism in the promoter region of human interleukin 1B (IL1β) gene is associated to differential cytokine synthesis and immuno-inflammatory response in obesity, dyslipidemias, cardiopathies, cancer, infections, other diseases, nutritional intervention and drug treatment. Objectives: To determine allelic and genotypic frequencies of -511 C/T polymorphism in the IL1β gene polymorphism in different Peruvian subpopulations. Design: Descriptive, cross-sectional study. Settings: Faculties of Human Medicine, Universidad Nacional Mayor de San Marcos and Universidad San Martin de Porres, Lima, Peru. Participants: Peruvian subjects. Interventions: Genomic DNA was extracted from 168 individuals from Lima (23 mestizos), 33 Amazonians (20 Pucallpa and 13 Amazonas) and 112 Andeans (12 Ancash, 10 Cajamarca, 18 Huarochiri-Lima, 25 Puno-Taquile, 25 Puno-Uros and 22 Puno-Anapia) according to standard methodology and amplification using PCR-RFLP technique. PCR products were digested with AvaI restriction enzyme and fragments were separated by 2% agarose gel electrophoresis and ethidium bromide stain. Main outcomes measures: Allelic and genotypic frequencies of the -511 C/T polymorphism in the IL1β gene. Results: CC=0,024, CT=0,369, and TT=0,607 genotypes frequencies were found, consistent with Hardy-Weinberg equilibrium, as well as alleles frequencies C = 0,208, and T= 0,792. The frequency of (mutant) T allele was very high in Puno-Uros (0,940) and low in Lima-mestizos (0,609). Comparison of genotypes (TT versus CT+CC) and alleles (T versus C) showed significant differences (p <0.01) between pairs Lima-mestizos and Puno-Uros and Puno-Taquile. Differences were significant (p <0.001) when compared to other world populations. Conclusions: T allele of IL1β gene -511 polymorphism related to increased production of the cytokine was frequent in these Peruvian subpopulations. Because of these differences, it is important to consider ethnicity in association studies and risk of this gene, factor of inflammatory response in obesity, dyslipidemias, cardiopathies, cancer, infections, other diseases, nutritional intervention and drug treatment.

Comportamiento de los alelos HLA-DQB1*02 y HLA-DQB1*03 en pacientes con diagnóstico presuntivo de enfermedad celíaca / Behavior of HLA-DQB1*02 and HLA-DQB1*03 alleles in patients with a presumptive diagnosis of celiac disease

La enfermedad celíaca (EC) es autoinmune y se observa en individuos genéticamente predispuestos, se caracteriza por la intolerancia a determinadas proteínas llamadas gluten (gliadinas y gluteínas) que se encuentran en el trigo, el centeno y la cebada. Se sabe que existe una asociación del sistema HLA y la enfermedad celíaca (HLA-DQ2/HLA-DQ8), pero no existen estudios cubanos acerca de esa asociación por lo que nos propusimos analizar el comportamiento de los alelos DQB1*02 y DQB1*03 mediante un estudio analítico observacional en 65 pacientes con diagnóstico presuntivo de enfermedad celíaca con el objetivo de incluir la detección de estos alelos en el esquema diagnóstico de esta compleja enfermedad. Se halló que los individuos portadores del alelo DQB1*02 (OR: 2,26) fueron más susceptibles de padecer la enfermedad que los no portadores, que el 60 por ciento de los presuntos pacientes con enfermedad celíaca presentaron el alelo HLA-DQ2 y el 3 por ciento, el alelo HLA-DQ8. Se concluyóque el genotipaje HLA-DQ2/HLA-DQ8 es de gran utilidad para el diagnóstico de enfermedad celíaca

The celiac disease (CD) is autoimmune and it is present in genetically predisposed subjects, characterized by the intolerance to determined proteins present in wheat, rye and barley: called gluten and gliadin. It is known that there is an association between HLA-system and celiac disease (HLA-DQ2/HLA-DQ8), but there aren't Cuban studies on this association, thus we analyzed the behavior of DQB1*02 and DQB1*03 alleles by means of an observational and analytical study in 65 patients with a presumptive diagnosis of celiac disease to include its detection in the diagnostic scheme of this complex disease. There was found that subjects carriers of the DQB1*02 allele (OR: 2,26) were more susceptible to suffer this disease than those non-carriers, that the 60 percent of the supposed patients presenting with the celiac disease had the HLA-DQ2 allele and the 3 percent had the HLA-DQ8 allele. We conclude that the HLA-DQ2/HLA-DQ8 genotyping is very useful for the diagnosis of the celiac disease

A novel A2 allele found in Leishmania (Leishmania) infantum chagasi / Novo alelo do gene A2 descrito em Leishmania (Leishmania) infantum chagasi

Visceral leishmaniasis (VL) is a widely spread zoonotic disease. In Brazil the disease is caused by Leishmania (Leishmania) infantum chagasi. Peridomestic sandflies acquire the etiological agent by feeding on blood of infected reservoir animals, such as dogs or wildlife. The disease is endemic in Brazil and epidemic foci have been reported in densely populated cities all over the country. Many clinical features of Leishmania infection are related to the host-parasite relationship, and many candidate virulence factors in parasites that cause VL have been studied such as A2 genes. The A2 gene was first isolated in 1994 and then in 2005 three new alleles were described in Leishmania (Leishmania) infantum. In the present study we amplified by polymerase chain reaction (PCR) and sequenced the A2 gene from the genome of a clonal population of L. (L.) infantum chagasi VL parasites. The L. (L.) infantum chagasi A2 gene was amplified, cloned, and sequenced in. The amplified fragment showed approximately 90 percent similarity with another A2 allele amplified in Leishmania (Leishmania) donovani and in L.(L.) infantum described in literature. However, nucleotide translation shows differences in protein amino acid sequence, which may be essential to determine the variability of A2 genes in the species of the L. (L.) donovani complex and represents an additional tool to help understanding the role this gene family may have in establishing virulence and immunity in visceral leishmaniasis. This knowledge is important for the development of more accurate diagnostic tests and effective tools for disease control.

A leishmaniose visceral (LV) é uma zoonose amplamente disseminada, causada no Brasil pela Leishmania (Leishmania) infantum chagasi. Flebotomíneos vetores adquirem o agente etiológico, alimentando-se do sangue de animais contaminados, como cachorros ou animais selvagens. A doença é endêmica no Brasil, e focos de epidemia são relatados em cidades densamente povoadas por todo o país. Muitas manifestações clínicas relacionadas à infecção por Leishmania estão ligadas à relação parasito-hospedeiro, e vários possíveis fatores de virulência dos parasitas, que causam a LV, são alvos de estudo, tais como os genes A2. O gene A2 foi isolado pela primeira vez em 1994 e, em seguida, em 2005, três novos alelos foram descritos em Leishmania (Leishmania) infantum. No presente estudo, um fragmento do gene A2 de uma população clonal de L.(L.) infantum chagasi foi amplificado por PCR e sua sequência de nucleotídeos determinada. O fragmento mostrou 90 por cento de similaridade com alelos do gene A2 de Leishmania (Leishmania) donovani e de L. (L.) infantum, descritos na literatura. Entretanto, a tradução da sequência de nucleotídeos mostra diferenças na sequência de aminoácidos da proteína, que podem ser essenciais em determinar a variabilidade do gene A2 em espécies do complexo L. (L.) donovani e representa uma ferramenta adicional na compreenssão do papel dessa família de genes na virulência e imunidade da leishmaniose visceral. O conhecimento dessa variação é importante para o desenvolvimento de testes diagnósticos mais precisos e ferramentas mais eficazes no controle da doença.

Estudo de HLA classes I e II em trinta pacientes equatorianos com artrite reumatoide em comparação com alelos de indivíduos sadios e afetados com outras doenças reumáticas / Study of class I and II HLA alleles in 30 ecuadorian patients with rheumatoid arthritis compared with alleles from healthy and affected subjects with other rheumatic diseases

INTRODUÇÃO: A artrite reumatoide (AR) é uma doença inflamatória crônica sistêmica autoimune que provém de uma desordem incapacitante. Até hoje, a etiologia da AR é desconhecida. No entanto, já se cogitou a existência de indivíduos geneticamente passíveis de tê-la. Muitos estudos já foram realizados em todo o mundo, como, por exemplo, na Polônia, Argentina, Chile, México, Brasil, Colômbia, entre outros países, com relação à influência entre os alelos HLA-DR e a doença, mas não no Equador. OBJETIVO: O principal objetivo deste estudo foi determinar a participação dos alelos de HLA classes I e II em pacientes com AR. PACIENTES E MÉTODOS: Esta pesquisa foi desenvolvida em 30 pacientes adultos com AR, previamente diagnosticados de acordo com os critérios de classificação do Colégio Norte-Americano de Reumatologia (ACR, 1987) e 28 controles. Para a tipificação de HLA classes I e II, adotou-se a técnica PCR-SSP, e as significâncias estatísticas foram avaliadas pelo teste de Qui-Quadrado. RESULTADOS: O HLA-DR4 está presente em 76,7 por cento dos pacientes, com uma frequência alélica de 45 por cento, enquanto apenas 21 por cento dos sujeitos controle o apresentaram. O teste de Qui-Quadrado confirma que as variáveis HLA-DR4 e RA estão altamente vinculadas (X² = 11,38, P = 0,00074). CONCLUSÃO: Há frequência maior de HLA-DR4 e HLA-DR14. Os resultados encontrados são similares aos encontrados em outros estudos. Porém, seria desejável aumentar o tamanho da amostra para encontrar um maior número de perfis genéticos e de alelos envolvidos.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease that originates from a disabling disorder. To date, the etiology of RA is unknown. However, the existence of genetically susceptible individuals was considered. Many studies have been performed worldwide, for example, in Poland, Argentina, Chile, Mexico, Brazil, and Colombia, among others, regarding the influence between HLA-DR alleles and disease, but not in Ecuador. OBJECTIVE: The aim of this study was to determine the involvement of Class I and II HLA alleles in patients with RA. PATIENTS AND METHODS: This study was conducted in 30 adult patients with RA previously diagnosed, according to the classification criteria of the American College of Rheumatology (ACR, 1987) and 28 controls. For Class I and II HLA typing, we adopted the PCR-SSP, and statistical significances were evaluated by Chi-Square. RESULTS: HLA-DR4 is present in 76.7 percent of patients, with an allele frequency of 45 percent, while only 21 percent of control subjects presented it. The chi-square confirms that HLA-DR4 and RA variables are highly bound (X2 = 11.38, P = 0.00074). CONCLUSION: There is increased frequency of HLA-DR4 and HLA-DR14. The results are similar to those found in other studies. But it would be desirable to increase the sample size in order to find a greater number of genetic profiles and alleles involved.

Un caso de grupo sanguíneo raro: fenotipo p / A rare blood group: p phenotype

Un individuo con un fenotipo eritrocitario raro carece de uno o varios antígenos presentes en la mayor parte de la población de pertenencia. Cuando presenta el anticuerpo correspondiente, se pueden producir complicaciones perinatales, transfusionales y/o transplantológicas. Se presenta el caso de una embarazada aloinmunizada derivada a nuestro servicio en la semana 12 de su tercera gesta para su evaluación y seguimiento. El diagnóstico inmunohematológico le asignó el excepcional fenotipo "p" (aproximadamente 1/200 000 individuos), asociado con una mayor tasa de abortos espontáneos y a reacciones transfusionales graves cuando se transfunden unidades incompatibles. El estudio del gen A4GALT demostró la presencia de la mutación c.752C > T en doble dosis. Esta mutación lleva a un cambio de una prolina por una leucina en el residuo 251 de la 4-α-galactosiltransferasa. Por parto inducido por sufrimiento fetal, nace a las 36 semanas una bebé con prueba de antiglobulina (Coombs) directa negativa, eluido reactivo, con ictericia que requirió luminoterapia. Una semana después el neonato fue externado sin secuelas aparentes. Posteriormente, a raíz de una cirugía inminente y la improbabilidad de encontrar sangre compatible, se elaboró un plan para cubrir las posibles demandas. Este caso pone en evidencia la necesidad de contar a nivel nacional con un laboratorio de referencia de inmunohematología y un banco de sangre de grupos raros, que permita resolver con celeridad situaciones que requieran transfundir a estos individuos.

A rare blood group is usually defined as the absence of a high prevalence antigen or the absence of several antigens within a single blood group system. These individuals may develop clinically significant red cell antibodies to the high incidence red cell antigens they lack. A 33-year-old alloimmunized woman was referred to our center at the 12th week of her third pregnancy for evaluation and follow up. The laboratory work-up grouped her as belonging to "p" phenotype, associated with difficulties to find compatible blood for transfusion and a high incidence of recurrent miscarriage. At 36 weeks, a baby girl was born by induced labor due to fetal suffering. With a negative direct antiglobulin test but a positive elution test, she was in the neonatology ward for one week receiving luminotherapy. Homozygosity for a missense mutation at position 752 (c.752C > T) in the A4GALT gene was found to be responsible for the p phenotype. This mutation changes a proline to a leucine at codon 251 of the 4-α-galactosyltransferase. Recently, due to an imminent chirurgical intervention and the impossibility to have compatible blood available for transfusion, an autologous donation plan was designed to satisfy probable demand. This case showed the need for blood bank facilities capable to respond satisfactorily to these situations in Argentina. This would facilitate the storage of cryopreserved blood from individuals with rare blood groups for homologous use or to develop rare blood donors programs.

Prevalence of the HLA-DQB1*0602 allele in narcolepsy and idiopathic hypersomnia patients seen at a sleep disorders outpatient unit in São Paulo / Prevalência do alelo HLA-DQB1*0602 em pacientes com narcolepsia e hipersonolência idiopática atendidos em ambulatório de sonolência em São Paulo

OBJECTIVE: Narcolepsy (with and without cataplexy) and idiopathic hypersomnia, are disorders with common features but with different HLA-DQB1*0602 allele prevalence. The present study describes the prevalence of HLA-DQB1*0602 allele in narcoleptics with and without cataplexy and in patients with idiopathic hypersomnia. METHOD: Subjects comprised 68 patients who were diagnosed for narcolepsy or idiopathic hypersomnia and 23 healthy controls according to the International Classification of Sleep Disorders-2. Subjects comprised 43 patients with narcolepsy and cataplexy, 11 patients with narcolepsy but without cataplexy, 14 patients with idiopathic hypersomnia and 23 healthy controls. Genotyping of HLA-DQB1*0602 allele was performed for all subjects. RESULTS: The prevalence of the HLA-DQB1*0602 allele was increased in idiopathic hypersomnia and in narcoleptic patients with and without cataplexy when compared to healthy subjects (p = 0.04; p = 0.03 and p < 0.0001, respectively). CONCLUSIONS: This finding is in accordance with those of previous studies. The gold standard exam of narcolepsy with cataplexy is Hypocretin-1 dosage, but in patients without cataplexy and idiopathic hypersomnia, there are no specific diagnostic lab findings. The presence of the HLA-DQB1* 0602 allele may be important for the differential diagnosis of situations that resemble those sleep disorders such as secondary changes in sleep structure due to drugs' consumption.

OBJETIVO: Narcolepsia (com e sem cataplexia) e hipersonolência idiopática são transtornos com características clínicas comuns, mas com prevalências do alelo HLA-DQB1*0602 diferentes. Este estudo descreve a prevalência do alelo HLA-DQB1*0602 em pacientes narcolépticos com e sem cataplexia e em pacientes com hipersonolência idiopática. MÉTODO: A amostra consistiu de 68 pacientes com diagnóstico de narcolepsia ou hipersonolência idiopática e 23 controles saudáveis segundo o International Classification of Sleep Disorders-2. A amostra foi composta de 43 pacientes com narcolepsia e cataplexia, 11 pacientes com narcolepsia e sem cataplexia, 14 pacientes com hipersonolência idiopática e 23 controles saudáveis. A análise da presença do alelo HLA-DQ*0602 foi realizada em todos os sujeitos. RESULTADOS: A prevalência do alelo HLA-DQB1*0602 foi maior nos grupos de pacientes com hipersonolência idiopática e em pacientes narcolépticos com e sem cataplexia quando comparada com a dos sujeitos saudáveis (p = 0,04; p = 0,03 e p < 0,0001, respectivamente). CONCLUSÕES: Os resultados são compatíveis com o de estudos anteriores. O exame padrão-ouro para a confirmação da narcolepsia em pacientes com cataplexia é a dosagem de hipocretina, mas em pacientes sem cataplexia e hipersonolência idiopática não há testes laboratoriais específicos para o diagnóstico. A presença do alelo HLA-DQB1*0602 pode ser importante no diagnóstico diferencial de situações semelhantes a esses distúrbios do sono, como alterações secundárias na estrutura do sono causadas por consumo de drogas.

Prevalence of HLA DQB1*0602 allele in patients with migraine

BACKGROUND: Studies have shown a high prevalence of migraine among narcoleptic patients. HLA-DQB1*0602 and HLA DRB1 alleles are closely associated with narcolepsy. An increase in the HLA-DRB1 allele frequency in patients with visual aura has raised greater awareness of the genetic background in migraine. PURPOSE: Since the regions DR and DQ of the HLA are in tightly linkage desiquilibrium we hypothesize that HLA-DQB1*0602 might be associated to the pathophysiology of migraine. METHOD: We analyzed the presence of HLA DQB1*0602 allele in 50 healthy subjects with no history of migraine, 53 patients with migraine without aura and 52 patients with migraine with aura. RESULTS: There was no difference in the frequency of HLA DQB1*0602 allele when control subjects and all patients were compared. We failed to note any difference in frequencies when comparing migraine patients with and without aura. CONCLUSION: Further studies with different patient populations, with other hypothalamic markers (melatonin, hypocretin) in migraine patients may shed light on to its pathophysiology.

CONTEXTO: Estudos têm demonstrado o aumento da prevalência de enxaqueca em pacientes com narcolepsia, um distúrbio de sono associado a um gene do sistema HLA, o alelo HLA-DQB1*0602. As regiões DQ e DR do HLA estão em alto desequilíbrio de ligação e já foi descrito um aumento da freqüência do alelo HLA DRB1 em pacientes com enxaqueca com aura visual, o que fortalece uma hipótese de herança genética para a enxaqueca. OBJETIVO: Nossa hipótese é que o alelo HLA-DQB1*0602 pode estar relacionado com a fisiopatologia da enxaqueca destes pacientes. MÉTODO: Nós analisamos a presença do alelo HLA-DQB1*0602 em 50 voluntários sadios sem história de enxaqueca, 53 pacientes com enxaqueca sem aura e 52 pacientes com aura. RESULTADOS: Não houve diferença entre os controles sadios e os pacientes com enxaqueca. Não houve diferença entre os pacientes com enxaqueca com e sem aura. CONCLUSÃO: Futuros estudos com diferentes populações, com outros marcadores (melatonina e hipocretina) em pacientes com enxaqueca devem ser realizados para melhor esclarecimento de fisiopatologia.

Association analysis between a VNTR intron 8 polymorphism of the dopamine transporter gene (SLC6A3) and obsessive- compulsive disorder in a Brazilian sample

Family, twin and segregation analysis have provided evidences that genetic factors are implicated in the susceptibility for obsessive-compulsive disorder (OCD). Several lines of research suggest that the dopaminergic system may be involved in the pathophysiology of OCD. Thus, the aim of the present study was to investigate a possible association between a polymorphism located in intron 8 of the dopamine transporter gene (SLC6A3) and OCD in a Brazilian sample composed by 208 patients and 865 healthy controls. No statistically differences were observed in allelic and genotype distributions between cases and controls. No association was also observed when the sample was divided according to specific phenotypic features such as gender, presence of tic disorders co-morbidity and age at onset of obsessive-compulsive symptoms (OCS). Our results suggest that the intron 8 VNTR of the SLC6A3 investigated in this study is not related to the susceptibility for OCD in our Brazilian sample.

Estudos de família, gêmeos e de segregação têm demonstrado que fatores genéticos estão envolvidos na susceptibilidade para o desenvolvimento do transtorno obsessivo-compulsivo (TOC). Várias linhas de pesquisa sugerem que o sistema dopaminérgico possa estar envolvido na fisiopatologia do TOC. Assim, o objetivo do presente estudo foi investigar uma possível associação entre o polimorfismo localizado no intron 8 do gene do transportador da dopamina (SLC6A3) e o TOC em uma amostra brasileira composta por 208 pacientes e 865 controles sadios. Nenhuma diferença estatisticamente significante foi observada nas distribuições alélicas e genotípicas entre os grupos de pacientes e controles. Nenhuma associação também foi observada quando as amostras foram divididas de acordo com características fenotípicas específicas, tais como gênero, presença de co-morbidade com tiques e idade de início dos sintomas obsessivo-compulsivo (SOC). Nossos resultados sugerem que o VNTR do intron 8 investigado neste estudo não está relacionado com o TOC na nossa amostra brasileira.