New candidate SNPs for genetic association with Alzheimer's disease: a linkage disequilibrium analysis for the FCGRIIB and PILRA genes

Background Two new SNPs have been recently associated to Alzheimer's disease in African American populations: FCGRIIB rs1050501 C/T, and PILRA rs1859788 A/G. The risk of Alzheimer's disease in FCGRIIB C and PILRA A allele carriers is three times higher than in non-carriers. However, the association between these and other single nucleotide polymorphisms (SNPs) has not been assessed. Methods Linkage disequilibrium analysis, with r= 0.8 as a threshold value, was used to impute new candidate SNPs, on genomic data from both genes in 26 populations worldwide (n= 2504) from the 1000Genomes database. Results Four SNPs (rs13376485, rs3767640, rs3767639 and rs3767641) were linked to rs1050501 and one (rs2405442) to rs1859788 in the whole sample. Conclusions Five novel SNPs could be associated with Alzheimer's disease susceptibility and play a causal role, even if none of them are exon variants since their potential roles in the regulation of gene expression.

Antecedentes Recientemente se han asociado dos nuevos polimorfismos de un solo nucleótido (SNP) a la enfermedad de Alzheimer en poblaciones afroamericanas: FCGRIIB rs1050501 C/T, y PILRA rs1859788 A/G. El riesgo de enfermedad de Alzheimer en los portadores de los alelos FCGRIIB C y PILRA A es tres veces mayor que en los no portadores. Sin embargo, no se ha evaluado la asociación entre estos y otros SNP. Métodos Se utilizó el análisis de desequilibrio de ligamiento, con r2= 0,8 como valor umbral, para imputar nuevos SNPs candidatos, sobre datos genómicos de ambos genes en 26 poblaciones de todo el mundo (n= 2504) de la base de datos 1000Genomes. Resultados Cuatro SNPs (rs13376485, rs3767640, rs3767639 y rs3767641) se vincularon al rs1050501 y uno (rs2405442) al rs1859788 en toda la muestra. Conclusiones Cinco nuevos SNP podrían estar asociados con la susceptibilidad a la enfermedad de Alzheimer y desempeñar un papel causal, aunque ninguno de ellos sea una variante de exón, dado su papel potencial en la regulación de la expresión génica.

population analysis of the CLOCK rs3749474T-rs4864548A haplotype and its relationship with obesity / Análisis poblacional in silico del haplotipo CLOCK rs3749474T-rs4864548A y su relación con obesidad

Se ha sugerido que el haplotipo rs3749474T/rs4864548A del gen CLOCK aumentaría el riesgo de obesidad, pero se desconoce el patrón de variabilidad poblacional de estos alelos y del haplotipo. El objetivo de este estudio es determinar el nivel de ligamiento entre los alelos de riesgo rs3749474T y rs4864548A a partir de la base de datos 1000Genomes para confirmar la existencia del haplotipo TA de los polimorfismos rs3749474-rs4864548 del gen CLOCK y su frecuencia cinco macro poblaciones. Se analizó el desequilibrio de ligamiento y las frecuencias haplotípicas para 2504 individuos, de 26 poblaciones, utilizando el estadístico r y la prueba exacta de Fisher. Existe una alta frecuencia del haplotipo TA en Latinoamérica (44,8%), un alto desequilibrio de ligamiento (r= 0,92) a nivel mundial entre esos alelos, una alta diferenciación entre macro poblaciones y una alta homogeneidad al interior de ellas. La evidencia presentada permite sugerir la realización de posteriores estudios de asociación entre este haplotipo y el nivel de riesgo de obesidad y sobrepeso en poblaciones latinoamericanas.

It has been suggested that the rs3749474T/rs4864548A haplotype of the CLOCK gene increases the risk of obesity, but the population variability of these alleles and the haplotype is unknown. This research aims to determine the linkage between the rs3749474T and rs4864548A alleles from the database of 1000Genomes to confirm the existence of the TA haplotype polymorphisms of these alleles and their frequency in five macro populations. Linkage disequilibrium and haplotype frequencies for 2504 individuals from 26 populations were analyzed using the r statistic and Fisher's exact test. There is a high frequency of the TA haplotype in Latin America (44.8%), a high linkage disequilibrium (r2= 0.92) worldwide between these alleles, a high differentiation between macro populations, and a high homogeneity. The evidence warrants further studies on the association between this haplotype and the risk of obesity and overweight in Latin American populations.

Strong Linkage Disequilibrium and Haplotype Association of Neovascular Age-related Macular Degeneration in Indonesian Patients

@#Introduction: The aim of this study was to investigate the linkage disequilibrium (LD) and haplotype of three most associated SNP with nAMD of 80 patients in Indonesia. Methods: All patients underwent standard ophthalmic tests including fundoscopy and optical coherence tomography. Genomic DNA was extracted using commercially available DNA isolation kits. Genotyping of rs11200638, rs1061170 and del443ins54 used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. The acquired genotype data were analyzed using Haploview and R package software. Results: Linkage Disequilibrium analyses showed high LD value in the 10q26 region of 80 patients with AMD and 85 controls. The PCR-RFLP showed TTA was the most frequent haplotype while GTG was the most associated haplotype in the study sample. Conclusion: There was a high LD in the 10q26 region and strong association in GTG haplotype of Indonesian patients with AMD.

Interaction analysis of FTO and IRX3 genes with obesity and related metabolic disorders in an admixed Latin American population: a possible risk increases of body weight excess / Análisis de la interacción entre los genes FTO e IRX3 con obesidad y desórdenes metabólicos relacionados en una población mixta de América Latina: un posible aumento del riesgo de exceso de peso

Abstract Background: Fat Mass and Obesity-related (FTO) has been one of the genes consistently related to common obesity. Single nucleotide polymorphisms (SNPs) in FTO have been linked with the IRX3 gene. Aim: This study was designed by testing the hypothesis that: i) common SNPs in FTO and IRX3 are associated with obesity and related disorders; ii) there is significant linkage disequilibrium between both genes. Methods: A cross-sectional study was carried out on the Colombian Caribbean Coast. Anthropometric and biochemical variables were measured, and obesity and metabolic disorders were diagnosed. Four SNPs were genotyped: 3 at FTO locus (rs17817449, rs8050136, rs9939609) and one at IRX3 locus (rs3751723). LD between these SNPs was estimated. A logistic regression model was applied to estimate associations. Results: A total of 792 subjects were included. FTO and IRX3 were not in LD (D'≤ 0.03; R2≤ 0.03). TT genotype (rs9939609) was found to be associated with waist circumference (p= 0.04; adj-p= 0.01), and IRX3 SNP with Body Weight Excess (BWE) (OR= 1.06, adj-p= 0.03). One FTO-IRX3 haplotype was associated with BWE (G-A-A-T, rs17817449-rs8050136-rs9939609-rs3751723; OR= 0.67, p= 0.04). The statistical significance of these relations continued after admixture adjustment for a three-hybrid population (p= 0.03). Conclusions: FTO was related to waist circumference, and IRX3 was associated with BWE in Latin American adults. This relation remained statistically significant after an adjustment for sex, age, and genetic ancestry was performed. Despite that these genes were not in LD, findings of a haplotype involving FTO-IRX3 suggest a gene-gene interaction associated with an increased risk of BWE.

Resumen Introducción: FTO (Fat Mass and Obesity-related) se ha relacionado de manera consistente con la obesidad. Recientemente, Polimorfismos de Nucleótido Único (SNP) en este gen se han relacionado con el gen IRX3. Objetivo: Probar la hipótesis de que: i) SNPs en FTO e IRX3 están asociados con la obesidad y trastornos relacionados; ii) existe desequilibrio de ligamiento (LD) significativo entre ambos genes. Métodos: se realizó un estudio transversal en la costa caribe colombiana. Se valoraron variables antropométricas y bioquímicas, la obesidad y trastornos metabólicos. Se genotipificaron 4 SNPs: 3 en FTO (rs17817449, rs8050136, rs9939609) y uno en IRX3 (rs3751723). Se estimó el LD entre estos SNPs. Se aplicó un modelo de regresión logística para estimar asociaciones. Resultados: Se incluyeron 792 sujetos. FTO e IRX3 no se encontraron en LD (D' ≤0.03; R2 ≤0.03). El genotipo TT (rs9939609) se encontró asociado con la circunferencia de la cintura (p= 0.04; adj-p= 0.01), y el SNP IRX3 con el Exceso de Peso (EP) (OR= 1.06, adj-p= 0.03). Se encontró un haplotipo FTO-IRX3 asociado con EP (G-A-A-T, rs17817449-rs8050136-rs9939609-rs3751723; OR= 0.67, p= 0.04). Esta asociación persistió después del ajuste para una población mixta (p= 0.03). Conclusiones: FTO se encontró asociado con la circunferencia de la cintura e IRX3 con EP en adultos latinoamericanos. Estas asociaciones persistieron tras el ajuste por sexo, edad y ascendencia genética. Aunque estos genes no estaban en LD, los hallazgos de un haplotipo entre FTO-IRX3 sugieren una interacción gen-gen asociada con un mayor riesgo de EP.

Identification of patterns related to linkage groups or disequilibrium by factor analysis / Identificação de padrões relacionados a grupos de ligação ou de desequilíbrio por análise de fatores

ABSTRACT: Empirical patterns of linkage disequilibrium (LD) can be used to increase the statistical power of genetic mapping. This study was carried out with the objective of verifying the efficacy of factor analysis (AF) applied to data sets of molecular markers of the SNP type, in order to identify linkage groups and haplotypes blocks. The SNPs data set used was derived from a simulation process of an F2 population, containing 2000 marks with information of 500 individuals. The estimation of the factorial loadings of FA was made in two ways, considering the matrix of distances between the markers (A) and considering the correlation matrix (R). The number of factors (k) to be used was established based on the graph scree-plot and based on the proportion of the total variance explained. Results indicated that matrices A and R lead to similar results. Based on the scree-plot we considered k equal to 10 and the factors interpreted as being representative of the bonding groups. The second criterion led to a number of factors equal to 50, and the factors interpreted as being representative of the haplotypes blocks. This showed the potential of the technique, making it possible to obtain results applicable to any type of population, helping or corroborating the interpretation of genomic studies. The study demonstrated that AF was able to identify patterns of association between markers, identifying subgroups of markers that reflect factor binding groups and also linkage disequilibrium groups.

RESUMO: Padrões empíricos de desequilíbrio de ligação (LD) podem ser utilizados para aumentar o poder estatístico do mapeamento genético. Este trabalho foi realizado com o objetivo de verificar a eficácia da análise de fatores (AF) aplicada a conjuntos de dados de marcadores moleculares do tipo SNP, visando identificar grupos de ligação e blocos de haplótipos. O conjunto de dados SNPs utilizado foi oriundo de um processo de simulação de uma população F2, contendo 2000 marcas com informações de 500 indivíduos. A estimação das cargas fatoriais (loadings) da AF foi feita de duas formas, considerando a matriz de distâncias entre os marcadores (A) e considerando a matriz de correlação (R). O número de fatores (k) a ser utilizado foi estabelecido com base no gráfico scree-plot e com base na proporção da variância total explicada. Os resultados indicam que as matrizes A e R conduzem a resultados similares. Com base no scree-plot considerou-se k igual a 10 e os fatores interpretados como sendo representativos dos grupos de ligação. O segundo critério conduziu a um número de fatores igual a 50, e os fatores interpretados como sendo representativos dos blocos de haplótipos. Isto mostra o potencial da técnica que permite obter resultados aplicáveis ​​a qualquer tipo de população, corroborando a interpretação de estudos genômicos. O trabalho demonstrou que a AF foi capaz de identificar padrões de associação entre marcadores, identificando subgrupos de marcadores que refletem grupos de ligação fatorial e também grupos de desequilíbrio de ligação.

Linkage disequilibrium and haplotypes of five TP53 polymorphisms in oesophageal cancer patients

The aim of present study was to evaluate the linkage disequilibrium (LD) of p.R72P, PIN3 Ins16bp, p.P47S, p.R213R and r.13494g[a polymorphism of TP53 and their haplotypes association with oesophageal cancer risk in patients from Punjab, northwest India. A total of 466 samples, including 233 oesophageal cancer patients and 233 healthy individuals were analysed. Data analysis revealed the gender specific association. In female group, arginine–proline (RP) genotype (P = 0.08) and P allele (P = 0.07) of p.R72P polymorphism was marginally associated with increased risk of oesophageal cancer. A1A2 genotype (P = 0.06) and A2 allele (P = 0.07) of PIN3 Ins16bp polymorphism was marginally associated with decreased risk of oesophageal cancer in male group. A1A2–GA genotype combination (P = 0.04) of PIN3 and r.13494g[a polymorphisms was significantly associated with decreased risk of oesophageal cancer in male group. In female group, PP–GA genotype combination (P = 0.02) of p.R72P and r.13494g[a polymorphisms and RP–A1A1–GG genotype combination (P = 0.04) of p.R72P, PIN3 and r.13494g[a polymorphisms was significantly associated with increased risk of oesophageal cancer. We observed moderate LD between two intronic polymorphisms PIN3 Ins16bp and r.13494g[a (D0 = 0.90; r 2 = 0.68). Haplotype analysis revealed that none of the haplotype combination was associated with oesophageal cancer risk when both the genders were considered. Stratification on the basis of gender showed that P-A2-P-A-A haplotype of p.R72P, PIN3 Ins16bp, p.P47S, p.R213R and r.13494g[a polymorphisms was marginally associated with reduced oesophageal cancer risk in male group (P = 0.08). Replication of these findings in independent cohorts may be insightful for the role of TP53 in oesophageal cancer pathogenesis.

The association of stromal antigen 3 (STAG3) sequence variations with spermatogenic impairment in the male Korean population / 亚洲男科学杂志(英文版)

The stromal antigen 3 (STAG3) gene, encoding a meiosis-specific cohesin component, is a strong candidate for causing male infertility, but little is known about this gene so far. We identified STAG3 in patients with nonobstructive azoospermia (NOA) and normozoospermia in the Korean population. The coding regions and their intron boundaries of STAG3 were identified in 120 Korean men with spermatogenic impairments and 245 normal controls by using direct sequencing and haplotype analysis. A total of 30 sequence variations were identified in this study. Of the total, seven were exonic variants, 18 were intronic variants, one was in the 5'-UTR, and four were in the 3'-UTR. Pathogenic variations that directly caused NOA were not identified. However, two variants, c.3669+35C>G (rs1727130) and +198A>T (rs1052482), showed significant differences in the frequency between the patient and control groups (P = 0.021, odds ratio [OR]: 1.79, 95% confidence interval [CI]: 1.098-2.918) and were tightly linked in the linkage disequilibrium (LD) block. When pmir-rs1052482A was cotransfected with miR-3162-5p, there was a substantial decrease in luciferase activity, compared with pmir-rs1052482T. This result suggests that rs1052482 was located within a binding site of miR-3162-5p in the STAG3 3'-UTR, and the minor allele, the rs1052482T polymorphism, might offset inhibition by miR-3162-5p. We are the first to identify a total of 30 single-nucleotide variations (SNVs) of STAG3 gene in the Korean population. We found that two SNVs (rs1727130 and rs1052482) located in the 3'-UTR region may be associated with the NOA phenotype. Our findings contribute to understanding male infertility with spermatogenic impairment.

Association between mandibular prognathism and the candidate gene GHR in the Han Chinese in Hong Kong / 医学研究生学报

Objective　Studies on the location of the susceptibility genes of mandibular prognathism are mostly conducted by association analysis. The aim of this study was to investigate the correlation between the single nucleotide polymorphism (SNP) of the candidate gene of the growth hormone receptor (GHR) and mandibular prognathism in the Han Chinese in Hong Kong. Methods We selected 7 tag SNPs (tSNP) in the GHR gene from 211 cases of mandibular prognathism and 224 controls among the Han Chinese in Hong Kong. We genotyped the tSNPs using the MassARRAY System and analyzed the association of individual SNPs and the relevant haplotypes with mandibular prognathism.　Results　The SNP rs6898743 of the GHR gene was found associated with mandibular prognathism in genotypic frequency (P = 0.036) and allelic distribution (P = 0.015), and the G allele of rs6898743 associated with a significantly decreased risk of mandibular prognathism (OR: 0.72; 95% CI: 0.55-0.94). Linkage disequilibrium analysis revealed the association of mandibular prognathism with the haplotypes GAA (P = 0.014) and GAG (P = 0.012).　Conclusion　The SNP locus rs6898743 of the GHR gene is associated with mandibular prognathism in the Han Chinese in Hong Kong

Presence of Non-African Haplotypes Increase Genetic Diversity in Sickle Cell Anemia Patients in Colombia / Presencia de haplotipos no africanos incrementa la diversidad genética en pacientes con anemia falciforme en colombia

RESUMEN El objetivo de este estudio fue identificar la frecuencia de haplotipos dentro del cluster de Beta globina presente en pacientes con anemia falciforme en Colombia, establecer la presencia de haplotipos no africanos en esta población, así como verificar variaciones en el patrón de desequilibrio de ligamiento dentro del cluster de Beta globina. Se analizaron 83 individuos con anemia falciforme, los haplotipos se formaron utilizando cinco sitios de restricción dentro del cluster de Beta globina, se estableció la frecuencia de haplotipos, se calculó el grado de desequilibrio de ligamiento entre los sitios de restricción, así como la similitud genética de esta población con otra de afectados en América. Los haplotipos más frecuentes en la población fueron Benin (35,1 %) y Bantú (26, 5 %), ambos africanos. Sin embargo, haplotipos presentes en poblaciones indígenas americanas y europeas alcanzaron frecuencias entre el 2 - 10 %, así como haplotipos que no han sido reportados en otras poblaciones. Los sitios de restricción presentaron bajo o nulo desequilibrio de ligamiento entre ellos. Al compararse con otras poblaciones, la población colombiana presentó mayor similitud con la población de Venezuela en donde Benin y Bantú son también predominantes. Nuestros resultados muestran que el mestizaje ha facilitado el paso de la mutación para la anemia falciforme a un contexto genético no africano (amerindio y europeo). Además, el mestizaje también ha alterado el patrón de desequilibrio de ligamiento dentro del cluster de Beta globina generando modificaciones que pueden tener influencia en estudios de asociación dentro de esta población de afectados.

ABSTRACT The objective of this study was identify the frequency of Beta globin cluster's haplotypes present in sickle cell anemia patients in Colombia, to establish the presence of non-African haplotypes in this population, to verify variations in the pattern of linkage disequilibrium in the Beta globin cluster. It was analyzed 83 individuals affected with sickle cell anemia, the haplotypes were formed using five restriction sites into Beta globin cluster. The haplotype frequency was calculated, as well as the linkage disequilibrium among restriction sites, the genetic similarity among Colombian population and other affected American population was determined. The haplotypes most frequent were Benin (35.1 %) and Bantu (26.5 %), both African. However, haplotypes present in American indigenous and European populations got frequency between two to ten percent, as well as haplotypes not reported in others population were observed in our population. The restriction sites showed low or null linkage disequilibrium. When compare with other populations, the Colombian population showed higher similarity with Venezuelan population where Benin and Bantu are predominant too. Our results showed that admixture has facilitated the move of sickle cell mutation to a non-African genetic context (Amerindian and European). Further, the admixture has also modified the pattern of linkage disequilibrium into the Beta globin cluster generating modifications that could have influence in association studies in this affected population.

Polimorfismos de un solo nucleótido representativos para los alelos clásicos del antígeno leucocitario humano en familias antioqueñas con diabetes mellitus tipo 1 / Classical HLA alleles tag SNP in families from Antioquia with type 1 diabetes mellitus

Resumen Introducción. La región del antígeno leucocitario humano (Human Leukocyte Antigen, HLA) se ha asociado claramente con enfermedades autoinmunitarias, como la diabetes mellitus de tipo 1. Los polimorfismos representativos de un solo nucleótido (tag Single Nucleotide Polymorphism, tag SNP) constituyen una forma alternativa de evaluar los alelos clásicos del HLA. En la población europea se ha reportado un grupo de tag SNP para múltiples alelos clásicos relacionados con la predisposición o la resistencia frente a dicha enfermedad. Objetivo. Validar la metodología basada en los tag SNP enfocada en la inferencia de alelos HLA clásicos, y evaluar su asociación con la diabetes mellitus de tipo 1 en una muestra de familias antioqueñas. Materiales y métodos. Se estudió una muestra de 200 familias antioqueñas con uno a dos hijos afectados por diabetes mellitus de tipo 1. Se genotipificaron 13 SNP mediante el ARMS-PCR (Amplification Refractory Mutation System-Polymerase Chain Reaction) con cuatro iniciadores, o mediante la PCR-RFLP (PCR-Restriction Fragment Length Polymorphism). Además, se evaluó la validez de los tag SNP de 1.000 genomas reportados en europeos en una muestra de 60 individuos de la población colombiana de Medellín. Se hicieron las pruebas de desequilibrio de la transmisión, de desequilibrio de ligamiento y de equilibrio de Hardy-Weinberg. Resultados. En la población de estudio no se encontró suficiente desequilibrio de ligamiento entre los SNP y los alelos clásicos evaluados, por lo cual no fue posible inferir los alelos clásicos del HLA para el conjunto de familias con diabetes mellitus de tipo 1. El estudio de asociación evidenció que esta región aporta factores tanto de riesgo como de protección para el desarrollo de la enfermedad. Los tag SNP apropiados para la muestra de estudio se determinaron usando los SNP ubicados en la región HLA en la base de datos del 1000 Genomes Project en la mencionada población. Conclusiones. Los patrones de desequilibrio de ligamiento en la población estudiada fueron diferentes a los reportados para la población europea. A pesar de esto, se encontró evidencia clara sobre el papel de la región HLA en el riesgo de padecer diabetes mellitus de tipo 1 en la población de estudio.

abstract Introduction: The HLA region strongly associates with autoimmune diseases, such as type 1 diabetes. An alternative way to test classical HLA alleles is by using tag SNP. A set of tag SNP for several classical HLA alleles has been reported as associated with susceptibility or resistance to this disease in Europeans. Objective: We aimed at validating the methodology based on tag SNP focused on the inference of classical HLA alleles, and at evaluating their association with type 1 diabetes mellitus in a sample of 200 families from Antioquia. Materials and methods: We studied a sample of 200 families from Antioquia. Each family had one or two children with T1D. We genotyped 13 SNPs using tetra-primer ARMS-PCR or PCRRFLP. In addition, we tested the validity of the tag SNP reported for Europeans in 60 individuals from a population of Colombians living in Medellín (CLM) from the 1000 Genomes Project database. Statistical analyses included the Hardy-Weinberg equilibrium, the transmission disequilibrium and the linkage disequilibrium tests. Results: The linkage disequilibrium was low in reported tag SNP and classical HLA alleles in this CLM population. Association analyses revealed both risk and protection factors to develop type 1 diabetes mellitus. Appropriate tag SNPs for the CLM population were determined by using the genotype information available in the 1000 Genome Project database. Conclusions: Although linkage disequilibrium patterns in this CLM population were different from those reported in Europeans, we did find strong evidence of the role of HLA in the development of type 1 diabetes mellitus in the study population.

Polymorphisms at HLA-A,-B,-DRB1 loci in Dalian Han population / 中国免疫学杂志

Objective:To investigate the polymorphisms at HLA-A,-B,-DRB1 loci in Dalian Han population. Methods: A total of 10 000 unrelated marrow donors who live in Dalian were genotyped by SBT and SSO methods. Haplotype frequencies and linkage dis-equilibrium values were calculated by ARLEQUIN software,and DA genetic distances between populations were calculated by poptree2 software. Results: A total of 18 HLA-A alleles, 32 HLA-B alleles and 13 HLA-DRB1 alleles were found in Dalian Han population. HLA-A?02 (31. 65% ),B?40(14. 84% ) and DRB1?15(15. 82% ) occurred most frequently. A?30-B?13-DRB1?07 (4. 56% ) was determined to be the most common three-locus haplotype and the second predominant haplotype was A?02-B?46-DRB1?09 ( 2. 43% ) . A ?30-B ?13 ( 6. 00% ) and B ?13-DRB1 ?07 ( 59. 89% ) were the most common two-locus haplotypes. Moreover,A?33-B?58 and B?13-DRB1?07 were strongest haplotypes with the linkage disequilibria values 0. 336 6 and 0. 665 1,respectively. In China,the closest genetic distances were found with Heilongjiang (0. 001) followed by Jilin (0. 002) and Shandong (0. 002),the furthest was found with Taiwan (0. 047). Compared with other populations worldwide,the closest genetic distances were found with Thailand (0. 029) and Korea (0. 03),the furthest was found with Italy (0. 183). Conclusion: Dalian Han population had rich polymorphism at HLA-A,-B,-DRB1 loci,and the distribution of HLA-A,-B and-DRB1 was in line with the charac-teristics of the northern population.

Associations among PRDM16 polymorphisms, environmental exposure factors during mother's pregnancy, and nonsyndromic cleft lip with or without cleft palate / 华西口腔医学杂志

OBJECTIVE@#We aimed to study the association between rs7525173, rs2236518, rs2493264 single nucleotide polymorphism (SNP) in the PRDM16 gene, smoking, alcohol exposures, and nonsyndromic cleft lip with or without cleft palate (NSCL/P).@*METHODS@#A total of 157 case-parent trios were selected, and SNPs were genotyped by using ligase detection reaction (LDR) and direct sequencing methods. Transmission disequilibrium test (TDT) and linkage disequilibrium (LD) tests were con-ducted to analyze the data. A total of 1 710 patients with orofacial clefts and 956 healthy newborns were enrolled in the epidemiological survey. The smoking and drinking exposures of parents during early pregnancy were analyzed.@*RESULTS@#The C allele at rs2236518 was over-transmitted for NSCPO (P<0.05). Statistical differences were observed among three factors, namely, maternal smoking, maternal passive smoking, and maternal drinking (P<0.05).@*CONCLUSIONS@#The rs2236518 at PRDM16 gene, maternal smoking, maternal passive smoking, and maternal drinking were closely related to the occurrence of NSCL/P.

Genome-wide association study of pre-harvest sprouting resistance in Chinese wheat founder parents

Abstract Pre-harvest sprouting (PHS) is a major abiotic factor affecting grain weight and quality, and is caused by an early break in seed dormancy. Association mapping (AM) is used to detect correlations between phenotypes and genotypes based on linkage disequilibrium (LD) in wheat breeding programs. We evaluated seed dormancy in 80 Chinese wheat founder parents in five environments and performed a genome-wide association study using 6,057 markers, including 93 simple sequence repeat (SSR), 1,472 diversity array technology (DArT), and 4,492 single nucleotide polymorphism (SNP) markers. The general linear model (GLM) and the mixed linear model (MLM) were used in this study, and two significant markers (tPt-7980 and wPt-6457) were identified. Both markers were located on Chromosome 1B, with wPt-6457 having been identified in a previously reported chromosomal position. The significantly associated loci contain essential information for cloning genes related to resistance to PHS and can be used in wheat breeding programs.

Human leukocyte antigen allele linkage disequilibrium and haplotype structure in volunteer bone marrow donors of Paraná State

Abstract Background Bone marrow transplantation has been used in the treatment of various diseases, especially hematologic diseases. The success of this treatment, among other factors, requires human leukocyte antigens (HLA) compatibility between patient and donor. Knowing the human leukocyte antigens allele group and haplotype frequencies as well as the linkage disequilibrium between alleles of different human leukocyte antigens loci can shorten the search time for a compatible bone marrow donor. Objective To assemble and analyze data on human leukocyte antigens frequencies available in the Laboratory of Immunogenetics and Histocompatibility (LIGH) database of the Universidade Federal do Paraná adding an estimation of the Hardy-Weinberg equilibrium and linkage disequilibrium. Methods The sample was composed of seven populations grouped by self-declared ancestry or inferred from the surname as follows: Laboratory of Immunogenetics and Histocompatibility database (all groups), descendants of Italians, Poles, and Asians, Afro-Brazilians, Mulattos (mixed ancestry) and Amerindians. Human leukocyte antigens genotyping was carried out using the polymerase chain reaction-sequence specific primers (PCR-SSP) and -sequence specific oligonucleotide (PCR-SSO) technologies. Results There were high frequencies of the HLA-A*02, HLA-B*35 and HLA-DRB1*13 allelic groups in all groups. The same was observed for the HLA-A*01-B*08-DRB1*03 haplotype except for Asian descendants. It was observed that the human leukocyte antigens Laboratory of Immunogenetics and Histocompatibility database and the Asian group are not in Hardy-Weinberg equilibrium. The Italian, Polish, Asian, Mulatto and Amerindian descendants showed haplotypes in complete linkage disequilibrium. Our results were compared with data on the human leukocyte antigens in the Paraná population available from the Brazilian Voluntary Bone Marrow Donor Registry (REDOME) and data published on the population of Curitiba and the northern region of Paraná. Conclusions Haplotypes frequent in the Asian group were not the most frequently observed in the Laboratory of Immunogenetics and Histocompatibility database and the National Bone Marrow Donor Registry for the state of Paraná. Linkage disequilibrium information may prove useful in the search for bone marrow donors for patients awaiting a suitable donor.

Asociación de variantes polimorfas de los genes PTPN22 , TNF y VDR en niños con nefritis lúpica: un estudio de tríos en familias colombianas / Association of polymorphic variants of PTPN22 , TNF and VDR genes in children with lupus nephritis: A study in Colombian family triads

RESUMEN Introducción. El lupus eritematoso sistémico es una enfermedad autoinmunitaria cuya gravedad varía según la raza, el sexo y la edad de aparición. Esta disparidad también se observa en los marcadores genéticos asociados con la enfermedad presentes en los genes PTPN22, VDR y TNF. La estratificación genética que presentan las diferentes poblaciones en el mundo puede influir en dicha variabilidad. Objetivo. Analizar la asociación de variantes genéticas de los genes PTPN22, VDR y TNF con nefritis lúpica en niños y su caracter de hereditarias en familias colombianas. Materiales y métodos. Se llevó a cabo un estudio basado en familias con 46 tríos (caso, padre y madre). Se hizo la genotipificación de las variantes rs2476601 de PTPN22, rs361525 y rs1800629 del TNF, y TaqI [rs731236], ApaI [rs7975232], BsmI [rs1544410] y FokI [rs2228570] del VDR, mediante reacción en cadena de la polimerasa cuantitativa (quantitative Polymerase Chain Reaction, qPCR). Se estimó el efecto de la transmisión del alelo de riesgo de padres a hijos y el desequilibrio de ligamiento de los loci VDR y TNF. Resultados. Se observó que el alelo A de rs2476601 en PTPN22 se distribuyó en 8,69 % (n=16) de los padres y en 19,5 % (n=18) de los casos, y que su transmisión de padres a hijos fue 17 veces mayor con relación al alelo G (p=0,028). Los polimorfismos de TNF y VDR no presentaron desequilibrio de transmisión. Las variantes TaqI, ApaI y BsmI del VDR presentaron desequilibrio de ligamiento. Conclusión. Estos hallazgos evidenciaron una asociación del polimorfismo rs2476601 de PTPN22 con la nefritis lúpica en niños, determinada por su transmisión en el grupo de familias estudiadas.

ABSTRACT Introduction: Systemic lupus erythematosus is an autoimmune disease in which the severity varies according to race, sex and age of onset. This variation is also observed in the genetic markers associated with the disease, including PTPN22, VDR and TNF genes. The genetic stratification in different populations worldwide can influence the variability. Objective: To analyze the heritability of PTPN22, VDR and TNF genetic variants and their association with pediatric lupus nephritis in Colombian families. Materials and methods: We conducted a family-based study including 46 triads (case, father and mother). The variants rs2476601 of PTPN22; rs361525 and rs1800629 of TNF, and TaqI [rs731236], ApaI [rs7975232], BsmI [rs1544410] and FokI [rs2228570] of VDR were genotyped by qPCR. The effects of overtransmission of the risk allele from parents to children and linkage disequilibrium at the VDR and TNF loci were estimated. Results: We found that allele A of rs2476601 in PTPN22 was distributed among 8.69 % (n=16) of the parents and 19.5 % (n=18) of the cases; this allele was overtransmitted from parents to children 17 times more often than the G allele (p=0.028). TNF and VDR polymorphisms did not exhibit transmission disequilibrium. VDR TaqI, ApaI and BsmI variants exhibited linkage disequilibrium. Conclusion: These findings showed an association between the PTPN22 rs2476601 polymorphism and pediatric lupus nephritis due to its overtransmission in the group of families studied.

Association study on interaction effects of 5-HT receptor related genes and suicidal behavior in major depressive disorder / 中华行为医学与脑科学杂志

Objective To investigate the single nucleotide polymorphisms(SNPs) of 5-HT1BR(rs6298),5-HT2AR(rs6311,rs6313) and 5-HT2BR(rs765458) gene,and their gene-gene interactions on suicidal behavior in major depressive disorder.Methods The blood samples were taken from 281 depression patients with impulsive suicide attempt and 281 age-matched healthy controls from a hospital in Harbin city,Heilongjiang province.The DNA isolated from blood samples and was genotyped using TapMan SNP genotyping probe.χ2 test was used to compare differences in the distribution of gene alleles between cases and controls.Haplotype and linkage disequilibrium(LD) analysis was performed using Haploview 4.0 software.GMDR was used to analyze the gene-gene interaction.Results The rs6313 and rs6311 of the 5-HT2AR gene were in strong linkage disequilibrium (D=0.756,r2=0.375).There was a significant gene-gene interaction of 5-HT1BR (rs6298),5-HT2AR (rs6311,rs6313) and 5-HT2BR(rs765458) on suicidal behavior(P<0.05).In this model,the test accuracy was 0.6182 and CV value was 10/10.Conclusion A haplotype containing rs6311 and rs6313 of 5-HT2AR gene is associated with suicidal behavior.The interaction of 5-HT1BR gene (rs6298),5-HT2AR gene (rs6311,rs6313) and 5-HT2BR gene (rs765458) are associated with depression suicidal behavior.

Meta-analysis of the relevance between Megsin rs1055901 ,rs1055902 and rs2689399 polymorphism and susceptibility of IgA nephrology in Asian population / 重庆医学

Objective To assess the association of three polymorphisms in Megsin (rs1055901,rs1055902 and rs2689399) and susceptibility of IgA nephropathy in Asian population.Methods We conducted a comprehensive search of electronic CNKI,VIP,WangFang Data,CBM,Pubmed,Web of Science and Google Scholar database on the association between Megsin rs1055901,rs1055902 and rs2689399 polymorphism and susceptibility of IgA nephrology in Asian population (last search update on 2 May 2016).Stata 12.0 software was used to calculate the odds ratio (OR) and 95 ％ CI (confidence interval),as well as sensitivity and publication bias analyses.Results Six publications encompassing mine case-control studies were finally included,including 2 179 cases and 1 769 controls.Finally,no significant association between Megsin rs1055901 and rs1055902 polymorphism and IgA nephrology in Asian population was identified,while a significantly decreased risk of IgA nephrology for rs2689399 polymorphism,was identified in Asian population (G and C:OR=0.754,95％CI 0.592-0.961,P=0.022;GG and CC:OR=0.506,95％CI 0.287-0.892,P=0.019;GG and GC+CC:OR=0.551,95％CI 0.316-0.961,P=0.036).Conclusion Rs2689399 G allele and GG genotype of Megsin may be the protective factors for IgA nephropathy in Asian population.

Effects of the polymorphisms in ABCG1 gene on the transcription activity and the susceptibility with coronary artery disease / 中华急诊医学杂志

Objective To investigate the effects of the polymorphisms in the promoter of ATP binding cassette transporter (ABCG1) on the transcription activity,and the relationship of the polymorphisms with the susceptibility to coronary artery disease (CAD).Methods A case-control study was conducted,217 CADpatients and 142 controls were enrolled in this study.Thesingle nucleotide polymorphisms (SNPs) in the promoter of ABCG1 were identified by sequencing.The promoter haplotypes of ABCG1 were determined with allele specific primer sequencing or Gene cloning sequencing.The transcription activity of the promoter haplotypes were evaluated with dual luciferase reporter system.The frequency of SNPs and haplotypes were analyzed between CAD group and the control group,premature CAD and non-premature CAD group,as well as multivessel lesion and single vessel lesion group.The frequency distribution was compared between two groups with x2 test or Fisher exact test.The difference of the luciferase activity was compared between groups by t-test or one-way analysis of variance.Results Only 3 SNPs were found in ABCG1 promoter sequence of about 1 000 bp upstream of the transcription start site,which are-384 (A/G),-204 (A/C) and-134 (T/G),respectively.The 3 SNPs are in strong linkage disequilibrium,Tajima's D =2.655 (P ＜ 0.01),which constituted 3 haplotypes.There was no significant difference in SNPs and haplotype frequency between the CAD group and the normal control group,and the severity of vascular disease and the early onset of coronary heart disease were not associated with the polymorphisms in ABCG1 promoter.There was no significant difference in the transcriptional activity of the three constitutive promoter haplotypes,but the transcriptional activity was notably elevated as the GAT haplotype was mutated into GAG (P ＜ 0.05).Conclusions The 3 SNPs identified in ABCG1 promoter region A did not alter the promoter activity.There was no significant correlation between the frequency distribution of SNPs and promoter haplotypes and the susceptibility to CAD.

The pilot study of the phasing method for STR haplotypes / 中国法医学杂志

Referring to the statistical model for the SNP haplotype phasing which was based on the allele frequencies and advised by Browning SR, we investigated and deduced the phasing method of STR haplotype with linkage disequilibrium inpaternity testing preliminarily. Haplotype phasing of two X-STRs in linkage disequilibrium were illustrated. This method provides an idea for the haplotype phasing of STR markers, which is helpful for interpreting the typing results of STR more scientifically and accurately.

Analysis of haplotype and linkage disequilibrium of PPARγgene rs3856806, rs12490265, rs1797912, and rs1175543 in patients with metabolic syndrome in Kazakhs of Xinjiang / 中华内分泌代谢杂志

Objective To investigate the effect of haplotype and linkage disequilibrium of PPARγgene rs3856806, rs12490265, rs1797912, and rs1175543 in patients with metabolic syndrome ( MS) in Kazakhs of Xinjiang.Methods MALDI-TOF-MS was used to detect PPARγgene rs3856806, rs12490265, rs1797912, and rs1175543 genotypes in 489 subjects ( including 245 MS and 244 controls ) .Results ( 1 ) The frequencies of rs3856806T, rs12490265A, rs1797912C and rs1175543G alleles for MS group in Kazakhs were all significantly lower than those for controls [ rs3856806T allele:12.53% vs 17.01%; rs12490265A allele: 31.84% vs 38.52%;rs1797912C allele:35.31%vs 43.24%;rs1175543G allele:40.61%vs 47.54%(all P<0.05)].(2)Significant linkage disequilibrium were observed between PPARγgene rs1797912 and rs1175543, rs12490265, and rs1175543 polymorphisms.(3)AGCC and GAAT were significantly different between MS and control group in Kazakhs(both P<0.05).(4) Carrying rs3856806T, rs12490265A, rs1797912C, rs1175543G was 0.267 times that of carrying rs3856806C, rs12490265G, rs1797912A, rs1175543A.Conclusions The PPARγgene rs3856806, rs12490265, rs1797912 and rs1175543 polymorphisms were associated with metabolic syndrome in Kazakhs.There were very strong linkage disequilibrium between PPARγgene rs1797912 and rs1175543, rs12490265 and rs1175543 polymorphisms, The AGCC haplotype and GAAT haplotype may serve as protective factors of metabolic syndrome.Carrying rs3856806T, rs12490265A, rs1797912C, and rs1175543G may confer lower risk of MS in Kazakhs.