Two-phase SSU and SKAT in genetic association studies

The sum of squared score (SSU) and sequence kernel association test (SKAT) are the two good alternative tests for genetic association studies in case–control data. Both SSU and SKAT are derived through assuming a dose-response model between the risk of disease and genotypes. However, in practice, the real genetic mode of inheritance is impossible to know. Thus, these two tests might lose power substantially as shown in simulation results when the genetic model is misspecified. Here, to make both the tests suitable in broad situations, we propose two-phase SSU (tpSSU) and two-phase SKAT (tpSKAT), where the Hardy–Weinberg equilibrium test is adopted to choose the genetic model in the first phase and the SSU and SKAT are constructed corresponding to the selected genetic model in the second phase. We found that both tpSSU and tpSKAT outperformed the original SSU and SKAT in most of our simulation scenarios. By applying tpSSU and tpSKAT to the study of type 2 diabetes data, we successfully identified some genes that have direct effects on obesity. Besides, we also detected the significant chromosomal region 10q21.22 in GAW16 rheumatoid arthritis dataset, with P \10-6 . These findings suggest that tpSSU and tpSKAT can be effective in identifying genetic variants for complex diseases in case–control association studies

Power divergence test statistics for testing Hardy–Weinberg equilibrium

The Hardy–Weinberg equilibrium (HWE) model states that allele and genotype frequencies in a population will remain constant for generations in the absence of evolutionary effects. A goodness-of-fit test can be used to test if a population is significantly different from the expectations of HWE. Pearson statistics are commonly used in goodness-of-fit tests for testing the HWE. In this paper, a simulation study is carried out to evaluate the performance of power divergence statistics under different sample sizes, effect sizes and minor allele frequencies. A real genotype dataset is also analysed to compare the results of several power divergence test statistics.

GENETIC DIVERSITY IN A POPULATION OF CREOLE MAIZE (Zea mays L.) EVALUATED BY MICROSATELLITE MARKERS IN PUERTO LIBERTADOR, CORDOBA / DIVERSIDAD GENÉTICA EN UNA POBLACIÓN DE MAÍZ CRIOLLO (Zea mays L.) EVALUADA MEDIANTE MARCADORES MICROSATÉLITES EN PUERTO LIBERTADOR, CÓRDOBA

ABSTRACT Maize a plant of Mesoamerican origin, has evolved in different microenvironments, generating the great diversity of maize that exists in the world. In order to determine the genetic diversity of a population of Creole maize, twelve microsatellite markers were evaluated in 30 accessions, in Puerto Libertador, Córdoba. The DNA of each accession was extracted using the PROMEGA kit, the markers were amplified by the PCR technique and the amplicons were run on polyacrylamide gels, the gels were digitalized and the molecular sizes were determined by an exponential model. Results showed a total of 66 alleles and an average of alleles of 5.5, the expected heterozygosity was 0.655, the values of the polymorphic information content (PIC) ranged from 0.352 to 0.838, with an average of 0.592 and the Hardy-Weinberg equilibrium showed imbalance (p <0.05). This work revealed that the studied accessions of Creole maize showed a high degree of polymorphism, high genetic variability and microsatellite markers were the appropriate for the evaluation of genetic diversity. This information shows to be useful for the conservation and protection of the genetic diversity of the studied Creole Maize.

RESUMEN El maíz una planta de origen mesoamericano, se ha desarrollado en los más variados microambientes, lo que ha generado una gran diversidad de variedades alrededor del mundo. Con el objetivo de determinar la diversidad genética de una población de maíz criollo, se evaluaron doce marcadores microsatélite, en 30 accesiones, en Puerto Libertador, Córdoba. El ADN de cada accesión fue extraído, mediante el kit de PROMEGA; los marcadores se amplificaron, mediante la técnica de PCR y los amplicones, se corrieron en geles de poliacrilamida. Los geles fueron digitalizados y los tamaños moleculares se determinaron, mediante un modelo exponencial. Los resultados mostraron un total de 66 alelos y un promedio de alelos de 5,5; la heterocigosidad esperada fue 0,655. Los valores del contenido de información polimórfica (PIC) variaron de 0,352 a 0,838, con un promedio de 0,592 y la prueba de Hardy-Weinberg mostró desequilibrio (p<0,05). Este trabajo reveló que las accesiones de maíz criollo estudiadas mostraron alto grado de polimorfismo, alta variabilidad genética y los marcadores microsatélites resultaron los apropiados para la evaluación de la diversidad genética. Esta información muestra ser útil para la conservación de la diversidad genética del maíz criollo estudiado y su protección.

Asociación de los polimorfismos T352C y A16974C con la lepra lepromatosa en pacientes cubanos / Association of T352C and A16974C polymorphisms with lepromatose leprosy in cuban patients

Introducción: La Lepra es una enfermedad infecciosa causada por el Mycobacterium leprae. Los patrones dermatoglíficos de pacientes cubanos con lepra lepromatosa mostraron indicios probatorios de que existe predisposición genética para el desarrollo de esta enfermedad, que sugiere la búsqueda de la asociación con polimorfismos moleculares, de mayor precisión. Entre estos, unos de los más estudiados son el T352C del gen del receptor de la vitamina D y el A16974C del gen IL12p40, cuya utilidad relativa depende de la población. Objetivo: Determinar si existe asociación entre la presencia de los polimorfismos T352C y A16974C con la lepra lepromatosa en pacientes cubanos. Material y Métodos: Se realizó un estudio observacional, analítico, de tipo caso-control de asociación genética donde se estudiaron pacientes con lepra lepromatosa y controles. Fueron identificados los genotipos relacionados con los polimorfismos T352C y A16974C en cada grupo. La prueba Chi-cuadrado de Pearson fue utilizada para determinar si los controles se hallaban en equilibrio de Hardy Weinberg, así como si existía relación entre los polimorfismos y la presencia de la enfermedad. Resultados: Los pacientes estudiados fueron 32 para el polimorfismo T352C y 44 para el A16974C. Los controles fueron 64 y 44, respectivamente; estos se hallaron en equilibrio Hardy-Weinberg. No se detectó asociaciónentre los polimorfismos A16974C y T352C con la lepra lepromatosa. Conclusiones: Los polimorfismos T352C y A16974C no son útiles como factor de riesgo predisponente en el grupo de pacientes cubanos con lepra lepromatosa estudiados(AU)

Introduction: Leprosy is an infectious disease caused by Mycobacterium leprae. Dermatoglyphic patterns of Cuban patients with lepromatose leprosy showed evidential signs of the existence of genetic predisposition to the development of this disease, which suggests a search for the association with molecular polymorphisms of higher degree of accuracy. Among them, some of the most studied are the T352C vitamin D receptor gene and the A16974Cof the IL12p40 gene, which relative usefulness depends on the population. Objective: To determine whether there is an association between the T352Cand A16974C polymorphisms with lepromatose leprosy in Cuban patients. Material and methods: An observational analytical case-control type genetic association study was conducted where patients with lepromatose leprosy and controls were studied. Genotypes related to T352Cand A16974C polymorphisms were identified in each group. Pearson´s chi square test was used to determine whether the controls were in Hardy-Weinberg equilibrium, and also whether there was a relation between polymorphisms and the presence of diseases. Results: There were 32 patients under study for T352C polymorphism, and 42 for A16974C. The controls were 64 and 44, respectively; and these were in Hardy-Weinberg equilibrium. No association between T352Cand A16974C polymorphisms with lepromatose leprosy was detected. Conclusions: T352Cand A16974C polymorphisms are not useful as a predisposing risk factor in the group of Cuban patients with lepromatose leprosy studied(AU)

Diversidad genética de palomas domésticas (Columba livia) en Ciénaga de Oro (Colombia), utilizando genes del plumaje / Genetic diversity of domestic pigeons (Columba livia) in Ciénaga de Oro, Colombia, using plumage genes / Diversidade genética de pombos domésticos (Columba livia) em Ciénaga de Oro (Colômbia), utilizando genes da plumagem

Resumen El objetivo de este trabajo fue evaluar la diversidad genética de las poblaciones de palomas domésticas (Columba livia) por medio del uso de genes que codifican la coloración y diseño del plumaje, en Ciénaga de Oro (Córdoba, Colombia). Se realizaron muestreos aleatorios en cinco colonias de Ciénaga de Oro, en el periodo comprendido entre junio y agosto de 2015. Mediante excursiones urbanas, observación directa y registros fotográficos, se estudiaron 325 palomas. Se utilizaron los marcadores autosómicos que codifican la coloración y diseño del plumaje: Grizzle (G), Spread (S), Checker (C) y el locus ligado al sexo Ash-Red (B). Los parámetros genéticos -frecuencia alélica, diversidad genética, equilibrio Hardy-Weinberg y estructura poblacional- fueron calculados con el programa PopGene 1.31. La estructura genética y la distancia genética se evaluaron mediante el programa FSTAT v. 2.9.3.2. La elaboración del dendrograma se realizó con el programa MEGA 5.2. El marcador de mayor frecuencia alélica fue Spread, mientras que el marcador Ash-Red presentó los valores más bajos. Se obtuvo escasa diferenciación genética entre las poblaciones y un elevado flujo génico. Se observó un exceso de heterocigotos; a esto se le suma la ausencia de equilibrio Hardy-Weinberg. Se evidenció posible selección natural para el marcador Spread.

Abstract This study aimed to evaluate the genetic diversity of domestic pigeon populations (Columba livia), using genes that are responsible for encoding plumage color and design, in Ciénaga de Oro (Córdoba, Colombia). Random samplings were performed in 5 colonies of Ciénaga de Oro from June to August 2015. By means of urban excursions, direct observation and photographic records, 325 pigeons were studied. Autosomal markers encoding plumage color and design were used: Grizzle (G), Spread (S), Checker (C), and the sex-linked Ash-Red locus (B). Genetic parameters-allele frequency, genetic diversity, Hardy-Weinberg equilibrium, and population structure-were calculated using the PopGene 1.31 program. Genetic structure and genetic distance were evaluated using the FSTAT v. 2.9.3.2 program. A dendrogram was elaborated using the MEGA 5.2 program. The marker with the highest allele frequency was Spread, while the Ash-Red marker showed the lowest values. Little genetic differentiation between populations and high gene flow were obtained. An excess of heterozygotes was observed, in addition to the absence of Hardy-Weinberg equilibrium. A possible natural selection for the Spread marker was evidenced.

Resumo O objetivo deste trabalho foi avaliar a diversidade genética das populações de pombos domésticos (Columba livia) por meio do uso de genes que codificam a coloração e desenho da plumagem, em Ciénaga de Oro (Córdoba, Colômbia). Se realizaram amostragens aleatórias em 5 colônias de Ciénaga de Oro, no periodo compreendido entre junho e agosto de 2015. Mediante excursões urbanas, observação direta e registros fotográficos, se estudaram 325 pombos. Se utilizaram os marcadores autossômicos que codificam a coloração e desenho da plumagem: Grizzle (G), Spread (S), Checker (C) e o locus ligado ao sexo Ash-Red (B). Os parâmetros genéticos - frequência alélica, diversidade gené tica, equilíbrio Hardy-Weinberg e estrutura populacional - foram calculados com o programa PopGene 1.31. A estrutura genética e a distância genética foram avaliadas mediante o programa FSTAT v. 2.9.3.2. A elaboração do dendrograma se realizou com o programa MEGA 5.2. O marcador de maior frequência alélica foi Spread, em quanto que o marcador Ash-Red apresentou os valores mais baixos. Obteve-se escassa diferenciação genética entre as populações e um elevado fluxo génico. Pôde-se observar um excesso de heterozigotos; a isto soma-se a ausência de equilíbrio Hardy-Weinberg. Constatou-se possível seleção natural para o marcador Spread.

Detección de la Diversidad Genética del Cerdo Doméstico (Sus scrofa domestica) Utilizando Marcadores Microsatélites, en Sahagún-Córdoba, Colombia / Detection of Genetic Diversity of the Domestic Pig (Sus scrofa domestica) by means Microsatellite Markers in Sahagún - Córdoba, Colombia

En el presente trabajo se estudió la caracterización genética de una población de cerdo doméstico (Sus scrofa domestica) en Sahagún, Departamento de Córdoba, Colombia (8° 57’ 02’’ Norte y 75° 26’ 44’’ Oeste), para identificar su situación genética. Se estudiaron 51 muestras de la población. Se han emplearon 20 microsatélites, cinco pertenecen a la lista de los recomendados por la FAO / ISAG (Organización de las Naciones Unidas para la Alimentación y la Agricultura / Sociedad Internacional de Genética Animal) para estudios de biodiversidad porcina y los loci restantes representan la mayor parte del genoma porcino. Con los análisis se pudo determinar que todos los microsatélites utilizados han resultado polimórficos y se han detectado, entre 3 (S0385) y 13 (SW780) alelos, con un número medio de alelos de 6,05 y un total de 121 alelos. La heterocigosidad media esperada fue 0,5219 y la observada 0,5581. Los valores del PIC (Polymorphism Information Content, por sus siglas en inglés) oscilaron entre 0,2542 y 0,7021 para los loci S0385 y SW780 respectivamente. Los resultados obtenidos permiten concluir que el cerdo doméstico en Sahagún, presenta alto grado de variabilidad genética.

The objective of this research was to study the genetic diversity of a population of domestic pigs (Sus scrofa domestica) in the municipality of Sahagún, Department of Córdoba, Colombia (8 ° 57 ‘02’ ‘North and 75 ° 26 ‘44’ ‘West). For this purpose, 51 samples of the population were studied, using 20 microsatellites, 5 of which belong to the list recommended by FAO/ISAG (United Nations Food and Agriculture Organization/ International Society of Animal Genetics) for studies of porcine biodiversity and the remaining loci represent the major part of the porcine genome. From the analysis performed, it was possible to determine that all the microsatellites used were polymorphic, with 3 (S0385) and 13 (SW780) alleles, with an average number of alleles of 6.05 for a total of 121 alleles. The expected mean heterozygosity was 0.5219 and the observed was 0.5581. The values of the Polymorphism Informational Content (PIC) ranged from 0.2542 to 0.7021 for loci S0385 and SW780, respectively. The results allow us to conclude that the domestic pig in Sahagún, has a high degree of genetic variability.

Study about Genetic Variability of SE33 Locus.

Introduction: The HUMACTBP2 (SE33) locus is one of the most polymorphic markers commonly used in forensic human identification. Variability of SE33 was studied in 2 Calabria and Malta populations using the AmpFlSTR NGM SElect™ PCR Amplification Kit (Applied Biosystems) and the PowerPlex ESI 17 (Promega). Material & Methods: A total of 41 different alleles were observed in the 2 examined populations with no allele being more frequent than 10,5%. In the Maltese population more intermediate alleles than in Calabria were found. Allelic frequencies and statistical parameters of forensic interest (Dp,PE, RMP) were calculated using PowerStats v.1.2 software. Hardy-Weinberg equilibrium and other population parameters were calculated using Arlequin v.3.1 and TFPGA v1.3 softwares. Results: No significant deviations from Hardy–Weinberg equilibrium were found. Calabria and Malta allelic frequencies were compared to previously published population data and no significant differences were found. When comparing with Sicily no overall significant genetic distances were found, while comparison to other populations showed significant ones. Moreover comparison with non-European population showed no big distances between Germany and Morocco and between Hungary and Turkey. Conclusion: confirmed the locus is effectively highly polymorphic and useful not only for forensic identification but also in paternity cases in addition to the set of STRs loci commonly used..

SNPs analysis of ABCA4 gene in Han Chinese in Beijing / 实用口腔医学杂志

Objective:To provide the basis of single nucleotide polymorphism(SNPs)for identification and analysis of ABCA4 gene related etiologic studies in Han Chinese in Beijing(CHB).Methods:SNPs of ABCA4 gene were analyzed for minor allele frequencies (MAFs),haplotype frequencies,linkage disequilibrium patterns,and tag SNPs by Haploview program using the HapMap data.Re-sults:129(37.6%)of 343 SNPs were monotonic.95 tagging SNPs were identified in 214 eligible SNPs with 3 haplotype blocks identi-fied.The frequencies of the top 2 haplotypes among each of the 3 haplotype blocks were between 91.1% and 94.0%.Conclusion:SNPs in ABCA4 gene were analyzed by Haploview program.The analysis provides clues for future studies involving this gene.

Genetic variability of the bovine prolactin-Rsal loci in Holstein cattle in Antioquia province (Colombia) / Variabilidad genética del loci RsaI de la prolactina bovina en ganado Holstein de Antioquia, Colombia / Variabilidade genética do loci RsaI da prolactina bovina em gado Holandês de Antioquia, Colombia

The Holstein breed, widely used in Antioquia's dairy industry, has undergone genetic changes due to selection that have affected the frequencies of some polimorphisms within important genes. Objective: to identify polymorphism changes in the prolactin RsaI (PRL-Rsal) locus and to characterize the structure and allelic distribution within the Holstein population in Antioquia. Methods: a total of 1.462 Holstein cows from 11 subpopulations (municipalities) of Antioquia were used. The ADN was extracted from leucocytes using the salting-out method and genotyping was performed by PCR-RFLP. Genetic diversity was determined by heterozygosity. The Hardy-Weinberg equilibrium (HW) and the genetic differentiation among populations were performed using the Arlequin 2.0 software. Allelic and genotypic frequencies were assessed with the SAS 9.2 statistical software. Results: the genotypic frequencies found were 0.695 (AA), 0.276 (AB), and 0.029 (BB), while the frequencies of the A and B alleles were 0.833 and 0.167, respectively. There were no deviations from HW equilibrium in any population. Genetic diversity among populations, expressed in terms of heterozygosity, showed a medium value (Ho=0.276). The F ST value of the entire population was significant, indicating genetic differentiation. In addition, some matched F ST showed high differentiation. The F IT and F IS parameters were not significant, suggesting that population endogamy or exogamy is not occurring. Conclusions: the bovine PRL-RsaI polymorphism is a suitable marker to evaluate characteristics of economic importance and apparently it has not been influenced by selection pressure. In fact, a significantly high variability (p<0.05) in allele frequencies was observed within the Antioquian Holstein cattle subpopulations.

La raza Holstein en Antioquia ha sido utilizada ampliamente por la industria de lechería especializada, lo cual ha generado cambios genéticos en las diferentes poblaciones debido a algunas fuerzas de selección que han afectado las frecuencias de algunos alelos en genes de importancia económica. Objetivo: determinar las frecuencias alélicas y genotípicas de un polimorfismo del exón 4 del gen de prolactina bovino (PRL) en el cual se genera un sitio polimórfico para la endonucleasa de restricción RsaI y a partir de estas frecuencias estimar algunos parámetros de estructura poblacional en ganado Holstein. Métodos: el estudio se llevó a cabo en 1.462 vacas Holstein de 11 subpoblaciones (municipios) del departamento de Antioquia. Se extrajo ADN de leucocitos de sangre periférica por el método de Salting out y se realizó la genotipificación mediante la técnica de PCR-RFLPs. La diversidad genética se expresó mediante las heterocigosidades. Se determinó adicionalmente el equilibrio de Hardy-Weinberg y la estructuración genética poblacional mediante el software Arlequin 2.0. Las frecuencias alélicas y genotípicas se evaluaron mediante el paquete estadístico SAS 9.2. Resultados: las frecuencias genotípicas encontradas fueron 0.695 (AA), 0.276 (AB) y 0.029 (BB) y las frecuencias alélicas 0.833 (A) y 0.167 (B). No se encontraron desviaciones del Equilibrio de Hardy-weinberg en ninguna población. La heterocigosidad fue media entre poblaciones (Ho=0.276). El valor de F ST de toda la población fue significativo, indicando estructuración genética. Los estadísticos F IT y F IS no fueron significativos, por tanto no es posible asumir endogamia o exogamia en las poblaciones teniendo como referencia este polimorfismo. Conclusiones: el polimorfismo en el exón 4 del gen de la prolactina bovina es un marcador interesante para evaluar características de importancia económica, ya que este no parece haber sido sometido a selección directa, presenta frecuencias alélicas muy variables entre poblaciones, con diferenciación significativa e incluso muy alta entre algunas subpoblaciones (p<0.05).

A raça Holandesa em Antioquia tem sido muito utilizada pela indústria leiteira especializada, isto tem gerado mudanças genéticas nas diferentes populações devido a algumas forças de seleção que tem afetado as frequências de alguns alelos em genes de importância econômica. Objetivo: determinar as frequências alélicas e genotípicas de um polimorfismo no exon 4 do gene da prolactina bovina (PRL) no qual se gera um sitio polimórfico para a endonuclease de restrição RsaI e com essas frequências estimar alguns parâmetros da estrutura populacional no gado Holandês. Métodos: o estudo foi realizado em 1.462 vacas da raça Holandesa de 11 subpopulações (municípios) de Antioquia. A extração do ADN se fez pelo método de Salting Out e a genotipagem foi realizada pela técnica PCR-RFLP. A diversidade genética foi determinada mediante as heterozigosidades, e o equilíbrio de Hardy-Weinberg (HW) e a diferenciação genética entre as populações foram realizadas usando o software Arlequin v. 2.0. As frequências alélicas e genotípicas foram analisadas com o programa estatístico SAS v. 9.2. Resultados: as frequências genotípicas encontradas foram 0.695 (AA), 0.276 (AB) e 0.029 (BB) e as frequências alélicas 0.833 (A) e 0.167 (B). Não se encontraram desvios no equilíbrio de Hardy-Weinberg nas subpopulações. A diversidade genética expressada como a heterozigosidade observada foi media entre toda a população (Ho=0.276). O valor de F ST de toda a população foi significativo indicando estruturação genética. Os estatísticos F IT e F IS não foram significativos, por tal razão não foi possível assumir endogamia ou exogamia nas subpopulações. Conclusões: o SNP no exon 4 do gene da prolactina bovina é um marcador interessante para avaliar características de importância econômica, já que este não parece ter tido um processo de seleção direta, alem, tem frequências alélicas muito variáveis entre as diferentes subpopulações, com diferenciação significativa e ainda muito elevada entre as subpopulações avaliadas (p<0.05).

Determinación del polimorfismo C677T de metilentetrahidrofolato reductasa (MTHFR) en una población piloto de estudiantes de la Universidad del Rosario / Preliminary population study of Methylenetetrahydrofolate Reductase (MTHFR) C677T polymorphism determination in a pilot group of students from the University of Rosario

Introducción: la 5, 10-metilentetrahidrofolato reductasa (MTHFR) es una enzima clave en el metabolismo del folato; sus polimorfismos se han asociado al aumento de riesgo de padecer enfermedad coronaria, problemas obstétricos en mujeres gestantes, desarrollo de fetos con defectos de cierre del tubo neural y susceptibilidad a algunos tipos de cáncer. Este gen presenta una variación polimórfica de nucleótido único, que consiste en un cambio de C por T en la posición 677 el cual afecta de manera notable su actividad enzimática. Objetivo: Dada la importancia de esta enzima y la heterogeneidad genética de la población colombiana se realizó un estudio para determinar las frecuencias alélicas y genotípicas del polimorfismo C677T de MTHFR en individuos sanos, debido a que en el país sólo se han realizado estudios que involucran metodología de casos y controles. Materiales y métodos: Este polimorfismo se estudió a partir de ADN de una muestra poblacional de 206 estudiantes. Adicionalmente, se calcularon las frecuencias globales de Colombia utilizando los datos de controles sanos reportados en otros estudios. Resultados: En la muestra evaluada se detectó un desequilibrio Hardy-Weinberg, mientras que en los datos globales colombianos se encontró que la población está en equilibrio. Conclusión: la frecuencia poblacional del alelo T parece estar sometida a una presión de selección positiva, dado su incremento en la población a pesar de su efecto deletéreo. Un estudio español reporta resultados similares y argumenta como causa probable de este cambio en la frecuencia alélica de T la suplementación con ácido fólico a futuras madres.

Introduction: the 5, 10-methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in folate metabolism; their polymorphisms have been associated with heart disease risk increase, obstetric problems, neural tube defects in fetuses and cancer susceptibility. This gene has a single nucleotide polymorphism, a C-T change at nucleotide 677, which affects significantly its enzymatic activity. Objective: because of the biological importance of this enzyme and the Colombian population genetic heterogeneity characteristic, a study was performed to determine allele and genotype frequencies of MTHFR C677T polymorphism in healthy individuals, taking into account that in Colombia there are only studies that have involved case-control methodology. Methods: we analyzed this polymorphism trough the amplification of the DNA of a 206 students sample population. Additionally, Colombian overall frequencies were calculated, using data from healthy controls reported in other studies. Results: a Hardy-Weinberg disequilibrium was found in the sample tested. For the Colombian data, we found that the global population was in equilibrium. Conclusion: T allele population frequency seems to be under positive selection pressure, which is reflected in the population allele increase, despite its deleterious effect. A Spanish study reported similar results and identified folic acid supplementation on expectant mothers as a probably cause of this change.

Hardy-Weinberg equilibrium in genetic epidemiology / 中南大学学报(医学版)

Hardy-Weinberg equilibrium test is the base of genetic epidemiology. The new methods for Hardy-Weinberg equilibrium test involve: X chromosome-linked single nucleotide polymorphism Hardy-Weinberg test, inbreeding coefficient(F) test, an incomplete enumeration algorithm for an exact test of Hardy-Weinberg proportions with multiple alleles, and graphical tests for Hardy-Weinberg equilibrium based on the ternary plot. It is necessary to conduct Hardy-Weinberg equilibrium test in genetic epidemiology studies and adjust the associations as deviation of Hardy-Weinberg equilibrium occurs.

Distribución de las frecuencias alélicas y genotípicas del polimorfismo GHRd3 en pacientes venezolanos con talla baja

Objetivos. La deleción (GHRd3) o inserción (GHRfl) del exón 3 es un polimorfismo común en el gen del receptor de la hormona de crecimiento (GHR) en los seres humanos. La presencia del alelo GHRd3 se ha asociado con el grado de respuesta de terapia con Hormona de Crecimiento Recombinante Humana (rhGH). El objetivo de este estudio fue determinar las frecuencias alélicas y genotípicas de este polimorfismo en un grupo de 69 niños venezolanos con talla baja que estaban recibiendo rhGH. Métodos. Se extrajo DNA a través de la técnica del método combinado Fenol/Sevag e Inorgánica. Se determinó el genotipo del exón 3 del gen GHR usando tanto PCR- monoplex como PCR-multiplex. Resultados. Entre los pacientes con talla baja la frecuencia genotípica se distribuyó de la siguiente manera: GHRfl/GHRfl (55%) GHRfl/GHRd3 (35%) y GHRd3/GHRd3 (10%) y la frecuencia alélica fue de 0,27 para GHRd3 y 0,73 para GHRfl. Para el grupo testigo la frecuencia genotípica se distribuyo así: GHRfl/GHRfl (56%), GHRfl/ GHRd3 (30%) y GHRd3/GHRd3 (14%) y la frecuencia alélica era de 0,29 para GHRd3 y 0,71 para GHRfl. Las características clínicas basales de los pacientes con talla baja eran similares entre los diferentes genotipos encontrados en el grupo de estudio. Conclusiones. La proporción del genotipo y los alelos del gen GHR fueron similares entre el grupo testigo y los pacientes con talla baja, lo que traduce que la etiología de la talla baja no obedece a este polimorfismo.

Objective. The deletion (GHRd3) or insertion (GHRfl) of exon 3 is a common polymorphism in the receptor growth hormone gene (GHR) in humans. The presence of the allele GHRd3 has been associated with the degree of responsiveness to therapy with recombinant human Growth Hormone (rhGH). The aim of this study was to determine the genotypic and allele frequencies of this polymorphism in a group of 69 Venezuelan children with short stature who were receiving rhGH. Methods. Genomic DNA was extracted from blood lymphocytes using combined method Fenol/SEVAG + Salting out. The GHR-exon 3 was genotyped using both PCR monoplex and multiplex assays. Results. Among patients with short stature, genotype frequency was distributed as follows: GHRfl/GHRfl (55%), GHRfl/GHRd3 (35%) and GHRd3/GHRd3 (10%) and allele frequency for GHRd3 and GHRfl was 0.27 and 0.73, respectively. For the control group, genotype frequency was distributed as follows: GHRfl/GHRfl (56%), GHRfl/GHRd3 (30%) and GHRd3/GHRd3 (14%) and allele frequency for GHRd3 and GHRfl was 0.29 and 0.71, respectively. The baseline clinical features of patients with short stature were similar among different genotypes found in the study group. Conclusions. The proportion of genotype and allele of the GHR gene were similar between the control group and patients with short stature, which translates that the etiology of short stature is not due to this polymorphism.

A straightforward multiallelic significance test for the Hardy-Weinberg equilibrium law

Much forensic inference based upon DNA evidence is made assuming Hardy-Weinberg Equilibrium (HWE) for the genetic loci being used. Several statistical tests to detect and measure deviation from HWE have been devised, and their limitations become more obvious when testing for deviation within multiallelic DNA loci. The most popular methods-Chi-square and Likelihood-ratio tests-are based on asymptotic results and cannot guarantee a good performance in the presence of low frequency genotypes. Since the parameter space dimension increases at a quadratic rate on the number of alleles, some authors suggest applying sequential methods, where the multiallelic case is reformulated as a sequence of "biallelic" tests. However, in this approach it is not obvious how to assess the general evidence of the original hypothesis; nor is it clear how to establish the significance level for its acceptance/rejection. In this work, we introduce a straightforward method for the multiallelic HWE test, which overcomes the aforementioned issues of sequential methods. The core theory for the proposed method is given by the Full Bayesian Significance Test (FBST), an intuitive Bayesian approach which does not assign positive probabilities to zero measure sets when testing sharp hypotheses. We compare FBST performance to Chi-square, Likelihood-ratio and Markov chain tests, in three numerical experiments. The results suggest that FBST is a robust and high performance method for the HWE test, even in the presence of several alleles and small sample sizes.

Influential factors of Hardy-Weinberg equilibrium on the study of association between gene polymorphism and disease / 中华流行病学杂志

Objective According to the data collected from gastric cancer families comparative study, the influence factors of Hardy-Weinberg (H-W) equilibrium in the association studies of gene polymorphism and disease were analyzed to reveal the reasons that affecting the equilibrium deviation in the group. Methods Varieties of risk genotype for gastric cancer were analyzed and detected with H-W equilibrium, genetic linkage disequilibrium analysis and Cochran-Armitage trend test. Results (1) Significant deviations from H-W equilibrium were observed in IL-1B-31, IL-IB-511, IL-IRN and TNF-A-308 of the cases and controls (P<0.01). MIF-173 tended to be equilibrium in the population. (2)Deviations from expectations of phenotypes combination probability were observed in two-site H-W χ2 tests (P< 0.01). (3)The Cochran-Armitage trend test showed that distribution of IL-1B-511 and IL-1RN were significantly different(P<0.05), suggesting that population stratification might have existed in the group. Conclusions (1)Affected by frequency-dependent selection, under the combination of linkage disequilibrium, mutations and interaction, genotype frequency of IL-1B-31, IL-1B-511, IL-1RN and TNF-A-308 showed deviation from H-W equilibrium in population. (2)Two-site genetic equilibrium test model seemed better to reflect the differences of phenotypic combination fitness. (3)Population stratification was another factor to express the deviation from H-W equilibrium.

TaqI B1/B2 and -629A/C cholesteryl ester transfer protein (CETP) gene polymorphisms and their association with CETP activity and high-density lipoprotein cholesterol levels in a Tehranian population. Part of the Tehran Lipid and Glucose Study (TLGS)

We examined the cholesteryl ester transfer protein (CETP) gene TaqI intron 1 B1/B2 polymorphism and the -629A/C CETP promoter polymorphism in respect to high-density lipoprotein cholesterol (HDL-C) in a healthy Iranian population taken from the Tehran Lipid and Glucose Study (TLGS). The relationship between CETP activity and HDL-C level was also determined along with body mass index, blood pressure and tobacco smoking status. PCR-RFLP used to amplify a segment of the CETP intron 1 TaqI (B2/B1) polymorphism from 1021 individuals and we selected 345 individuals from the lowest, middle and highest HDL-C deciles and investigated the -629A/C polymorphism. We also evaluated the CETP activity of 103 of these individuals, each with at least one homozygous allele. The presence of the TaqI B2 and -629A/C A alleles were significantly associated with increased HDL-C levels (B2B2 = 1.19 ± 0.31 mmolL-1 vs. B1B1 = 1.01 ± 0.2 mmol L-1 for p < 0.001; AA = 1.15 ± 0.41 mmol L-1 vs. CC = 0.95 ± 0.28 mmol L-1 for p < 0.001) and decreased the CETP activity (B1B1 = 67.8 ± 8.9 pmol L-1 vs. B2B2 = 62.6 ± 9.6 pmol L-1 for p < 0.01; CC = 68.6 ± 8.4 pmol L-1 vs. AA = 62.7 ± 9.7 pmol L-1 for p < 0.002). The frequencies were 0.382 for the TaqI B2 allele and 0.462 for the -629A/C A allele, with linkage disequilibrium analysis giving D = 0.0965 and D' = 0.4695. We demonstrated that the TaqI B1 and B2 alleles and the -629A/C A and C alleles were in linkage disequilibrium in our population and that there was a significant association between the B2 and A alleles and high HDL-C levels and low CETP activity. Linkage disequilibrium between the TaqI A and B2 alleles also detected.

Genuine Bayesian multiallelic significance test for the Hardy-Weinberg equilibrium law

Statistical tests that detect and measure deviation from the Hardy-Weinberg equilibrium (HWE) have been devised but are limited when testing for deviation at multiallelic DNA loci is attempted. Here we present the full Bayesian significance test (FBST) for the HWE. This test depends neither on asymptotic results nor on the number of possible alleles for the particular locus being evaluated. The FBST is based on the computation of an evidence index in favor of the HWE hypothesis. A great deal of forensic inference based on DNA evidence assumes that the HWE is valid for the genetic loci being used. We applied the FBST to genotypes obtained at several multiallelic short tandem repeat loci during routine parentage testing; the locus Penta E exemplifies those clearly in HWE while others such as D10S1214 and D19S253 do not appear to show this.