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1.
Twin Res Hum Genet ; 21(2): 89-100, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29506594

RESUMEN

Blood eosinophil count is associated with a variety of common complex outcomes in epidemiological observation. The aim of this study was to explore the causal association between determined blood eosinophil count and 20 common complex outcomes (10 metabolic, 6 cardiac, and 4 pulmonary). Through Mendelian randomization, we investigated genetic evidence for the genetically determined eosinophil in association with each outcomes using individual-level LifeLines cohort data (n = 13,301), where a weighted eosinophil genetic risk score comprising five eosinophil associated variants was created. We further examined the associations of the genetically determined eosinophil with those outcomes using summary statistics obtained from genome-wide association study consortia (6 consortia and 14 outcomes). Blood eosinophil count, by a 1-SD genetically increased, was not statistically associated with common complex outcomes in the LifeLines. Using the summary statistics, we showed that a higher genetically determined eosinophil count had a significant association with lower odds of obesity (odds ratio (OR) 0.81, 95% confidence interval (CI) [0.74, 0.89]) but not with the other traits and diseases. To conclude, an elevated eosinophil count is unlikely to be causally associated to higher risk of metabolic, cardiac, and pulmonary outcomes. Further studies with a stronger genetic risk score for eosinophil count may support these results.


Asunto(s)
Asma , Presión Sanguínea/genética , Diabetes Mellitus Tipo 2 , Análisis de la Aleatorización Mendeliana , Síndrome Metabólico , Enfermedad Pulmonar Obstructiva Crónica , Carácter Cuantitativo Heredable , Asma/sangre , Asma/genética , Asma/fisiopatología , Glucemia/genética , Glucemia/metabolismo , Índice de Masa Corporal , Estudios de Cohortes , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Volumen Espiratorio Forzado/genética , Estudio de Asociación del Genoma Completo , Hemoglobina Glucada/genética , Hemoglobina Glucada/metabolismo , Humanos , Recuento de Leucocitos , Lípidos/sangre , Lípidos/genética , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/genética , Síndrome Metabólico/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología
2.
Am J Hum Genet ; 90(3): 410-25, 2012 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-22325160

RESUMEN

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Sitios Genéticos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/etnología , Etnicidad , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Adulto Joven
3.
Eur Respir J ; 44(4): 860-72, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24993907

RESUMEN

Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background ("Dutch hypothesis"). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the nuclear factor (NF) κß pathway) and GNG5P5, respectively. Single nucleotide polymorphisms (SNPs) rs9534578 in GNG5P5 reached genome-wide significance after first replication phase (p=9.96×10(-9)). The second replication phase, in seven independent cohorts, provided no significant replication. Expression quantitative trait loci (eQTL) analysis in blood cells and lung tissue on the top 20 associated SNPs identified two SNPs in COMMD10 that influenced gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NF-κß, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role for two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings suggest that there is either no common genetic component in asthma and COPD or, alternatively, different environmental factors, e.g. lifestyle and occupation in different countries and continents, which may have obscured the genetic common contribution.


Asunto(s)
Asma/genética , Estudio de Asociación del Genoma Completo , Enfermedad Pulmonar Obstructiva Crónica/genética , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Adulto Joven
4.
Hum Genet ; 129(3): 283-93, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21136274

RESUMEN

Cilia are small cellular projections that either act as sensors (primary cilia) or propel fluid over the epithelia of various organs (motile cilia). The organellum has gained much attention lately because of its involvement in a group of human diseases called ciliopathies. Primary ciliary dyskinesia (PCD) is an autosomal recessive ciliopathy caused by mutations in cilia motility genes. The disease is characterized by recurrent respiratory tract infections due to the lack of an efficient mucociliary clearance. We performed whole-genome gene expression profiling in bronchial biopsies from PCD patients. We used the quality threshold clustering algorithm to identify groups of genes that revealed highly correlated RNA expression patterns in the biopsies. The largest cluster contained 372 genes and was significantly enriched for genes related to cilia. The database and literature search showed that 164 genes in this cluster were known cilia genes, strongly indicating that the remaining 208 genes were likely to be new cilia genes. The tissue expression pattern of the 208 new cilia genes and the 164 known genes was consistent with the presence of motile cilia in a given tissue. The analysis of the upstream promotor sequences revealed evidence for RFX transcription factors binding site motif in both subgroups. Based on the correlated expression patterns in PCD-affected tissues, we identified 208 genes that we predict to be involved in cilia biology. Our predictions are based directly on the human material and not on model organisms. This list of genes provides candidate genes for PCD and other ciliopathies.


Asunto(s)
Perfilación de la Expresión Génica , Síndrome de Kartagener/genética , Algoritmos , Secuencia de Bases , Cilios/genética , Proteínas de Unión al ADN/genética , Dineínas/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Datos de Secuencia Molecular , Regiones Promotoras Genéticas/genética , Dominios y Motivos de Interacción de Proteínas/genética , Factores de Transcripción del Factor Regulador X , Factores de Transcripción/genética
5.
Ann Allergy Asthma Immunol ; 106(6): 502-10, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21624750

RESUMEN

BACKGROUND: Insect venom immunotherapy (VIT) is the only causative treatment of insect venom allergy (IVA). The immunological mechanism(s) responsible for long-term protection achieved by VIT are largely unknown. A better understanding is relevant for improving the diagnosis, prediction of anaphylaxis, and monitoring and simplifying treatment of IVA. OBJECTIVE: To find genes that are differentially expressed during the maintenance phase of VIT and after stopping, to get clues about the pathways involved in the long-term protective effect of immunotherapy. METHODS: Whole genome gene expression analysis was performed on RNA samples from 50 patients treated with VIT and 43 healthy controls. Patients were divided into three groups: (1) before the start of VIT; (2) on maintenance phase of VIT for at least 3 years still receiving injections; and (3) after VIT. RESULTS: Of all 48,804 probes present in the array, 48,773 transcripts had sufficient data for further analysis. The list of genes that were differentially expressed (at least log2 FC > 2; P < .05 corrected for multiple testing) during the maintenance phase of VIT as well as after successful VIT contains 89 entities. The function of these genes affects cell signaling, cell differentiation, and ion transport. CONCLUSION: This study shows that a group of genes is differentially expressed both during and after VIT in comparison with gene expression in patients before VIT. Although the results of this study should be confirmed prospectively, the relevance of these findings is supported by the fact that they are related to putative mechanisms of immunotherapy.


Asunto(s)
Anafilaxia/prevención & control , Venenos de Artrópodos/inmunología , Desensibilización Inmunológica , Expresión Génica , Hipersensibilidad Inmediata/prevención & control , Mordeduras y Picaduras de Insectos/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anafilaxia/genética , Anafilaxia/inmunología , Animales , Venenos de Abeja/inmunología , Femenino , Perfilación de la Expresión Génica , Humanos , Hipersensibilidad Inmediata/genética , Hipersensibilidad Inmediata/inmunología , Insectos/inmunología , Masculino , Mastocitos/inmunología , Persona de Mediana Edad , Venenos de Avispas/inmunología
6.
J Pediatr Gastroenterol Nutr ; 52(3): 307-13, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21206382

RESUMEN

OBJECTIVES: Microvillus inclusion disease (MVID) is a rare autosomal recessive enteropathy characterized by intractable diarrhea and malabsorption. Recently, various MYO5B gene mutations have been identified in patients with MVID. Interestingly, several patients with MVID showed only a MYO5B mutation in 1 allele (heterozygous) or no mutations in the MYO5B gene, illustrating the need to further functionally characterize the cell biological effects of the MYO5B mutations. PATIENTS AND METHODS: The genomic DNA of 9 patients diagnosed as having MVID was screened for MYO5B mutations, and quantitative polymerase chain reaction and immunohistochemistry on the material of 2 patients was performed to investigate resultant cellular consequences. RESULTS: We demonstrate for the first time that MYO5B mutations can be correlated with altered myosin Vb messenger RNA expression and with an aberrant subcellular distribution of the myosin Vb protein. Moreover, we demonstrate that the typical and myosin Vb-controlled accumulation of Rab11a- and FIP5-positive recycling endosomes in the apical cytoplasm of the cells is abolished in MVID enterocytes, which is indicative of altered myosin Vb function. Moreover, we report 8 novel MYO5B mutations in 9 patients of various ethnic backgrounds with MVID, including compound heterozygous mutations. CONCLUSIONS: Our functional analysis indicates that MYO5B mutations can be correlated with an aberrant subcellular distribution of the myosin Vb protein, and apical recycling endosomes, which, together with the additional compound heterozygous mutations, significantly strengthen the link between MYO5B and MVID.


Asunto(s)
Endosomas/metabolismo , Enterocitos/metabolismo , Síndromes de Malabsorción/genética , Mucolipidosis/genética , Mutación , Miosina Tipo V/genética , Alelos , Niño , Preescolar , Citoplasma/metabolismo , ADN , Femenino , Genoma , Heterocigoto , Humanos , Cuerpos de Inclusión/genética , Cuerpos de Inclusión/metabolismo , Lactante , Síndromes de Malabsorción/metabolismo , Masculino , Microvellosidades/genética , Microvellosidades/metabolismo , Microvellosidades/patología , Mucolipidosis/metabolismo , Miosina Tipo V/metabolismo , Reacción en Cadena de la Polimerasa , ARN Mensajero/metabolismo
7.
J Allergy Clin Immunol ; 125(5): 1092-7, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20334904

RESUMEN

BACKGROUND: Venom immunotherapy (VIT) enables longtime prevention of insect venom allergy in the majority of patients. However, in some, the risk of a resystemic reaction increases after completion of treatment. No reliable factors predicting individual lack of efficacy of VIT are currently available. OBJECTIVE: To determine the use of gene expression profiles to predict the long-term effect of VIT. METHODS: Whole genome gene expression analysis was performed on RNA samples from 46 patients treated with VIT divided into 3 groups: (1) patients who achieved and maintained long-term protection after VIT, (2) patients in whom insect venom allergy relapsed, and (3) patients still in the maintenance phase of VIT. RESULTS: Among the 48.071 transcripts analyzed, 1401 showed a >2 fold difference in gene expression (P < .05); 658 genes (47%) were upregulated and 743 (53%) downregulated. Forty-three transcripts still show significant differences in expression after correction for multiple testing; 12 of 43 genes (28%) were upregulated and 31 of 43 genes (72%) downregulated. A naive Bayes prediction model demonstrated a gene expression pattern characteristic of effective VIT that was present in all patients with successful VIT but absent in all subjects with failure of VIT. The same gene expression profile was present in 88% of patients in the maintenance phase of VIT. CONCLUSION: Gene expression profiling might be a useful tool to assess the long-term effectiveness of VIT. The analysis of differently expressed genes confirms the involvement of immunologic pathways described previously but also indicates novel factors that might be relevant for allergen tolerance.


Asunto(s)
Venenos de Artrópodos/administración & dosificación , Perfilación de la Expresión Génica/métodos , Hipersensibilidad Inmediata/terapia , Inmunoterapia/métodos , Mordeduras y Picaduras de Insectos/inmunología , Adulto , Anciano , Animales , Venenos de Artrópodos/inmunología , Venenos de Abeja/administración & dosificación , Venenos de Abeja/inmunología , Abejas/inmunología , Desensibilización Inmunológica , Femenino , Humanos , Hipersensibilidad Inmediata/etiología , Hipersensibilidad Inmediata/inmunología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Venenos de Avispas/administración & dosificación , Venenos de Avispas/inmunología , Avispas/inmunología
8.
Pharmacogenet Genomics ; 20(3): 179-86, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20124949

RESUMEN

RATIONALE: Arginase probably plays an important role in asthma development, severity and progression. Polymorphisms in arginase 1 and arginase 2 genes have been associated with childhood asthma and FEV1 reversibility to beta2 agonists. OBJECTIVES: We investigated the association between arginase 1 and arginase 2 polymorphisms and adult asthma, asthma severity and treatment response in a longitudinal cohort of 200 asthma patients. METHODS: Patients were studied during 1962-1975 and reexamined during 1990-1999, together with their families. Longitudinal data on lung function and treatment were extracted from medical records. Associations between haplotype-tagging polymorphisms in arginase 1 (n=3) and arginase 2 (n=8) and asthma, asthma severity, acute response to bronchodilators and chronic response to inhaled corticosteroids were analyzed. MEASUREMENTS AND MAIN RESULTS: Two polymorphisms in arginase 2 (rs17249437 and rs3742879) were associated with asthma and with more severe airway obstruction. Increased airway hyperresponsiveness and lower beta2 agonist reversibility, but not anticholinergic reversibility, were associated with both arginase 1 and arginase 2. Inhaled corticosteroids slowed down the annual FEV1 decline, which was significantly less effective in homozygote carriers of the C-allele of the arginase 1 polymorphism, rs2781667. CONCLUSION: We show that previously reported associations between arginase polymorphisms and childhood asthma are also present in adult asthma and the previously found associations with lower reversibility are specific for beta2 agonists. Furthermore, we identified associations of arginase 1 and arginase 2 genes with asthma severity, as reflected by a lower lung function, more severe airway hyperresponsiveness, and less long-term response to inhaled corticosteroids. Studies on the functionality of the polymorphisms are warranted to further unravel the complex mechanisms underlying these observations.


Asunto(s)
Agonistas Adrenérgicos beta/uso terapéutico , Antiasmáticos/uso terapéutico , Arginasa/genética , Asma/tratamiento farmacológico , Farmacogenética , Adulto , Estudios de Cohortes , Humanos , Isoenzimas/genética , Estudios Longitudinales , Polimorfismo Genético , Resultado del Tratamiento
9.
Am J Respir Crit Care Med ; 180(10): 929-35, 2009 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-19729670

RESUMEN

RATIONALE: Asthma is a chronic inflammatory airway disease that affects more than 300 million individuals worldwide. Asthma is caused by interaction of genetic and environmental factors. Bronchial hyperresponsiveness (BHR) is a hallmark of asthma and results from increased sensitivity of the airways to physical or chemical stimulants. BHR and asthma are linked to chromosome 5q31-q33. OBJECTIVES: To identify a gene for BHR on chromosome 5q31-q33. METHODS: In 200 Dutch families with asthma, linkage analysis and fine mapping were performed, and the Protocadherin 1 gene (PCDH1) was identified. PCDH1 was resequenced in 96 subjects from ethnically diverse populations to identify novel sequence variants. Subsequent replication studies were undertaken in seven populations from The Netherlands, the United Kingdom, and the United States, including two general population samples, two family samples, and three case-control samples. PCDH1 mRNA and protein expression was investigated using polymerase chain reaction, Western blotting, and immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: In seven out of eight populations (n = 6,168) from The Netherlands, United Kingdom, and United States, PCHD1 gene variants were significantly associated with BHR (P values, 0.005-0.05) This association was present in both families with asthma and general populations. PCDH1 mRNA and protein were expressed in airway epithelial cells and in macrophages. CONCLUSIONS: PCDH1 is a novel gene for BHR in adults and children. The identification of PCDH1 as a BHR susceptibility gene may suggest that a structural defect in the integrity of the airway epithelium, the first line of defense against inhaled substances, contributes to the development of BHR.


Asunto(s)
Hiperreactividad Bronquial/genética , Adulto , Asma/genética , Niño , Mapeo Cromosómico , Cromosomas Humanos Par 5 , Ligamiento Genético , Predisposición Genética a la Enfermedad/genética , Humanos , Países Bajos , Reino Unido , Estados Unidos
10.
Eur J Hum Genet ; 25(7): 877-885, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28401901

RESUMEN

Despite the recent explosive rise in number of genetic markers for complex disease traits identified in genome-wide association studies, there is still a large gap between the known heritability of these traits and the part explained by these markers. To gauge whether this 'heritability gap' is closing, we first identified genome-wide significant SNPs from the literature and performed replication analyses for 32 highly relevant traits from five broad disease areas in 13 436 subjects of the Lifelines Cohort. Next, we calculated the variance explained by multi-SNP genetic risk scores (GRSs) for each trait, and compared it to their broad- and narrow-sense heritabilities captured by all common SNPs. The majority of all previously-associated SNPs (median=75%) were significantly associated with their respective traits. All GRSs were significant, with unweighted GRSs generally explaining less phenotypic variance than weighted GRSs, for which the explained variance was highest for height (15.5%) and varied between 0.02 and 6.7% for the other traits. Broad-sense common-SNP heritability estimates were significant for all traits, with the additive effect of common SNPs explaining 48.9% of the variance for height and between 5.6 and 39.2% for the other traits. Dominance effects were uniformly small (0-1.5%) and not significant. On average, the variance explained by the weighted GRSs accounted for only 10.7% of the common-SNP heritability of the 32 traits. These results indicate that GRSs may not yet be ready for accurate personalized prediction of complex disease traits limiting widespread adoption in clinical practice.


Asunto(s)
Estudio de Asociación del Genoma Completo/métodos , Fenotipo , Carácter Cuantitativo Heredable , Recuento de Células Sanguíneas , Presión Sanguínea/genética , Genes Dominantes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/normas , Frecuencia Cardíaca/genética , Humanos , Polimorfismo de Nucleótido Simple , Respiración/genética
11.
Respir Res ; 7: 89, 2006 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-16780585

RESUMEN

BACKGROUND: Decorin, an extracellular matrix (ECM) proteoglycan, and TGF-beta1 are both involved in lung ECM turnover. Decorin and TGF-beta1 expression are decreased respectively increased in COPD lung tissue. Interestingly, they act as each other's feedback regulator. We investigated whether single nucleotide polymorphisms (SNPs) in decorin and TGF-beta1 underlie accelerated decline in FEV1 and development of COPD in the general population. METHODS: We genotyped 1390 subjects from the Vlagtwedde/Vlaardingen cohort. Lung function was measured every 3 years for a period of 25 years. We tested whether five SNPs in decorin (3'UTR and four intron SNPs) and three SNPs in TGF-beta1 (3'UTR rs6957, C-509T rs1800469 and Leu10Pro rs1982073), and their haplotypes, were associated with COPD (last survey GOLD stage = II). Linear mixed effects models were used to analyze genotype associations with FEV1 decline. RESULTS: We found a significantly higher prevalence of carriers of the minor allele of the TGF-beta1 rs6957 SNP (p = 0.001) in subjects with COPD. Additionally, we found a significantly lower prevalence of the haplotype with the major allele of rs6957 and minor alleles for rs1800469 and rs1982073 SNPs in TGF-beta1 in subjects with COPD (p = 0.030), indicating that this association is due to the rs6957 SNP. TGF-beta1 SNPs were not associated with FEV1 decline. SNPs in decorin, and haplotypes constructed of both TGF-beta1 and decorin SNPs were not associated with development of COPD or with FEV1 decline. CONCLUSION: Our study shows for the first time that SNPs in decorin on its own or in interaction with SNPs in TGF-beta1 do not underlie the disturbed balance in expression between these genes in COPD. TGF-beta1 SNPs are associated with COPD, yet not with accelerated FEV1 decline in the general population.


Asunto(s)
Proteínas de la Matriz Extracelular/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Proteoglicanos/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Factor de Crecimiento Transformador beta/genética , Decorina , Volumen Espiratorio Forzado/fisiología , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Modelos Genéticos , Países Bajos/epidemiología , Prevalencia , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Estudios Retrospectivos , Encuestas y Cuestionarios , Factor de Crecimiento Transformador beta1
12.
PLoS One ; 11(12): e0168480, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27978545

RESUMEN

There is ongoing debate on the association between eosinophil count and diseases, as previous studies were inconsistent. We studied the relationship of eosinophil count with 22 complex metabolic, cardiac, and pulmonary traits and diseases. From the population-based LifeLines Cohort Study (N = 167,729), 13,301 individuals were included. We focused on relationship of eosinophil count with three classes of metabolic (7 traits, 2 diseases), cardiac (6 traits, 2 diseases), and pulmonary (2 traits, 2 diseases) outcomes. Regression analyses were applied in overall, women and men, while adjusted for age, sex, BMI and smoking. A p-value of <0.00076 was considered statistically significant. 58.2% of population were women (mean±SD 51.3±11.1 years old). In overall, one-SD higher of ln-eosinophil count was associated with a 0.04 (±SE ±0.002;p = 6.0×10-6) SD higher levels in ln-BMI, 0.06 (±0.007;p = 3.1×10-12) SD in ln-TG, 0.04 (±0.003;p = 7.0×10-6) SD in TC, 0.04 (±0.004;p = 6.3×10-7) SD in LDL, 0.04 (±0.006;p = 6.0×10-6) SD in HbA1c; and with a 0.05 (±0.004;p = 1.7×10-8) SD lower levels in HDL, 0.05 (±0.007;p = 3.4×10-23) SD in FEV1, and 0.09 (±0.001;p = 6.6×10-28) SD in FEV1/FVC. A higher ln-eosinophil count was associated with 1.18 (95%CI 1.09-1.28;p = 2.0×10-5) odds ratio of obesity, 1.29 (1.19-1.39;p = 1.1×10-10) of metabolic syndrome, 1.40 (1.25-1.56;p = 2.7×10-9) of COPD and 1.81 (1.61-2.03;p = 1.0×10-23) of asthma. Similar results were found in women. We found no association between ln-eosinophil count either with blood pressure indices in overall, women and men; or with BMI, LDL, HbA1c and obesity in men. In a large population based cohort, we confirmed eosinophil count as a potential factor implicated in metabolic and pulmonary outcomes.


Asunto(s)
Eosinófilos/fisiología , Recuento de Leucocitos , Adulto , Anciano , Asma/sangre , Asma/metabolismo , Índice de Masa Corporal , Estudios de Cohortes , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Lipoproteínas HDL/sangre , Modelos Logísticos , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/metabolismo , Persona de Mediana Edad , Análisis Multivariante , Obesidad/sangre , Obesidad/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Análisis de Regresión , Factores Sexuales
13.
J Invest Dermatol ; 124(1): 99-102, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15654959

RESUMEN

The psoriasis susceptibility locus 1 (PSORS1) mutation is assumed to reside within a region around human leukocyte antigen-C spanning 250 kb, termed risk haplotype (RH) 1/2. By re-analyzing a published data set with a previously developed method, the haplotype sharing statistic, we confirm localization of PSORS1 to the RH1 region and refine its location to marker M6S168. We replicate this result in an independent patient sample. The target region harbors fragments of a human endogenous retrovirus K (HERV-K) endogenous retrovirus. Two single-nucleotide polymorphisms with alleles differing between high- and low-risk haplotypes are located within the HERV-K dUTPase. One of these encodes a predicted non-conserved Glu-Arg exchange. The HERV-K dUTPase is expressed in peripheral blood and in normal as well as lesional psoriatic skin. Our results indicate that an endogenous retroviral dUTPase constitutes a candidate gene for the PSORS1 mutation.


Asunto(s)
Cromosomas Humanos Par 6 , Retrovirus Endógenos/genética , Psoriasis/genética , Pirofosfatasas/genética , Predisposición Genética a la Enfermedad/genética , Antígenos HLA-C/genética , Haplotipos , Humanos , Polimorfismo de Nucleótido Simple
14.
Eur J Cancer ; 41(12): 1819-23, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16043347

RESUMEN

CHEK2 is low-penetrance breast cancer susceptibility gene. The 1100delC mutation may interact with variants/mutations in other breast cancer susceptibility loci. We identified a risk haplotype in the HLA class III region in breast cancer patients [de Jong MM, Nolte IM, de Vries EGE, et al. The HLA class III subregion is responsible for an increased breast cancer risk. Hum Mol Genet 2003, 12, 2311-2319] and tested whether it interacted with 1100delC mutation. The CHEK2 1100delC mutation was analysed in the same series of patients and controls as in the HLA breast cancer study. In 962 unselected breast cancer patients, the 1100delC mutation was observed in 2.9% and in 367 controls in 1.4% (NS). The highest 1100delC frequency occurred in high-risk (4.4%), followed by moderate-risk (3.8%), and lowest in low genetic risk patients (2.4%, P(trend) 0.029). In HLA risk haplotype carriers no increased breast cancer risk was observed in the presence of 1100delC mutation. Patients more often had one than both genetic risk factors. The 1100delC mutation and the HLA risk haplotype confer increased breast cancer risks, but an interactive effect on breast cancer between both factors is unlikely. In contrast, the effect of 1100delC mutation on breast cancer risk was limited to individuals without HLA risk haplotype, suggesting a mutual excluding effect between these risk factors.


Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad/genética , Antígenos HLA/genética , Mutación/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Anciano , Análisis de Varianza , Quinasa de Punto de Control 2 , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Factores de Riesgo
15.
Appl Biochem Biotechnol ; 120(1): 29-36, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15640555

RESUMEN

The efficiency of the genotyping process is determined by many simultaneous factors. In actual genotyping, a production run is often preceded by small-scale experiments to find optimal conditions. We propose to use statistical analysis of production run data as well, to gain insight into factors important for the outcome of genotyping. As an example, we show that analysis of variance (ANOVA) applied to the first-pass results of a genetic study reveals important determinants of genotyping success. The largest factor limiting genotyping appeared to be interindividual variation among DNA samples, explaining 20% of the variance, and a smaller reaction volume, sizing failure, and differences among markers all explained approximately 10%. Other potentially important factors, such as sample position within the plate and reusing electrophoresis matrix, appeared to be of minor influence. About 55% of the total variance could be explained by systematic factors. These results show that ANOVA can provide valuable feedback to improve genotyping efficiency. We propose to adjust genotype production runs using principles of experimental design in order to maximize genotyping efficiency at little additional cost.


Asunto(s)
Técnicas Genéticas , Análisis de Varianza , Ligamiento Genético , Marcadores Genéticos/genética , Técnicas Genéticas/economía , Genotipo , Repeticiones de Microsatélite/genética
16.
J Invest Dermatol ; 122(1): 61-4, 2004 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-14962090

RESUMEN

Type 1 interferon can trigger flares of psoriasis. Hypersensitivity to type 1 interferon signaling causes a psoriasis-like skin disease in mice deficient for the transcription factor interferon regulatory factor 2 (IRF2). The human IRF2 gene is located at a previously identified candidate psoriasis susceptibility locus on chromosome 4q (PSORS3 at D4S1535). Therefore, we tested association of psoriasis with IRF2. We generated a sample consisting of 157 families with a total of 521 individuals. Five novel microsatellite markers were developed and typed, and complemented with three known markers to yield a set of eight markers spaced within 600 kb around the IRF2 gene, three of which are located in the gene. We detected association of IRF2 with type 1 psoriasis at two markers in the IRF2 gene. Haplotype sharing analysis confirmed association of IRF2 with type 1 psoriasis (p=0.0017; pcorr=0.03). The 921G/A SNP in exon 9 was found to obliterate a predicted exon splice enhancer in an allele-specific manner. There was a suggestive increase of homozygosity for the splicing-deficient allele in type 1 psoriasis patients. Our data identify IRF2 as a potential susceptibility gene for psoriasis.


Asunto(s)
Proteínas de Unión al ADN/genética , Psoriasis/genética , Proteínas Represoras , Factores de Transcripción , Exones , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Factor 2 Regulador del Interferón , Repeticiones de Microsatélite , Polimorfismo de Nucleótido Simple , Empalme del ARN/genética
19.
Biopreserv Biobank ; 12(1): 13-6, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24620765

RESUMEN

Biobank sample storage is critical in population health and epidemiology studies. Biobanks bridge two very different worlds: they connect to the participants and patients at an individual level, but they also aggregate information and represent the cutting edge of scientific discovery. In this brief report, we describe how the LifeLines study in the Netherlands manages its resources for communication and services, and how it can serve as a model for the Human Heredity and Health in Africa Initiative (H3Africa Initiative).


Asunto(s)
Bancos de Muestras Biológicas , África , Bancos de Muestras Biológicas/organización & administración , Bancos de Muestras Biológicas/normas , Humanos , Difusión de la Información , Modelos Teóricos , Países Bajos , Manejo de Especímenes
20.
PLoS One ; 9(2): e88216, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24516614

RESUMEN

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disease characterized by recurrent respiratory tract infections, sinusitis, bronchiectasis and male infertility. The pulmonary phenotype in PCD is caused by the impaired motility of cilia in the respiratory epithelium, due to ultrastructural defects of these organelles. We hypothesized that defects of multi-protein ciliary complexes should be reflected by gene expression changes in the respiratory epithelium. We have previously found that large group of genes functionally related to cilia share highly correlated expression pattern in PCD bronchial tissue. Here we performed an explorative analysis of differential gene expression in the bronchial tissue from six PCD patients and nine non-PCD controls, using Illumina HumanRef-12 Whole Genome BeadChips. We observed 1323 genes with at least 2-fold difference in the mean expression level between the two groups (t-test p-value <0.05). Annotation analysis showed that the genes down-regulated in PCD biopsies (602) were significantly enriched for terms related to cilia, whereas the up-regulated genes (721) were significantly enriched for terms related to cell cycle and mitosis. We assembled a list of human genes predicted to encode ciliary proteins, components of outer dynein arms, inner dynein arms, radial spokes, and intraflagellar transport proteins. A significant down-regulation of the expression of genes from all the four groups was observed in PCD, compared to non-PCD biopsies. Our data suggest that a coordinated down-regulation of the ciliome genes plays an important role in the molecular pathomechanism of PCD.


Asunto(s)
Bronquios/patología , Cilios/genética , Cilios/patología , Regulación hacia Abajo/genética , Síndrome de Kartagener/genética , Estudios de Casos y Controles , Perfilación de la Expresión Génica , Genoma Humano/genética , Humanos , Síndrome de Kartagener/patología , Anotación de Secuencia Molecular , Mutación/genética , Regulación hacia Arriba/genética
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