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1.
Neuroepidemiology ; 56(2): 138-146, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35051933

RESUMEN

INTRODUCTION: Onset of febrile seizures varies with calendar season. However, it has not previously been assessed, how season of birth interacts with age and peak risk of febrile seizures, and whether season of birth correlates with the cumulative risk of febrile seizures at 5 years of age (i.e., when children are no longer of risk of febrile seizures). METHODS: We identified all singleton children born in Denmark between 1977 and 2011 who were alive at 3 months of age (N = 2,103,232). We used the Danish Civil Registration System to identify age and sex of the children and the Danish National Patient Register to identify children hospitalized with febrile seizures from 3 months to 5 years of age. Follow-up ended on December 31, 2016, when all children had reached 5 years of age. RESULTS: The relative risk of admission with a first febrile seizure varied with calendar month; in February (a winter month in Denmark), the risk was more than doubled (hazard ratio: 2.10 [95% confidence interval [CI]: 2.03-2.18]) compared with August (a summer month in Denmark). The age-specific incidence of a first febrile seizure by birth month identified the highest peak incidence of a first febrile seizure among children born in November (reaching a peak incidence of 350 first admissions with a febrile seizure per 100,000 person months at age 16 months) as compared to children born in July (reaching a peak incidence of 200 first admissions with a febrile seizure per 100,000 person months at age 16 months). However, the cumulative incidence of any admission with febrile seizures before 5 years was not correlated with season of birth (3.69% [95% CI: 3.64-3.74%] for winter births, 3.57% [95% CI: 3.52-3.62%] for spring births, 3.55% [95% CI: 3.50-3.59%] for summer births, and 3.64% [95% CI: 3.59-3.69%] for fall births). DISCUSSION/CONCLUSION: The study found a significant seasonal variation in onset of the first febrile seizure and in the age-specific peak incidence of febrile seizures. However, there was no correlation between season of birth and cumulative incidence of febrile seizures at 5 years of age suggesting that children who are predisposed to febrile seizures will eventually go on to experience a febrile seizure regardless of season of birth.


Asunto(s)
Convulsiones Febriles , Niño , Estudios de Cohortes , Dinamarca/epidemiología , Humanos , Incidencia , Lactante , Estaciones del Año , Convulsiones Febriles/epidemiología , Convulsiones Febriles/etiología
2.
Acta Neurol Scand ; 144(1): 51-57, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33822360

RESUMEN

OBJECTIVE: Febrile seizure is a common childhood disorder that affects 2-5% of all children, and is associated with later development of epilepsy and psychiatric disorders. This study determines how the incidence of febrile seizures correlates with birth characteristics, age, sex and brain development. METHODS: This is a cohort study of all children born Denmark between 1977 and 2011 who were alive at 3 months of age (N = 2,103,232). The Danish National Patient Register was used to identify children with febrile seizures up to 5 years of age. Follow-up ended on 31 December 2016 when all cohort members had potentially reached 5 years of age. RESULTS: In total, 75,593 (3.59%, 95% CI: 3.57-3.62%) were diagnosed with febrile seizures. Incidence peaked at 16.7 months of age (median: 16.7 months, interquartile range: 12.5-24.0). The 5-year cumulative incidence of febrile seizures increased with decreasing birth weight (<1500 g; 5.42% (95% CI: 4.98-5.88% vs. 3,000-4,000 g; 3.53% (95% CI: 3.50-3.56%)) and with decreasing gestational age at birth (31-32 weeks; 5.90% (95% CI: 5.40-6.44%) vs. 39-40 weeks; 3.56% (95% CI: 3.53-3.60)). Lower gestational age at birth was associated with higher age at onset of a first febrile seizure; an association that essentially disappeared when correcting for age from conception. CONCLUSIONS: The risk of febrile seizures increased with decreasing birth weight and gestational age at birth. The association between low gestational age at birth and age at first febrile seizure suggests that onset of febrile seizures is associated with the stage of brain development.


Asunto(s)
Peso al Nacer/fisiología , Desarrollo Infantil/fisiología , Edad Gestacional , Convulsiones Febriles/diagnóstico , Convulsiones Febriles/epidemiología , Preescolar , Estudios de Cohortes , Dinamarca/epidemiología , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Sistema de Registros , Factores de Riesgo , Convulsiones Febriles/fisiopatología , Factores Sexuales
3.
EMBO Rep ; 17(8): 1169-83, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27312110

RESUMEN

Foxp3(+) regulatory T cells (Tregs) exhibit plasticity, which dictates their function. Secretion of the inflammatory cytokine IFNγ, together with the acquisition of a T helper 1 (Th1)-like effector phenotype as observed in cancer, infection, and autoimmune diseases, is associated with loss of Treg suppressor function through an unknown mechanism. Here, we describe the signaling events driving the generation of human Th1-Tregs. Using a genome-wide gene expression approach and pathway analysis, we identify the PI3K/AKT/Foxo1/3 signaling cascade as the major pathway involved in IFNγ secretion by human Tregs. Furthermore, we describe the opposing roles of AKT isoforms in Th1-Treg generation ex vivo Finally, we employ multiple sclerosis as an in vivo model with increased but functionally defective Th1-Tregs. We show that the PI3K/AKT/Foxo1/3 pathway is activated in ex vivo-isolated Tregs from untreated relapsing-remitting MS patients and that blockade of the pathway inhibits IFNγ secretion and restores the immune suppressive function of Tregs. These data define a fundamental pathway regulating the function of human Tregs and suggest a novel treatment paradigm for autoimmune diseases.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Enfermedades Autoinmunes/genética , Biomarcadores , Diferenciación Celular , Citocinas , Factores de Transcripción Forkhead/metabolismo , Perfilación de la Expresión Génica , Silenciador del Gen , Humanos , Inmunomodulación , Interferón gamma/metabolismo , Fenotipo , Fosfatidilinositol 3-Quinasas/metabolismo , Isoformas de Proteínas , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/citología , Transcriptoma
4.
Nature ; 491(7422): 119-24, 2012 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-23128233

RESUMEN

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Interacciones Huésped-Patógeno , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/microbiología , Mycobacterium/inmunología , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/fisiopatología , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/microbiología , Enfermedad de Crohn/fisiopatología , Genoma Humano/genética , Haplotipos/genética , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/fisiopatología , Mycobacterium/patogenicidad , Infecciones por Mycobacterium/genética , Infecciones por Mycobacterium/microbiología , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/patogenicidad , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Reproducibilidad de los Resultados
6.
Nat Genet ; 56(5): 838-845, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38741015

RESUMEN

Autoimmune and inflammatory diseases are polygenic disorders of the immune system. Many genomic loci harbor risk alleles for several diseases, but the limited resolution of genetic mapping prevents determining whether the same allele is responsible, indicating a shared underlying mechanism. Here, using a collection of 129,058 cases and controls across 6 diseases, we show that ~40% of overlapping associations are due to the same allele. We improve fine-mapping resolution for shared alleles twofold by combining cases and controls across diseases, allowing us to identify more expression quantitative trait loci driven by the shared alleles. The patterns indicate widespread sharing of pathogenic mechanisms but not a single global autoimmune mechanism. Our approach can be applied to any set of traits and is particularly valuable as sample collections become depleted.


Asunto(s)
Alelos , Enfermedades Autoinmunes , Mapeo Cromosómico , Predisposición Genética a la Enfermedad , Sitios de Carácter Cuantitativo , Humanos , Enfermedades Autoinmunes/genética , Polimorfismo de Nucleótido Simple , Estudio de Asociación del Genoma Completo , Estudios de Casos y Controles , Herencia Multifactorial/genética
7.
Acta Chim Slov ; 57(2): 498-505, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24061752

RESUMEN

Single nucleotide polymorphism (SNP) analysis is important tool in the studies of genetic factors associated with complex diseases and with genetically influenced response to drug therapy (pharmacogenetics). Recently, a new generation of generic dsDNA binding dyes (LCGreenTM) contributed to the development of fast and low-cost method for SNP detection and/or genotyping based on high resolution melting (HRM) analysis. The aim of our study was to develop HRM assay for IL23R gene (rs7517847) and to perform association study in Slovenian inflammatory bowel diseases (IBD) patients. We genotyped 345 Slovenian healthy controls and 295 IBD patients including 159 with Crohn's disease (CD) and 136 with ulcerative colitis (UC) for rs7517847 polymorphism in IL23R gene using standard RFLP and optimized HRM methods. In this study, we showed, that HRM is a simple, fast and reliable method for genotyping of clinical samples where homozygotes (GG and TT) were determined by ¼Tm calling method« and difference between homozygotes and heterozygotes was determined by different melting curve shape using ¼gene scanning method«. With combination of results from ¼Tm calling« and ¼gene scanning« methods, we achieved 98,6% concordance between PCR-RFLP and PCR-HRM results, based on the analysis of 640 samples. We found statistically significant association of IL23R polymorphism with Slovenian Crohn's disease patients when comparing genotype and allele frequencies between CD patients and controls. Allele frequency of minor allele G was 0,46 in controls and was reduced to 0,33 in CD patients (p < 0,001, OR = 0,588). The frequency of T/T genotype carriers was higher in CD patients (50,3%) than in controls (26,7%, p = 0,002, OR = 2,558). We found weak association between IL23R polymorphism and Slovenian UC patients. Carriers of T/T genotype have higher risk for UC (p = 0,035, OR = 1,599). These results suggest IL23R plays important role in CD and UC development in Slovenian patients.

8.
Clin Transl Immunology ; 7(6): e1018, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29881546

RESUMEN

Large-scale genetic studies of multiple sclerosis have identified over 230 risk effects across the human genome, making it a prototypical common disease with complex genetic architecture. Here, after a brief historical background on the discovery and definition of the disease, we summarise the last fifteen years of genetic discoveries and map out the challenges that remain to translate these findings into an aetiological framework and actionable clinical understanding.

9.
Clin Transl Immunology ; 7(8): e1038, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30128152

RESUMEN

[This corrects the article DOI: 10.1002/cti2.1018.].

10.
Handb Clin Neurol ; 148: 723-730, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29478610

RESUMEN

Multiple sclerosis is a potentially progressive, autoimmune neurologic disorder of the central nervous system, resulting from an autoimmune attack on central nervous system white matter. It is a leading cause of neurologic symptoms in young adults, with no known cure. Emerging disease-modifying therapies aim to control symptoms, with increasingly sophisticated immune function modulation. Though several environmental exposures increase the risk of developing the disease, a large fraction of overall risk is heritable and can be attributed to hundreds of common genetic variants influencing gene regulation in specific immune subsets. Here, we review the history of the disease, the realization that risk is heritable, and the recent revelation of hundreds of genetic variants driving this risk by international consortia studying tens of thousands of patients. Finally, we discuss how these results are revealing the specific pathobiology of multiple sclerosis and how this knowledge is transforming drug discovery.


Asunto(s)
Sistema Nervioso Central/patología , Esclerosis Múltiple , Sustancia Blanca/patología , Estudios de Asociación Genética , Humanos , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología
11.
Elife ; 52016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26880555

RESUMEN

Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.


Asunto(s)
Autoinmunidad , Regulación de la Expresión Génica , Antígenos HLA-D/biosíntesis , Antígenos HLA-D/genética , Polimorfismo Genético , Células Dendríticas/química , Europa (Continente) , Humanos , Lupus Eritematoso Sistémico/patología , Proteínas de la Membrana/análisis , Estados Unidos , Población Blanca
12.
Sci Transl Med ; 7(291): 291ra93, 2015 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-26062845

RESUMEN

The transcription factor nuclear factor κB (NFκB) is a central regulator of inflammation, and genome-wide association studies in subjects with autoimmune disease have identified a number of variants within the NFκB signaling cascade. In addition, causal variant fine-mapping has demonstrated that autoimmune disease susceptibility variants for multiple sclerosis (MS) and ulcerative colitis are strongly enriched within binding sites for NFκB. We report that MS-associated variants proximal to NFκB1 and in an intron of TNFRSF1A (TNFR1) are associated with increased NFκB signaling after tumor necrosis factor-α (TNFα) stimulation. Both variants result in increased degradation of inhibitor of NFκB α (IκBα), a negative regulator of NFκB, and nuclear translocation of p65 NFκB. The variant proximal to NFκB1 controls signaling responses by altering the expression of NFκB itself, with the GG risk genotype expressing 20-fold more p50 NFκB and diminished expression of the negative regulators of the NFκB pathway: TNFα-induced protein 3 (TNFAIP3), B cell leukemia 3 (BCL3), and cellular inhibitor of apoptosis 1 (CIAP1). Finally, naïve CD4 T cells from patients with MS express enhanced activation of p65 NFκB. These results demonstrate that genetic variants associated with risk of developing MS alter NFκB signaling pathways, resulting in enhanced NFκB activation and greater responsiveness to inflammatory stimuli. As such, this suggests that rapid genetic screening for variants associated with NFκB signaling may identify individuals amenable to NFκB or cytokine blockade.


Asunto(s)
Autoinmunidad/genética , Predisposición Genética a la Enfermedad , Inflamación/genética , FN-kappa B/metabolismo , Polimorfismo de Nucleótido Simple/genética , Transducción de Señal/genética , Factores de Edad , Alelos , Linfocitos T CD4-Positivos/inmunología , Estudios de Casos y Controles , Núcleo Celular/metabolismo , Citocinas/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Transporte de Proteínas , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Factores de Riesgo , Caracteres Sexuales , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismo
13.
Nat Genet ; 45(6): 670-5, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23603763

RESUMEN

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.


Asunto(s)
Colangitis Esclerosante/genética , Estudios de Casos y Controles , Colangitis Esclerosante/inmunología , Frecuencia de los Genes , Sitios Genéticos/inmunología , Pleiotropía Genética , Estudio de Asociación del Genoma Completo , Técnicas de Genotipaje , Humanos , Desequilibrio de Ligamiento , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Factores de Riesgo
14.
PLoS One ; 7(9): e45287, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23028907

RESUMEN

BACKGROUND: Genome-wide association studies of two main forms of inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), have identified 99 susceptibility loci, but these explain only 23% of the genetic risk. Part of the 'hidden heritability' could be in transmissible genetic effects in which mRNA expression in the offspring depends on the parental origin of the allele (genomic imprinting), since children whose mothers have CD are more often affected than children with affected fathers. We analyzed parent-of-origin (POO) effects in Dutch and Indian cohorts of IBD patients. METHODS: We selected 28 genetic loci associated with both CD and UC, and tested them for POO effects in 181 Dutch IBD case-parent trios. Three susceptibility variants in NOD2 were tested in 111 CD trios and a significant finding was re-evaluated in 598 German trios. The UC-associated gene, BTNL2, reportedly imprinted, was tested in 70 Dutch UC trios. Finally, we used 62 independent Indian UC trios to test POO effects of five established Indian UC risk loci. RESULTS: We identified POO effects for NOD2 (L1007fs; OR = 21.0, P-value = 0.013) for CD; these results could not be replicated in an independent cohort (OR = 0.97, P-value = 0.95). A POO effect in IBD was observed for IL12B (OR = 3.2, P-value = 0.019) and PRDM1 (OR = 5.6, P-value = 0.04). In the Indian trios the IL10 locus showed a POO effect (OR = 0.2, P-value = 0.03). CONCLUSIONS: Little is known about the effect of genomic imprinting in complex diseases such as IBD. We present limited evidence for POO effects for the tested IBD loci. POO effects explain part of the hidden heritability for complex genetic diseases but need to be investigated further.


Asunto(s)
Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Sitios Genéticos , Impresión Genómica , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Butirofilinas , Niño , Femenino , Expresión Génica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Patrón de Herencia , Interleucina-10/genética , Subunidad p40 de la Interleucina-12/genética , Masculino , Glicoproteínas de Membrana/genética , Proteína Adaptadora de Señalización NOD2/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas Represoras/genética , Riesgo
15.
Dis Markers ; 30(5): 265-74, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21734346

RESUMEN

Inflammatory bowel diseases (IBD) are usually classified into Crohn's disease (CD) and ulcerative colitis (UC). NOD2/CARD15 was the first identified CD-susceptibility gene and was confirmed as the most potent disease gene in CD pathogenesis. Three NOD2/CARD15 variants, namely two missense polymorphisms R702W (rs2066844) and G908R (rs2066845), and a frame shift polymorphism L1007fs (rs2066847), were associated with CD in Caucasian populations. High resolution melting analysis (HRMA) with saturation LCGreen dyes was previously reported as a simple, inexpensive, accurate and sensitive method for genotyping and/or scanning of rare variants. For this reasons we used qPCR-HRMA for genotyping NOD2/CARD15 variants in 588 Slovenian IBD patients and 256 healthy controls. PCR-RFLP was used as a reference method for genotyping of clinical samples. The optimization of an HRM experiment required careful design and adjustment of main parameters, such as primer concentration, MgCl_{2} concentration, probe design and template DNA concentration. Different HRMA approaches were tested and used to develop a reliable and low-cost SNP genotyping assays for polymorphisms in NOD2/CARD15 gene. Direct HRMA was the fastest and cheapest HRMA approach for L1007fs and R702W polymorphisms, yet for G908R polymorphism sufficient reliability was achieved after introduction of unlabeled probe. In association analysis, we found statistically significant association of L1007fs (p =0.001, OR=3.011, CI95%=1.494-6.071) and G908R (p=2.62 × 10^{-4}, OR=14.117, CI95%= 1.884-105.799) polymorphisms with CD patients. At least one of NOD2/CARD15 polymorphisms was found in 78/354 (22.03% (12.69%) in UC patients and in 26/256 (10.15%) in healthy controls. We have successfully implemented NOD2/CARD15 HRMA assays, which may contribute to the development of genetic profiles for risk prediction of developing CD and for differential diagnosis of CD vs. UC.


Asunto(s)
Pruebas Genéticas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Enfermedades Inflamatorias del Intestino/genética , Proteína Adaptadora de Señalización NOD2/genética , Adulto , Algoritmos , Estudios de Casos y Controles , ADN/análisis , Femenino , Frecuencia de los Genes , Marcadores Genéticos , Genotipo , Humanos , Enfermedades Inflamatorias del Intestino/epidemiología , Masculino , Mutación , Desnaturalización de Ácido Nucleico/genética , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Prevalencia , Eslovenia/epidemiología
16.
Genome Med ; 3(2): 13, 2011 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-21392414

RESUMEN

Multiple genome-wide association studies (GWASs) and two large scale meta-analyses have been performed for Crohn's disease and have identified 71 susceptibility loci. These findings have contributed greatly to our current understanding of the disease pathogenesis. Yet, these loci only explain approximately 23% of the disease heritability. One of the future challenges in this post-GWAS era is to identify potential sources of the remaining heritability. Such sources may include common variants with limited effect size, rare variants with higher effect sizes, structural variations, or even more complicated mechanisms such as epistatic, gene-environment and epigenetic interactions. Here, we outline potential sources of this hidden heritability, focusing on Crohn's disease and the currently available data. We also discuss future strategies to determine more about the heritability; these strategies include expanding current GWAS, fine-mapping, whole genome sequencing or exome sequencing, and using family-based approaches. Despite the current limitations, such strategies may help to transfer research achievements into clinical practice and guide the improvement of preventive and therapeutic measures.

17.
Nat Genet ; 43(12): 1193-201, 2011 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-22057235

RESUMEN

Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.


Asunto(s)
Enfermedad Celíaca/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Mapeo Cromosómico , Frecuencia de los Genes , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Desequilibrio de Ligamiento , Factores de Riesgo
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