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1.
Epigenomics ; 11(12): 1371-1385, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31583916

RESUMO

Aim: Gestational diabetes mellitus (GDM) has been linked with adverse long-term health outcomes for the fetus and mother. These effects may be mediated by epigenetic modifications. Materials & methods: Genome-wide RNA sequencing was performed in placental tissue and maternal blood in six GDM and six non-GDM pregnancies. Promoter region DNA methylation was examined for selected genes and correlated with gene expression to examine an epigenetic modulator mechanism. Results: Reductions of mRNA expression and increases in promoter methylation were observed for G6PD in GDM women, and for genes encoding IGF-binding proteins in GDM-exposed placenta. Conclusion: GDM involves epigenetic attenuation of G6PD, which may lead to hyperglycemia and oxidative stress, and the IGF-axis, which may modulate fetal macrosomia.

2.
Hum Mutat ; 40(7): 865-878, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31026367

RESUMO

Mendelian diseases have shown to be an and efficient model for connecting genotypes to phenotypes and for elucidating the function of genes. Whole-exome sequencing (WES) accelerated the study of rare Mendelian diseases in families, allowing for directly pinpointing rare causal mutations in genic regions without the need for linkage analysis. However, the low diagnostic rates of 20-30% reported for multiple WES disease studies point to the need for improved variant pathogenicity classification and causal variant prioritization methods. Here, we present the exome Disease Variant Analysis (eDiVA; http://ediva.crg.eu), an automated computational framework for identification of causal genetic variants (coding/splicing single-nucleotide variants and small insertions and deletions) for rare diseases using WES of families or parent-child trios. eDiVA combines next-generation sequencing data analysis, comprehensive functional annotation, and causal variant prioritization optimized for familial genetic disease studies. eDiVA features a machine learning-based variant pathogenicity predictor combining various genomic and evolutionary signatures. Clinical information, such as disease phenotype or mode of inheritance, is incorporated to improve the precision of the prioritization algorithm. Benchmarking against state-of-the-art competitors demonstrates that eDiVA consistently performed as a good or better than existing approach in terms of detection rate and precision. Moreover, we applied eDiVA to several familial disease cases to demonstrate its clinical applicability.

3.
Sci Rep ; 9(1): 4579, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30872671

RESUMO

Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease with both autoimmune and autoinflammatory components. Recently, familial cases of systemic-onset JIA have been attributed to mutations in LACC1/FAMIN. We describe three affected siblings from a Moroccan consanguineous family with an early-onset chronic, symmetric and erosive arthritis previously diagnosed as rheumatoid factor (RF)-negative polyarticular JIA. Autozygosity mapping identified four homozygous regions shared by all patients, located in chromosomes 3, 6 (n:2) and 13, containing over 330 genes. Subsequent whole exome sequencing identified two potential candidate variants within these regions (in FARS2 and LACC1/FAMIN). Genotyping of a cohort of healthy Moroccan individuals (n: 352) and bioinformatics analyses finally supported the frameshift c.128_129delGT mutation in the LACC1/FAMIN gene, leading to a truncated protein (p.Cys43Tyrfs*6), as the most probable causative gene defect. Additional targeted sequencing studies performed in patients with systemic-onset JIA (n:23) and RF-negative polyarticular JIA (n: 44) revealed no pathogenic LACC1/FAMIN mutations. Our findings support the homozygous genotype in the LACC1/FAMIN gene as the defect underlying the family here described with a recessively inherited severe inflammatory joint disease. Our evidences provide further support to the involvement of LACC1/FAMIN deficiency in different types of JIA in addition to the initially described systemic-onset JIA.

4.
Genome Biol ; 19(1): 213, 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30514392

RESUMO

We present here miRTrace, the first algorithm to trace microRNA sequencing data back to their taxonomic origins. This is a challenge with profound implications for forensics, parasitology, food control, and research settings where cross-contamination can compromise results. miRTrace accurately (> 99%) assigns real and simulated data to 14 important animal and plant groups, sensitively detects parasitic infection in mammals, and discovers the primate origin of single cells. Applying our algorithm to over 700 public datasets, we find evidence that over 7% are cross-contaminated and present a novel solution to clean these computationally, even after sequencing has occurred. miRTrace is freely available at https://github.com/friedlanderlab/mirtrace .

5.
Hum Mutat ; 2018 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-30353964

RESUMO

In recent years, next-generation sequencing (NGS) has become a cornerstone of clinical genetics and diagnostics. Many clinical applications require high precision, especially if rare events such as somatic mutations in cancer or genetic variants causing rare diseases need to be identified. Although random sequencing errors can be modeled statistically and deep sequencing minimizes their impact, systematic errors remain a problem even at high depth of coverage. Understanding their source is crucial to increase precision of clinical NGS applications. In this work, we studied the relation between recurrent biases in allele balance (AB), systematic errors, and false positive variant calls across a large cohort of human samples analyzed by whole exome sequencing (WES). We have modeled the AB distribution for biallelic genotypes in 987 WES samples in order to identify positions recurrently deviating significantly from the expectation, a phenomenon we termed allele balance bias (ABB). Furthermore, we have developed a genotype callability score based on ABB for all positions of the human exome, which detects false positive variant calls that passed state-of-the-art filters. Finally, we demonstrate the use of ABB for detection of false associations proposed by rare variant association studies. Availability: https://github.com/Francesc-Muyas/ABB.

6.
Clin Rheumatol ; 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30238381

RESUMO

The objective was to explore changes in gene expression in Wnt pathway genes in skin samples of black South Africans with diffuse cutaneous systemic sclerosis (dcSSc). Affected (forearm) and unaffected (upper back) skin samples of eight Black South Africans with active early dcSSc were compared to skin samples from seven ethnically matched control subjects. The Wnt Pathway Plus RT2 Profiler qPCR Array was used to determine gene expression and analyzed for differential expression between cases and controls. Selective validation was done using single-gene TaqMan assays. Several genes were similarly upregulated in both affected and unaffected skin of the dcSSc patients compared to controls. These included the Wnt ligands WNT7A and WNT10A, the frizzled receptors FZD8 and FZD9, intracellular signaling proteins AXIN1 and AXIN2, and the pathway target genes FGF4 and MMP7. Principal component analysis revealed patients clustering into two groups, which co-segregated with clinical features of interstitial lung disease and/or inflammatory myopathy, or the absence of an inflammation phenotype. These two groups showed paradoxical gene expression of the genes TCF7, SOX17, and FRZB in affected and unaffected skin. This study provides further evidence of dysregulation of gene expression at various levels of the Wnt signaling pathway in dcSSc. Moreover, principal component analysis showed two distinct patient clusters of gene expression, which co-segregated with the presence or absence of clinical inflammatory features, and may reflect different pathological pathways in dcSSc.

7.
BMJ Open ; 8(9): e021311, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-30206078

RESUMO

PURPOSE: Essential to exposome research is the collection of data on many environmental exposures from different domains in the same subjects. The aim of the Human Early Life Exposome (HELIX) study was to measure and describe multiple environmental exposures during early life (pregnancy and childhood) in a prospective cohort and associate these exposures with molecular omics signatures and child health outcomes. Here, we describe recruitment, measurements available and baseline data of the HELIX study populations. PARTICIPANTS: The HELIX study represents a collaborative project across six established and ongoing longitudinal population-based birth cohort studies in six European countries (France, Greece, Lithuania, Norway, Spain and the UK). HELIX used a multilevel study design with the entire study population totalling 31 472 mother-child pairs, recruited during pregnancy, in the six existing cohorts (first level); a subcohort of 1301 mother-child pairs where biomarkers, omics signatures and child health outcomes were measured at age 6-11 years (second level) and repeat-sampling panel studies with around 150 children and 150 pregnant women aimed at collecting personal exposure data (third level). FINDINGS TO DATE: Cohort data include urban environment, hazardous substances and lifestyle-related exposures for women during pregnancy and their offspring from birth until 6-11 years. Common, standardised protocols were used to collect biological samples, measure exposure biomarkers and omics signatures and assess child health across the six cohorts. Baseline data of the cohort show substantial variation in health outcomes and determinants between the six countries, for example, in family affluence levels, tobacco smoking, physical activity, dietary habits and prevalence of childhood obesity, asthma, allergies and attention deficit hyperactivity disorder. FUTURE PLANS: HELIX study results will inform on the early life exposome and its association with molecular omics signatures and child health outcomes. Cohort data are accessible for future research involving researchers external to the project.

8.
Br J Sports Med ; 52(7): 456-459, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29500253

RESUMO

Through the widespread availability of location-identifying devices, geolocalisation could potentially be used to place athletes during out-of-competition testing. In light of this debate, the WADA Ethics Panel formulated the following questions: (1) should WADA and/or other sponsors consider funding such geolocalisation research projects?, (2) if successful, could they be proposed to athletes as a complementary device to Anti-Doping Administration and Management System to help geolocalisation and reduce the risk of missed tests? and (3) should such devices be offered on a voluntary basis, or is it conceivable that they would be made mandatory for all athletes in registered testing pools? In this position paper, the WADA Ethics Panel concludes that the use of geolocalisation could be useful in a research setting with the goal of understanding associations between genotype, phenotype and environment; however, it recognises that the use of geolocalisation as part of or as replacement of whereabouts rules is replete with ethical concerns. While benefits remain largely hypothetical and minimal, the potential invasion of privacy and the data security threats are real. Considering the impact on privacy, data security issues, the societal ramifications of offering such services and various pragmatic considerations, the WADA Ethics Panel concludes that at this time, the use of geolocalisation should neither be mandated as a tool for disclosing whereabouts nor implemented on a voluntary basis.


Assuntos
Atletas , Doping nos Esportes/prevenção & controle , Sistemas de Informação Geográfica , Detecção do Abuso de Substâncias/ética , Detecção do Abuso de Substâncias/métodos , Confidencialidade , Humanos , Privacidade
9.
PLoS One ; 13(3): e0193527, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29505615

RESUMO

Circulating small RNAs, including miRNAs but also isomiRs and other RNA species, have the potential to be used as non-invasive biomarkers for communicable and non-communicable diseases. This study aims to characterize and compare small RNA profiles in human biofluids. For this purpose, RNA was extracted from plasma and breast milk samples from 15 healthy postpartum mothers. Small RNA libraries were prepared with the NEBNext® small RNA library preparation kit and sequenced in an Illumina HiSeq2000 platform. miRNAs, isomiRs and clusters of small RNAs were annotated using seqBuster/seqCluster framework in 5 plasma and 10 milk samples that passed the initial quality control. The RNA yield was 81 ng/mL [standard deviation (SD): 41] and 3985 ng/mL (SD: 3767) for plasma and breast milk, respectively. Mean number of good quality reads was 4.04 million (M) (40.01% of the reads) in plasma and 12.5M (89.6%) in breast milk. One thousand one hundred eighty two miRNAs, 12,084 isomiRs and 1,053 small RNA clusters that included piwi-interfering RNAs (piRNAs), tRNAs, small nucleolar RNAs (snoRNA) and small nuclear RNAs (snRNAs) were detected. Samples grouped by biofluid, with 308 miRNAs, 1,790 isomiRs and 778 small RNA clusters differentially detected. In summary, plasma and milk showed a different small RNA profile. In both, miRNAs, piRNAs, tRNAs, snRNAs, and snoRNAs were identified, confirming the presence of non-miRNA species in plasma, and describing them for the first time in milk.


Assuntos
MicroRNAs/sangue , MicroRNAs/metabolismo , Leite Humano/metabolismo , Adulto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Adulto Jovem
10.
Sci Rep ; 7(1): 13124, 2017 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-29030609

RESUMO

Tumors are composed of an evolving population of cells subjected to tissue-specific selection, which fuels tumor heterogeneity and ultimately complicates cancer driver gene identification. Here, we integrate cancer cell fraction, population recurrence, and functional impact of somatic mutations as signatures of selection into a Bayesian model for driver prediction. We demonstrate that our model, cDriver, outperforms competing methods when analyzing solid tumors, hematological malignancies, and pan-cancer datasets. Applying cDriver to exome sequencing data of 21 cancer types from 6,870 individuals revealed 98 unreported tumor type-driver gene connections. These novel connections are highly enriched for chromatin-modifying proteins, hinting at a universal role of chromatin regulation in cancer etiology. Although infrequently mutated as single genes, we show that chromatin modifiers are altered in a large fraction of cancer patients. In summary, we demonstrate that integration of evolutionary signatures is key for identifying mutational driver genes, thereby facilitating the discovery of novel therapeutic targets for cancer treatment.

11.
Environ Res ; 159: 239-248, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28822308

RESUMO

The molecular basis of many health outcomes attributed to solar ultraviolet radiation (UVR) is unknown. We tested the hypothesis that they may originate from transcriptional changes in blood cells. This was determined by assessing the effect of fluorescent solar simulated radiation (FSSR) on the transcriptional profile of peripheral blood pre- and 6h, 24h and 48h post-exposure in nine healthy volunteers. Expression of 20 genes was down-regulated and one was up-regulated at 6h after FSSR. All recovered to baseline expression at 24h or 48h. These genes have been associated with immune regulation, cancer and blood pressure; health effects attributed to vitamin D via solar UVR exposure. Plasma 25-hydroxyvitamin D3 [25OHD3] levels increased over time after FSSR and were maximal at 48h. The increase was more pronounced in participants with low basal 25OHD3 levels. Mediation analyses suggested that changes in gene expression due to FSSR were independent of 25OHD3 and blood cell subpopulations.


Assuntos
Sangue/metabolismo , Calcifediol/sangue , Transcriptoma , Raios Ultravioleta/efeitos adversos , Vitaminas/sangue , Adulto , Humanos , Masculino , Reino Unido , Adulto Jovem
12.
Am J Hum Genet ; 100(5): 695-705, 2017 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-28475856

RESUMO

Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.


Assuntos
Cooperação Internacional , Doenças Raras/diagnóstico , Doenças Raras/genética , Bases de Dados Factuais , Exoma , Genoma Humano , Humanos
13.
Psychiatr Genet ; 27(4): 152-158, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28368970

RESUMO

Anorexia nervosa (AN) is a serious and heritable psychiatric disorder. To date, studies of copy number variants (CNVs) have been limited and inconclusive because of small sample sizes. We conducted a case-only genome-wide CNV survey in 1983 female AN cases included in the Genetic Consortium for Anorexia Nervosa. Following stringent quality control procedures, we investigated whether pathogenic CNVs in regions previously implicated in psychiatric and neurodevelopmental disorders were present in AN cases. We observed two instances of the well-established pathogenic CNVs in AN cases. In addition, one case had a deletion in the 13q12 region, overlapping with a deletion reported previously in two AN cases. As a secondary aim, we also examined our sample for CNVs over 1 Mbp in size. Out of the 40 instances of such large CNVs that were not implicated previously for AN or neuropsychiatric phenotypes, two of them contained genes with previous neuropsychiatric associations, and only five of them had no associated reports in public CNV databases. Although ours is the largest study of its kind in AN, larger datasets are needed to comprehensively assess the role of CNVs in the etiology of AN.


Assuntos
Anorexia Nervosa/genética , Anorexia Nervosa/psicologia , Variações do Número de Cópias de DNA/genética , Adulto , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
14.
RNA ; 23(4): 433-445, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28062594

RESUMO

miRNAs are small 22-nucleotide RNAs that can post-transcriptionally regulate gene expression. It has been proposed that dietary plant miRNAs can enter the human bloodstream and regulate host transcripts; however, these findings have been widely disputed. We here conduct the first comprehensive meta-study in the field, surveying the presence and abundances of cross-species miRNAs (xenomiRs) in 824 sequencing data sets from various human tissues and body fluids. We find that xenomiRs are commonly present in tissues (17%) and body fluids (69%); however, the abundances are low, comprising 0.001% of host human miRNA counts. Further, we do not detect a significant enrichment of xenomiRs in sequencing data originating from tissues and body fluids that are exposed to dietary intake (such as liver). Likewise, there is no significant depletion of xenomiRs in tissues and body fluids that are relatively separated from the main bloodstream (such as brain and cerebro-spinal fluids). Interestingly, the majority (81%) of body fluid xenomiRs stem from rodents, which are a rare human dietary contribution but common laboratory animals. Body fluid samples from the same studies tend to group together when clustered by xenomiR compositions, suggesting technical batch effects. Last, we performed carefully designed and controlled animal feeding studies, in which we detected no transfer of plant miRNAs into rat blood, or bovine milk sequences into piglet blood. In summary, our comprehensive computational and experimental results indicate that xenomiRs originate from technical artifacts rather than dietary intake.


Assuntos
Líquidos Corporais/química , Química Encefálica , Dieta , Fígado/química , MicroRNAs/isolamento & purificação , RNA de Plantas/isolamento & purificação , Animais , Artefatos , Bovinos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fígado/metabolismo , MicroRNAs/sangue , MicroRNAs/líquido cefalorraquidiano , MicroRNAs/classificação , Plantas/química , RNA de Plantas/sangue , RNA de Plantas/líquido cefalorraquidiano , RNA de Plantas/classificação , Ratos
15.
Nephrol Dial Transplant ; 32(1): 151-156, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-26940125

RESUMO

Background: The TTC21B gene was initially described as causative of nephronophthisis (NPHP). Recently, the homozygous TTC21B p.P209L mutation has been identified in families with focal segmental glomerulosclerosis (FSGS) and tubulointerstitial lesions. Heterozygous TTC21B variants have been proposed as genetic modifiers in ciliopathies. We aimed to study the causative and modifying role of the TTC21B gene in glomerular and cystic kidney diseases. Methods: Mutation analysis of the TTC21B gene was performed by massive parallel sequencing. We studied the causative role of the TTC21B gene in 17 patients with primary diagnosis of FSGS or NPHP and its modifying role in 184 patients with inherited glomerular or cystic kidney diseases. Results: Disease-causing TTC21B mutations were identified in three families presenting nephrotic proteinuria with FSGS and tubulointerstitial lesions in which some family members presented hypertension and myopia. Two families carried the homozygous p.P209L and the third was compound heterozygous for the p.P209L and a novel p.H426D mutation. Rare heterozygous TTC21B variants predicted to be pathogenic were found in five patients. These TTC21B variants were significantly more frequent in renal patients compared with controls (P = 0.0349). Two patients with a heterozygous deleterious TTC21B variant in addition to the disease-causing mutation presented a more severe phenotype than expected. Conclusions: Our results confirm the causal role of the homozygous p.P209L TTC21B mutation in two new families with FSGS and tubulointerstitial disease. We identified a novel TTC21B mutation demonstrating that p.P209L is not the unique causative mutation of this nephropathy. Thus, TTC21B mutation analysis should be considered for the genetic diagnosis of families with FSGS and tubulointerstitial lesions. Finally, we provide evidence that heterozygous deleterious TTC21B variants may act as genetic modifiers of the severity of glomerular and cystic kidney diseases.


Assuntos
Glomerulosclerose Segmentar e Focal/genética , Doenças Renais Císticas/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Análise Mutacional de DNA , Progressão da Doença , Feminino , Glomerulosclerose Segmentar e Focal/patologia , Heterozigoto , Humanos , Doenças Renais Císticas/patologia , Masculino , Linhagem
16.
Hum Mol Genet ; 26(3): 567-581, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28025331

RESUMO

The growing catalogue of structural variants in humans often overlooks inversions as one of the most difficult types of variation to study, even though they affect phenotypic traits in diverse organisms. Here, we have analysed in detail 90 inversions predicted from the comparison of two independently assembled human genomes: the reference genome (NCBI36/HG18) and HuRef. Surprisingly, we found that two thirds of these predictions (62) represent errors either in assembly comparison or in one of the assemblies, including 27 misassembled regions in HG18. Next, we validated 22 of the remaining 28 potential polymorphic inversions using different PCR techniques and characterized their breakpoints and ancestral state. In addition, we determined experimentally the derived allele frequency in Europeans for 17 inversions (DAF = 0.01-0.80), as well as the distribution in 14 worldwide populations for 12 of them based on the 1000 Genomes Project data. Among the validated inversions, nine have inverted repeats (IRs) at their breakpoints, and two show nucleotide variation patterns consistent with a recurrent origin. Conversely, inversions without IRs have a unique origin and almost all of them show deletions or insertions at the breakpoints in the derived allele mediated by microhomology sequences, which highlights the importance of mechanisms like FoSTeS/MMBIR in the generation of complex rearrangements in the human genome. Finally, we found several inversions located within genes and at least one candidate to be positively selected in Africa. Thus, our study emphasizes the importance of careful analysis and validation of large-scale genomic predictions to extract reliable biological conclusions.


Assuntos
Inversão Cromossômica/genética , Genoma Humano/genética , Anotação de Sequência Molecular , Inversão de Sequência/genética , Evolução Molecular , Humanos , Polimorfismo Genético , Seleção Genética/genética , Análise de Sequência de DNA
17.
Ann Rheum Dis ; 76(5): 906-913, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27927641

RESUMO

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA. METHODS: We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes. RESULTS: The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes. CONCLUSIONS: The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways.


Assuntos
Artrite Juvenil/genética , Cromossomos Humanos Par 1/genética , Complexo Principal de Histocompatibilidade/genética , Artrite Juvenil/tratamento farmacológico , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
18.
J Clin Invest ; 126(11): 4319-4330, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27721240

RESUMO

Huntington's disease (HD) is a polyglutamine disorder caused by a CAG expansion in the Huntingtin (HTT) gene exon 1. This expansion encodes a mutant protein whose abnormal function is traditionally associated with HD pathogenesis; however, recent evidence has also linked HD pathogenesis to RNA stable hairpins formed by the mutant HTT expansion. Here, we have shown that a locked nucleic acid-modified antisense oligonucleotide complementary to the CAG repeat (LNA-CTG) preferentially binds to mutant HTT without affecting HTT mRNA or protein levels. LNA-CTGs produced rapid and sustained improvement of motor deficits in an R6/2 mouse HD model that was paralleled by persistent binding of LNA-CTG to the expanded HTT exon 1 transgene. Motor improvement was accompanied by a pronounced recovery in the levels of several striatal neuronal markers severely impaired in R6/2 mice. Furthermore, in R6/2 mice, LNA-CTG blocked several pathogenic mechanisms caused by expanded CAG RNA, including small RNA toxicity and decreased Rn45s expression levels. These results suggest that LNA-CTGs promote neuroprotection by blocking the detrimental activity of CAG repeats within HTT mRNA. The present data emphasize the relevance of expanded CAG RNA to HD pathogenesis, indicate that inhibition of HTT expression is not required to reverse motor deficits, and further suggest a therapeutic potential for LNA-CTG in polyglutamine disorders.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Huntingtina , Doença de Huntington , RNA Antissenso , Repetições de Trinucleotídeos , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Proteína Huntingtina/biossíntese , Proteína Huntingtina/genética , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doença de Huntington/terapia , Masculino , Camundongos , Camundongos Transgênicos , RNA Antissenso/genética , RNA Antissenso/farmacologia
19.
Int J Epidemiol ; 45(5): 1644-1655, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27591263

RESUMO

BACKGROUND: We conducted an epigenome-wide association study (EWAS) of DNA methylation in placenta in relation to maternal tobacco smoking during pregnancy and examined whether smoking-induced changes lead to low birthweight. METHODS: DNA methylation in placenta was measured using the Illumina HumanMethylation450 BeadChip in 179 participants from the INfancia y Medio Ambiente (INMA) birth cohort. Methylation levels across 431 311 CpGs were tested for differential methylation between smokers and non-smokers in pregnancy. We took forward three top-ranking loci for further validation and replication by bisulfite pyrosequencing using data of 248 additional participants of the INMA cohort. We examined the association of methylation at smoking-associated loci with birthweight by applying a mediation analysis and a two-sample Mendelian randomization approach. RESULTS: Fifty CpGs were differentially methylated in placenta between smokers and non-smokers during pregnancy [false discovery rate (FDR) < 0.05]. We validated and replicated differential methylation at three top-ranking loci: cg27402634 located between LINC00086 and LEKR1, a gene previously related to birthweight in genome-wide association studies; cg20340720 (WBP1L); and cg25585967 and cg12294026 (TRIO). Dose-response relationships with maternal urine cotinine concentration during pregnancy were confirmed. Differential methylation at cg27402634 explained up to 36% of the lower birthweight in the offspring of smokers (Sobel P-value < 0.05). A two-sample Mendelian randomization analysis provided evidence that decreases in methylation levels at cg27402634 lead to decreases in birthweight. CONCLUSIONS: We identified novel loci differentially methylated in placenta in relation to maternal smoking during pregnancy. Adverse effects of maternal smoking on birthweight of the offspring may be mediated by alterations in the placental methylome.


Assuntos
Peso ao Nascer/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Placenta/metabolismo , Fumar Tabaco/efeitos adversos , Adulto , Estudos de Coortes , Cotinina/urina , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Modelos Lineares , Masculino , Exposição Materna/efeitos adversos , Análise da Randomização Mendeliana , Gravidez , Espanha
20.
Hum Mol Genet ; 25(18): 4127-4142, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27559109

RESUMO

More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.


Assuntos
Diarreia/genética , Fucosiltransferases/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Alelos , Pré-Escolar , Diarreia/patologia , Feminino , Genótipo , Humanos , Lactente , Masculino , Polimorfismo de Nucleotídeo Único
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