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INTRODUCTION: Pain constitutes a major component of the global burden of diseases. Recent studies suggest a strong genetic contribution to pain susceptibility and severity. Whereas most of the available evidence relies on candidate gene association or linkage studies, research on the genetic basis of pain sensitivity using genome-wide association studies (GWAS) is still in its infancy. This protocol describes a proposed GWAS on genetic contributions to baseline pain sensitivity and nociceptive sensitisation in a sample of unrelated healthy individuals of mixed Latin American ancestry. METHODS AND ANALYSIS: A GWAS on genetic contributions to pain sensitivity in the naïve state and following nociceptive sensitisation will be conducted in unrelated healthy individuals of mixed ancestry. Mechanical and thermal pain sensitivity will be evaluated with a battery of quantitative sensory tests evaluating pain thresholds. In addition, variation in mechanical and thermal sensitisation following topical application of mustard oil to the skin will be evaluated. ETHICS AND DISSEMINATION: This study received ethical approval from the University College London research ethics committee (3352/001) and from the bioethics committee of the Odontology Faculty at the University of Antioquia (CONCEPTO 01-2013). Findings will be disseminated to commissioners, clinicians and service users via papers and presentations at international conferences.
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Estudo de Associação Genômica Ampla/métodos , Limiar da Dor , Dor/genética , Colômbia , Voluntários Saudáveis , Humanos , Nociceptores/fisiologiaRESUMO
Historical records and genetic analyses indicate that Latin Americans trace their ancestry mainly to the intermixing (admixture) of Native Americans, Europeans and Sub-Saharan Africans. Using novel haplotype-based methods, here we infer sub-continental ancestry in over 6,500 Latin Americans and evaluate the impact of regional ancestry variation on physical appearance. We find that Native American ancestry components in Latin Americans correspond geographically to the present-day genetic structure of Native groups, and that sources of non-Native ancestry, and admixture timings, match documented migratory flows. We also detect South/East Mediterranean ancestry across Latin America, probably stemming mostly from the clandestine colonial migration of Christian converts of non-European origin (Conversos). Furthermore, we find that ancestry related to highland (Central Andean) versus lowland (Mapuche) Natives is associated with variation in facial features, particularly nose morphology, and detect significant differences in allele frequencies between these groups at loci previously associated with nose morphology in this sample.
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Migração Humana , Indígenas Norte-Americanos/genética , Indígenas Sul-Americanos/genética , Haplótipos , Humanos , México , Nariz/anatomia & histologia , América do SulRESUMO
Functional immunological evidence supports the impact that the host genetic variability has on the susceptibility to develop asymptomatic or symptomatic dengue infection. Children are more prone to develop severe dengue. Thus, we have evaluated possible associations between single-nucleotide polymorphisms (SNPs) located in immune genes and the development of symptomatic dengue in children from two Colombian populations with differences in genetic backgrounds and geographical features. We genotyped 15 SNPs (in 12 genes) in 298 symptomatic children and 648 healthy controls. Ancestry proportions (APs) were inferred by genotyping 29 ancestry informative markers. We observed four SNPs associated with susceptibility to develop dengue in NOD1, RIPK2, MICB, or PLCE1 genes. Conversely, we found one SNP in TNF gene and two haplotypes in the IKBKE gene associated with resistance to develop dengue. These associations were adjusted by gender, APs, and the population of origin because the association of polymorphisms may be different in admixed populations like Colombian. To our knowledge, this is the first reported association study with dengue in IKBKE, RIPK2, and NOD1 genes. We have also confirmed previously reported associations in MICB and PLCE1 genes with dengue. Overall, our results contribute to the understanding of the genetic susceptibility/resistance to develop symptomatic dengue. Nevertheless, these associations must be validated through functional analysis.
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Dengue/genética , Quinase I-kappa B/genética , Proteína Adaptadora de Sinalização NOD1/genética , Polimorfismo de Nucleotídeo Único , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Colômbia , Feminino , Predisposição Genética para Doença , Genótipo , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Masculino , Fosfoinositídeo Fosfolipase C/genética , Fatores Sexuais , Fator de Necrose Tumoral alfa/genéticaRESUMO
Resumen Introducción. La composición genética del huésped determina, entre otros aspectos, el perfil clínico del dengue, lo cual se debería al efecto de variantes en los genes que codifican citocinas proinflamatorias. Objetivo. Evaluar la asociación entre las variantes de tres polimorfismos en los genes candidatos TNFA, IL6 e IFNG con la gravedad del dengue en una población colombiana. Materiales y métodos. Se evaluaron los polimorfismos rs1800750, rs2069843 y rs2069705 de los genes TNFA, IL6 e IFNG, respectivamente, en 226 pacientes con dengue. Los genotipos se tipificaron usando la reacción en cadena de la polimerasa (PCR) y los polimorfismos de la longitud de los fragmentos de restricción (Restriction Fragment Length Polymorphism, RFLP). Para determinar el riesgo de diferentes fenotipos del dengue, se compararon las frecuencias alélicas con la prueba de ji al cuadrado, y los genotipos y los haplotipos, con regresión logística. Por último, los análisis se ajustaron utilizando datos de autoidentificación o del componente genético ancestral. Resultados. El alelo A del rs2069843, ajustado por autoidentificación, se asoció con casos de dengue hemorrágico en afrocolombianos. En la muestra completa, dicho polimorfismo, ajustado por componente genético ancestral, fue reproducible. Además, hubo asociaciones significativas entre las combinaciones alélicas GGT y GAC de los rs1800750, rs2069843 y rs2069705 en pacientes con dengue hemorrágico, con ajuste por componente genético ancestral y sin él. Además, la combinación alélica AGC produjo 58,03 pg/ml más de interleucina 6 que la GGC, independientemente de los componentes genéticos europeo, amerindio y africano. Conclusión. Las variantes de los polimorfismos GGT y GAC de los rs1800750, rs2069843 y rs2069705 en los genes TNFA, IL6 e IFNG, respectivamente, se correlacionaron con la gravedad del dengue en esta muestra de población colombiana.
Abstract Introduction: The genetic makeup of the host contributes to the clinical profile of dengue. This could be due to the effect of variants in the genes encoding pro-inflammatory cytokines. Objective: To evaluate the association between the variants of three polymorphisms in TNFA, IL6 and IFNG candidate genes with dengue severity in a sample of Colombian population. Materials and methods: We evaluated the rs1800750, rs2069843, and rs2069705 polymorphisms in TNFA, IL6 and IFNG candidate genes, respectively, in 226 patients with dengue infection. The genotypes were typed using both polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). To determine the risk of different dengue phenotypes, we compared allele frequencies with chisquare and genotypes and haplotypes using logistic regression. Finally, these analyzes were adjusted with data from self-identification or the ancestral genetic component. Results: The A allele in the rs2069843 polymorphism, adjusted by self-identification, was associated with dengue hemorrhagic fever cases in Afro-Colombians. In the entire sample, this polymorphism, adjusted by the ancestral genetic component, was reproducible. In addition, there were significant associations between GGT and GAC allelic combinations of rs1800750, rs2069843, and rs2069705 in dengue hemorrhagic fever patients, with and without adjustment by ancestral genetic component. Additionally, the AGC allelic combination produced 58.03 pg/ml of interleukin-6 more than the GGC combination, regardless of European, Amerindian and African genetic components. Conclusions: The variants of GGT and GAC polymorphisms of rs1800750, rs2069843, and rs2069705 in the TNFA, IL6 and IFNG genes, respectively, were correlated with the susceptibility to dengue severity in a sample of Colombian population.
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Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Interleucina-6/genética , Interferon gama/genética , Fator de Necrose Tumoral alfa/genética , Polimorfismo de Nucleotídeo Único , Dengue/genética , Polimorfismo de Fragmento de Restrição , DNA Viral/genética , Etnicidade/genética , Reação em Cadeia da Polimerase , Risco , Estudos Transversais , Estudos Prospectivos , Colômbia/epidemiologia , Predisposição Genética para Doença , Dengue/epidemiologia , Vírus da Dengue/classificação , Vírus da Dengue/genética , Alelos , Estudos de Associação Genética , Frequência do Gene , GenótipoRESUMO
INTRODUCTION: The genetic makeup of the host contributes to the clinical profile of dengue. This could be due to the effect of variants in the genes encoding pro-inflammatory cytokines. OBJECTIVE: To evaluate the association between the variants of three polymorphisms in TNFA, IL6 and IFNG candidate genes with dengue severity in a sample of Colombian population. MATERIALS AND METHODS: We evaluated the rs1800750, rs2069843, and rs2069705 polymorphisms in TNFA, IL6 and IFNG candidate genes, respectively, in 226 patients with dengue infection. The genotypes were typed using both polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). To determine the risk of different dengue phenotypes, we compared allele frequencies with chi-square and genotypes and haplotypes using logistic regression. Finally, these analyzes were adjusted with data from self-identification or the ancestral genetic component. RESULTS: The A allele in the rs2069843 polymorphism, adjusted by self-identification, was associated with dengue hemorrhagic fever cases in Afro-Colombians. In the entire sample, this polymorphism, adjusted by the ancestral genetic component, was reproducible. In addition, there were significant associations between GGT and GAC allelic combinations of rs1800750, rs2069843, and rs2069705 in dengue hemorrhagic fever patients, with and without adjustment by ancestral genetic component. Additionally, the AGC allelic combination produced 58.03 pg/ml of interleukin-6 more than the GGC combination, regardless of European, Amerindian and African genetic components. CONCLUSIONS: The variants of GGT and GAC polymorphisms of rs1800750, rs2069843, and rs2069705 in the TNFA, IL6 and IFNG genes, respectively, were correlated with the susceptibility to dengue severity in a sample of Colombian population.
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Dengue/genética , Interferon gama/genética , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/genética , Adolescente , Adulto , Alelos , Criança , Colômbia/epidemiologia , Estudos Transversais , DNA Viral/genética , Dengue/epidemiologia , Vírus da Dengue/classificação , Vírus da Dengue/genética , Etnicidade/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Estudos Prospectivos , Risco , Adulto JovemRESUMO
The wide variation in severity displayed during Dengue Virus (DENV) infection may be influenced by host susceptibility. In several epidemiological approaches, differences in disease outcomes have been found between some ethnic groups, suggesting that human genetic background has an important role in disease severity. In the Caribbean, It has been reported that populations of African descent present considerable less frequency of severe forms compared with Mestizo and White self-reported groups. Admixed populations offer advantages for genetic epidemiology studies due to variation and distribution of alleles, such as those involved in disease susceptibility, as well to provide explanations of individual variability in clinical outcomes. The current study analysed three Colombian populations, which like most of Latin American populations, are made up of the product of complex admixture processes between European, Native American and African ancestors; having as a main goal to assess the effect of genetic ancestry, estimated with 30 Ancestry Informative Markers (AIMs), on DENV infection severity. We found that African ancestry has a protective effect against severe outcomes under several systems of clinical classification: Severe Dengue (OR: 0.963 for every 1% increase in African ancestry, 95% confidence interval (0.934-0.993), p-value: 0.016), Dengue Haemorrhagic Fever (OR: 0.969, 95% CI (0.947-0.991), p-value: 0.006), and occurrence of haemorrhages (OR: 0.971, 95% CI (0.952-0.989), p-value: 0.002). Conversely, decrease from 100% to 0% African ancestry significantly increases the chance of severe outcomes: OR is 44-fold for Severe Dengue, 24-fold for Dengue Haemorrhagic Fever, and 20-fold for occurrence of haemorrhages. Furthermore, several warning signs also showed statistically significant association given more evidences in specific stages of DENV infection. These results provide consistent evidence in order to infer statistical models providing a framework for future genetic epidemiology and clinical studies.