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1.
RNA Biol ; 17(1): 75-86, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31559901

RESUMO

High-throughput sequencing is increasingly favoured to assay the presence and abundance of microRNAs (miRNAs) in biological samples, even from low RNA amounts, and a number of commercial vendors now offer kits that allow miRNA sequencing from sub-nanogram (ng) inputs. Although biases introduced during library preparation have been documented, the relative performance of current reagent kits has not been investigated in detail. Here, six commercial kits capable of handling <100ng total RNA input were used for library preparation, performed by kit manufactures, on synthetic miRNAs of known quantities and human total RNA samples. We compared the performance of miRNA detection sensitivity, reliability, titration response and the ability to detect differentially expressed miRNAs. In addition, we assessed the use of unique molecular identifiers (UMI) sequence tags in one kit. We observed differences in detection sensitivity and ability to identify differentially expressed miRNAs between the kits, but none were able to detect the full repertoire of synthetic miRNAs. The reliability within the replicates of all kits was good, while larger differences were observed between the kits, although none could accurately quantify the relative levels of the majority of miRNAs. UMI tags, at least within the input ranges tested, offered little advantage to improve data utility. In conclusion, biases in miRNA abundance are heavily influenced by the kit used for library preparation, suggesting that comparisons of datasets prepared by different procedures should be made with caution. This article is intended to assist researchers select the most appropriate kit for their experimental conditions.

2.
Nat Commun ; 10(1): 4955, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672989

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

3.
BMJ ; 367: l5654, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619437

RESUMO

OBJECTIVE: To assess the efficacy of three months of antibiotic treatment compared with placebo in patients with chronic low back pain, previous disc herniation, and vertebral endplate changes (Modic changes). DESIGN: Double blind, parallel group, placebo controlled, multicentre trial. SETTING: Hospital outpatient clinics at six hospitals in Norway. PARTICIPANTS: 180 patients with chronic low back pain, previous disc herniation, and type 1 (n=118) or type 2 (n=62) Modic changes enrolled from June 2015 to September 2017. INTERVENTIONS: Patients were randomised to three months of oral treatment with either 750 mg amoxicillin or placebo three times daily. The allocation sequence was concealed by using a computer generated number on the prescription. MAIN OUTCOME MEASURES: The primary outcome was the Roland-Morris Disability Questionnaire (RMDQ) score (range 0-24) at one year follow-up in the intention to treat population. The minimal clinically important between group difference in mean RMDQ score was predefined as 4. RESULTS: In the primary analysis of the total cohort at one year, the difference in the mean RMDQ score between the amoxicillin group and the placebo group was -1.6 (95% confidence interval -3.1 to 0.0, P=0.04). In the secondary analysis, the difference in the mean RMDQ score between the groups was -2.3 (-4.2 to-0.4, P=0.02) for patients with type 1 Modic changes and -0.1 (-2.7 to 2.6, P=0.95) for patients with type 2 Modic changes. Fifty patients (56%) in the amoxicillin group experienced at least one drug related adverse event compared with 31 (34%) in the placebo group. CONCLUSIONS: In this study on patients with chronic low back pain and Modic changes at the level of a previous disc herniation, three months of treatment with amoxicillin did not provide a clinically important benefit compared with placebo. Secondary analyses and sensitivity analyses supported this finding. Therefore, our results do not support the use of antibiotic treatment for chronic low back pain and Modic changes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02323412.


Assuntos
Amoxicilina , Degeneração do Disco Intervertebral/complicações , Deslocamento do Disco Intervertebral/complicações , Dor Lombar , Vértebras Lombares , Adulto , Amoxicilina/administração & dosagem , Amoxicilina/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Dor Crônica/diagnóstico , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Avaliação da Deficiência , Método Duplo-Cego , Feminino , Humanos , Dor Lombar/diagnóstico , Dor Lombar/tratamento farmacológico , Dor Lombar/etiologia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/patologia , Masculino , Pessoa de Meia-Idade , Noruega , Medição da Dor/métodos , Resultado do Tratamento
4.
Sleep ; 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31606740

RESUMO

STUDY OBJECTIVES: To explore HLA (human leukocyte antigen) in post-H1N1 narcolepsy type 1 patients (NT1), first-degree relatives and healthy controls, and assess HLA associations with clinical and sleep parameters in patients and first-degree relatives. METHODS: Ninety post-H1N1 NT1 patients and 202 of their first-degree relatives were HLA-genotyped (next generation sequencing) and phenotyped (semi-structured interviews, Stanford Sleep Questionnaire, polysomnography, multiple sleep latency test). HLA allele distributions were compared between DQB1*06:02-heterozygous individuals (77 patients, 59 parents, 1230 controls). A subsample (74 patients, 114 relatives) was investigated for associations between HLA-loci and continuous sleep variables using logistic regression. Identified candidate HLA-loci were explored for HLA allele associations with hypnagogic hallucinations and sleep paralysis in 90 patients, and patient allele findings were checked for similar associations in 202 relatives. RESULTS: DQB1*06:02 heterozygous post-H1N1 NT1 patients (84.4% H1N1-vaccinated), showed several significant HLA associations similar to those reported previously in samples of mainly sporadic NT1 i.e. DQB1*03:01, DRB1*04:01, DRB1*04:02, DRB1*04:07, DRB1*11:04, A*25:01, B*35:03 and B*51:01, and novel associations i.e. B*14:02, C*01:02 and C*07:01. Parents HLA alleles did not deviate significantly from controls. The HLA-C locus was associated with sleep parameters in patients and relatives. In patients C*02:02 seems to be associated with protective effects against sleep paralysis and hypnagogic hallucinations. CONCLUSION: Our findings of similar risk/protective HLA-alleles in post-H1N1 as in previous studies of mainly sporadic narcolepsy support similar disease mechanisms. We also report novel allelic associations. Associations between HLA-C and sleep parameters were seen independent of NT1 diagnosis, supporting involvement of HLA-C in sleep subphenotypes.

5.
Noncoding RNA ; 5(4)2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31661777

RESUMO

A necessary pre-processing data analysis step is the removal of adapter sequences from the raw reads. While most adapter trimming tools require adapter sequence as an essential input, adapter information is often incomplete or missing. This can impact quantification of features, reproducibility of the study and might even lead to erroneous conclusions. Here, we provide examples to highlight the importance of specifying the adapter sequence by demonstrating the effect of using similar but different adapter sequences and identify additional potential sources of errors in the adapter trimming step. Finally, we propose solutions by which users can ensure their small RNA-seq data is fully annotated with adapter information.

6.
PLoS One ; 14(7): e0218858, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31261375

RESUMO

Antigen presenting cells (APCs) in the thymus play an essential role in the establishment of central tolerance, i.e. the generation of a repertoire of functional and self-tolerant T cells to prevent autoimmunity. In this study, we have compared the transcriptomes of four primary APCs from human thymus (mTECs, CD19+ B cells, CD141+ and CD123+ DCs). We investigated a set of genes including the HLA genes, genes encoding transcriptional regulators and finally, tissue-enriched genes, i.e, genes with a five-fold higher expression in a particular human tissue. We show that thymic CD141+ DCs express the highest levels of all classical HLA genes and 67% (14/21) of the HLA class I and II pathway genes investigated in this study. CD141+ DCs also expressed the highest levels of the transcriptional regulator DEAF1, whereas AIRE and FEZF2 expression were mainly found in primary human mTECs. We found expression of "tissue enriched genes" from the Human Protein Atlas (HPA) in all four APC types, but the mTECs were clearly dominating in the number of uniquely expressed tissue enriched genes (20% in mTECs, 7% in CD19+ B cells, 4% in CD123+ DCs and 2% in CD141+ DCs). The tissue enriched genes also overlapped with reported human autoantigens. This is, to our knowledge, the first study that performs RNA sequencing of mTECs, CD19+ B cells, CD141+ and CD123+ DCs isolated from the same individuals and provides insight into the transcriptomes of these human thymic APCs.

7.
Pediatr Diabetes ; 20(6): 728-735, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31173445

RESUMO

BACKGROUND: Maternal microchimerism (MMc), the transmission of small quantities of maternal cells to the fetus, is relatively common and persistent. MMc has been detected with increased frequency in the circulation and pancreas of type 1 diabetes (T1D) patients. We investigated for the first time whether MMc levels at birth predict future T1D risk. We also tested whether cord blood MMc predicted MMc in samples taken at T1D diagnosis. METHODS: Participants in the Norwegian Mother and Child Cohort study were human leukocyte antigen (HLA) class II typed to determine non-inherited, non-shared maternal alleles (NIMA). Droplet digital (dd) polymerase chain reaction (PCR) assays specific for common HLA class II NIMA (HLADQB1*03:01, *04:02, and *06:02/03) were developed and validated. MMc was estimated as maternal DNA quantity in the fetal circulation, by NIMA specific ddPCR, measured in cord blood DNA from 71 children who later developed T1D and 126 controls within the cohort. RESULTS: We found detectable quantities of MMc in 34/71 future T1D cases (48%) and 53/126 controls (42%) (adjusted odds ratio [aOR] 1.27, 95% confidence interval (CI) 0.68-2.36), and no significant difference in ranks of MMc quantities between cases and controls (Mann-Whitney P = .46). There was a possible association in the NIMA HLA-DQB1*03:01 subgroup with later T1D (aOR 3.89, 95%CI 1.05-14.4). MMc in cord blood was not significantly associated with MMc at T1D diagnosis. CONCLUSIONS: Our findings did not support the hypothesis that the degree of MMc in cord blood predict T1D risk. The potential subgroup association with T1D risk should be replicated in a larger cohort.

8.
Blood Adv ; 3(7): 945-951, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30923048

RESUMO

HLA-DRB3*01:01 is a predisposing factor for human platelet antigen 1a (HPA-1a) immunization, which is responsible for most cases of fetal and neonatal alloimmune thrombocytopenia. The aim of this study was to investigate if the HLA-DRB3*01:01 allele imposes a dose-dependent effect on anti-HPA-1a levels and neonatal platelet counts. One hundred and thirty HPA-1a-immunized women were divided into 3 groups: HLA-DRB3*01:01 negative, HLA-DRB3*01:01 hemizygous or heterozygous, and HLA-DRB3*01:01 homozygous. The dose of the HLA-DRB3*01:01 allele was determined by sequencing exon 2 of the HLA-DRB3 gene followed by HLA-DRB3 and HLA-DRB1 typing of selected samples. Anti-HPA-1a levels at time of delivery and neonatal platelet counts were compared among groups. There was a significant dose-dependent effect of the HLA-DRB3*01:01 allele on anti-HPA-1a levels (global P value [P global] = .0032). Median (range) anti-HPA-1a levels were 1.5 IU/mL (0.0-19.0 IU/mL), 21.1 IU/mL (0.0-1967 IU/mL), and 43.7 IU/mL (1.0-980 IU/mL) in women with 0, 1, and 2 copies of the HLA-DRB3*01:01 allele, respectively. There was also a significant, but opposite, dose-dependent effect of the mother's HLA-DRB3*01:01 allele on the platelet count of the newborn (P global = .0155). Median (range) neonatal platelet counts were 241 × 109/L (59 × 109/L to 393 × 109/L), 107 × 109/L (4 × 109/L to 387 × 109/L) and 32 × 109/L (4 × 109/L to 352 × 109/L) for newborns of mothers with 0, 1, and 2 copies of the HLA-DRB3*01:01 allele, respectively. Thus, the HLA-DRB3*01:01 allele exhibits a dose-dependent impact on maternal anti-HPA-1a levels in HPA-1a-immunized women.

9.
Diabetes Care ; 42(4): 553-559, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30692241

RESUMO

OBJECTIVE: Circumstantial evidence links 25-hydroxy vitamin D [25(OH)D], vitamin D-binding protein (DBP), vitamin D-associated genes, and type 1 diabetes (T1D), but no studies have jointly analyzed these. We aimed to investigate whether DBP levels during pregnancy or at birth were associated with offspring T1D and whether vitamin D pathway genetic variants modified associations between DBP, 25(OH)D, and T1D. RESEARCH DESIGN AND METHODS: From a cohort of >100,000 mother/child pairs, we analyzed 189 pairs where the child later developed T1D and 576 random control pairs. We measured 25(OH)D using liquid chromatography-tandem mass spectrometry, and DBP using polyclonal radioimmunoassay, in cord blood and maternal plasma samples collected at delivery and midpregnancy. We genotyped mother and child for variants in or near genes involved in vitamin D metabolism (GC, DHCR7, CYP2R1, CYP24A1, CYP27B1, and VDR). Logistic regression was used to estimate odds ratios (ORs) adjusted for potential confounders. RESULTS: Higher maternal DBP levels at delivery, but not in other samples, were associated with lower offspring T1D risk (OR 0.86 [95% CI 0.74-0.98] per µmol/L increase). Higher cord blood 25(OH)D levels were associated with lower T1D risk (OR = 0.87 [95% CI 0.77-0.98] per 10 nmol/L increase) in children carrying the VDR rs11568820 G/G genotype (P interaction = 0.01 between 25(OH)D level and rs11568820). We did not detect other gene-environment interactions. CONCLUSIONS: Higher maternal DBP level at delivery may decrease offspring T1D risk. Increased 25(OH)D levels at birth may decrease T1D risk, depending on VDR genotype. These findings should be replicated in other studies. Future studies of vitamin D and T1D should include VDR genotype and DBP levels.


Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Receptores de Calcitriol/genética , Proteína de Ligação a Vitamina D/sangue , Vitamina D/sangue , Adolescente , Adulto , Idade de Início , Estudos de Casos e Controles , Criança , Estudos de Coortes , Análise Mutacional de DNA , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Feminino , Genótipo , Humanos , Recém-Nascido , Masculino , Noruega/epidemiologia , Polimorfismo de Nucleotídeo Único , Gravidez , Vitamina D/análogos & derivados , Adulto Jovem
10.
J Rheumatol ; 45(9): 1211-1219, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29858238

RESUMO

OBJECTIVE: We aimed to jointly investigate the role of antipeptidyl arginine deiminase type 4 antibodies (anti-PAD4) and polymorphisms in the PADI4 gene together with clinical variables in rheumatoid arthritis (RA). METHODS: Serum IgG autoantibodies to human recombinant PAD4 were identified by DELFIA technique in 745 patients with RA (366 available from previous studies). Genotyping of PADI4 was performed using TaqMan assays in 945 patients and 1118 controls. Clinical data, anticitrullinated protein antibodies (ACPA) status, shared epitope status, and a combined genetic risk score were also available. RESULTS: Anti-PAD4 antibodies were detected in 193 (26%) of 745 patients with RA; 149 (77%) of these were also ACPA-positive. No association was observed between anti-PAD4 status and clinical characteristics, PADI4 polymorphisms, or genetic risk scores after stratification for ACPA status. CONCLUSION: Taken together, the results from these combined serological, genetic, and clinical analyses suggest that anti-PAD4 appears to be a bystander autoantibody with no current clinical utility in RA.


Assuntos
Artrite Reumatoide/genética , Autoanticorpos , Polimorfismo de Nucleotídeo Único , Desiminases de Arginina em Proteínas/genética , Adulto , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Epitopos , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Desiminases de Arginina em Proteínas/imunologia
11.
Sci Rep ; 8(1): 9067, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29899542

RESUMO

Iron overload due to environmental or genetic causes have been associated diabetes. We hypothesized that prenatal iron exposure is associated with higher risk of childhood type 1 diabetes. In the Norwegian Mother and Child cohort study (n = 94,209 pregnancies, n = 373 developed type 1 diabetes) the incidence of type 1 diabetes was higher in children exposed to maternal iron supplementation than unexposed (36.8/100,000/year compared to 28.6/100,000/year, adjusted hazard ratio 1.33, 95%CI: 1.06-1.67). Cord plasma biomarkers of high iron status were non-significantly associated with higher risk of type 1 diabetes (ferritin OR = 1.05 [95%CI: 0.99-1.13] per 50 mg/L increase; soluble transferrin receptor: OR = 0.91 [95%CI: 0.81-1.01] per 0.5 mg/L increase). Maternal but not fetal HFE genotypes causing high/intermediate iron stores were associated with offspring diabetes (odds ratio: 1.45, 95%CI: 1.04, 2.02). Maternal anaemia or non-iron dietary supplements did not significantly predict type 1 diabetes. Perinatal iron exposures were not associated with cord blood DNA genome-wide methylation, but fetal HFE genotype was associated with differential fetal methylation near HFE. Maternal cytokines in mid-pregnancy of the pro-inflammatory M1 pathway differed by maternal iron supplements and HFE genotype. Our results suggest that exposure to iron during pregnancy may be a risk factor for type 1 diabetes in the offspring.


Assuntos
Diabetes Mellitus Tipo 1/etiologia , Sobrecarga de Ferro/complicações , Ferro/efeitos adversos , Complicações na Gravidez , Adolescente , Criança , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Suplementos Nutricionais , Feminino , Genótipo , Proteína da Hemocromatose/sangue , Proteína da Hemocromatose/genética , Humanos , Incidência , Ferro/administração & dosagem , Ferro/sangue , Sobrecarga de Ferro/sangue , Masculino , Noruega/epidemiologia , Gravidez , Fatores de Risco
12.
Hum Immunol ; 79(7): 527-529, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29684411

RESUMO

We report HLA-A, -C, -B, -DRB1, -DQB1 and -DPB1 allele frequencies and estimated haplotype frequencies from 4514 healthy Norwegians who volunteered to participate in the Norwegian Bone Marrow Donor Registry. HLA genotyping was conducted on a Next Generation Sequencing platform. Data were analyzed using Arlequin and Pypop software. No significant deviations from Hardy-Weinberg Equilibrium were noted at any of the loci studied. We discuss the representability for the Norwegian population and argue that the presented HLA data could serve as a Norwegian reference panel.


Assuntos
Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadeias beta de HLA-DP/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Sistema de Registros , Transplante de Medula Óssea , Frequência do Gene , Genótipo , Haplótipos , Voluntários Saudáveis , Sequenciamento de Nucleotídeos em Larga Escala , Teste de Histocompatibilidade , Humanos , Noruega , Doadores de Tecidos
13.
J Clin Endocrinol Metab ; 102(11): 4072-4079, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28938476

RESUMO

Objective: Several genetic polymorphisms determine vitamin D status. We aimed to estimate the strength of association of established 25-hydroyxvitamin D (25OHD)-associated variants in the mother and in the fetus, with 25OHD concentration in newborn umbilical cord plasma. Methods: We randomly selected 578 mother and child dyads from the prospective Norwegian Mother and Child Cohort study. 25OHD was assayed in maternal samples taken shortly after delivery and in cord samples. We genotyped the mother and child for single nucleotide polymorphisms in or near GC, DHCR7, CYP2R1, and CYP24A1, previously confirmed to be associated with 25OHD, and computed genetic risk score (GRS). The genetic associations were replicated in an independent sample of 594 subjects. Results: Although both fetal and maternal GRS were associated with cord 25OHD, only fetal GRS remained significantly associated with cord 25OHD in a regression model with maternal and fetal GRS simultaneously (1.6 nmol/L per fetal 25OHD-increasing allele; 95% confidence interval, 0.6 to 2.5, P = 0.0001). Two fetal single nucleotide polymorphisms in the GC gene (rs2282679 and rs222040) were the strongest genetic predictors of cord 25OHD [4.0 (2.1 to 5.9) and 3.0 (1.3 to 4.8) nmol/L per fetal allele, P < 0.001], followed by rs12785878 in DHCR7 [2.0 (0.1 to 3.8) nmol/L, P = 0.037]. The independent replication sample gave similar results. With fetal genotype included in a regression model with environmental factors, R2 for cord 25OHD was 0.28. Conclusions: We show that fetal 25OHD-modifying genotype was a stronger predictor of cord 25OHD than corresponding maternal genotype. This raises interesting questions about fetal acquisition and placental transfer of 25OHD.


Assuntos
Estado Nutricional/genética , Polimorfismo de Nucleotídeo Único , Deficiência de Vitamina D/congênito , Deficiência de Vitamina D/genética , Vitamina D/sangue , Adulto , Estudos de Coortes , Suplementos Nutricionais , Feminino , Feto/metabolismo , Predisposição Genética para Doença , Genótipo , Humanos , Recém-Nascido , Troca Materno-Fetal/genética , Mães , Gravidez , Cuidado Pré-Natal , Fenômenos Fisiológicos da Nutrição Pré-Natal/genética , Vitamina D/administração & dosagem , Deficiência de Vitamina D/sangue , Adulto Jovem
14.
PLoS One ; 12(7): e0179080, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28686601

RESUMO

BACKGROUND: Low concentration of 25-hydroxyvitamin D during pregnancy may be associated with offspring autoimmune disorders. Little is known about environmental triggers except gluten for celiac disease, a common immune-mediated disorder where seasonality of birth has been reported as a risk factor. We therefore aimed to test whether low maternal and neonatal 25-hydroxyvitamin D predicted higher risk of childhood celiac disease. METHODS AND FINDINGS: In this Norwegian nationwide pregnancy cohort (n = 113,053) and nested case-control study, we analyzed 25-hydroxyvitamin D in maternal blood from mid-pregnancy, postpartum and cord plasma of 416 children who developed celiac disease and 570 randomly selected controls. Mothers and children were genotyped for established celiac disease and vitamin D metabolism variants. We used mixed linear regression models and logistic regression to study associations. There was no significant difference in average 25-hydroxyvitamin D between cases and controls (63.1 and 62.1 nmol/l, respectively, p = 0.28), and no significant linear trend (adjusted odds ratio per 10 nM increase 1.05, 95% CI: 0.93-1.17). Results were similar when analyzing the mid-pregnancy, postpartum or cord plasma separately. Genetic variants for vitamin D deficiency were not associated with celiac disease (odds ratio per risk allele of the child, 1.00; 95% CI, 0.90 to 1.10, odds ratio per risk allele of the mother 0.94; 95% CI 0.85 to 1.04). Vitamin D intake in pregnancy or by the child in early life did not predict later celiac disease. Adjustment for established genetic risk markers for celiac disease gave similar results. CONCLUSIONS: We found no support for the hypothesis that maternal or neonatal vitamin D status is related to the risk of childhood celiac disease.


Assuntos
Doença Celíaca/sangue , Complicações na Gravidez/sangue , Deficiência de Vitamina D/sangue , Vitamina D/sangue , Adulto , Doença Celíaca/genética , Doença Celíaca/patologia , Criança , Feminino , Genótipo , Humanos , Lactente , Masculino , Fenômenos Fisiológicos da Nutrição Materna/genética , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/patologia , Fatores de Risco , Vitamina D/genética , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/patologia
15.
JAMA Neurol ; 74(7): 780-792, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28586827

RESUMO

Importance: Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. Objectives: To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. Design, Setting, and Participants: Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. Main Outcomes and Measures: The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases. Results: Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes. Conclusions and Relevance: The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.


Assuntos
Doenças Autoimunes/genética , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doença de Parkinson/genética , Artrite Reumatoide/genética , Doença Celíaca/genética , Colite Ulcerativa/genética , Doença de Crohn/genética , Diabetes Mellitus Tipo 1/genética , Loci Gênicos , Humanos , Esclerose Múltipla/genética , Psoríase/genética , Fatores de Risco
16.
Am J Hum Genet ; 100(1): 64-74, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28041642

RESUMO

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10-54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10-10, OR = 1.28; and rs128738, p = 4.60 × 10-9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.


Assuntos
Alelos , Predisposição Genética para Doença/genética , Variação Genética , Estudo de Associação Genômica Ampla , Arterite de Células Gigantes/genética , Plasminogênio/genética , Prolil Hidroxilases/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Europa (Continente)/etnologia , Feminino , Humanos , Masculino , Neovascularização Fisiológica , Polimorfismo de Nucleotídeo Único/genética , Risco
17.
Liver Int ; 37(3): 458-465, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27558072

RESUMO

BACKGROUND & AIMS: The strongest genetic risk factors in primary sclerosing cholangitis (PSC) are encoded in the HLA complex. Antineutrophil cytoplasmic antibodies (ANCA) have been reported in up to 94% of PSC patients, but their clinical significance and immunogenetic basis are ill defined. We aimed to characterize clinical and genetic associations of ANCA in PSC. METHODS: Antineutrophil cytoplasmic antibodies were analysed with indirect immunofluorescence in 241 Norwegian PSC patients. HLA-B and HLA-DRB1 genotyping was performed in the patients and in 368 healthy controls. Data on perinuclear ANCA (pANCA) and HLA-DRB1 were available from 274 ulcerative colitis (UC) patients without known liver disease. RESULTS: Antineutrophil cytoplasmic antibodies were found in 193 (80%) of the PSC patients, with pANCA in 169 (70%). ANCA-positive patients were younger than ANCA negative at diagnosis of PSC and had a lower frequency of biliary cancer (9% vs 19%, P=.047). There were no differences between PSC patients with and without inflammatory bowel disease. Genetically, the strong PSC risk factors HLA-B*08 (frequency in healthy 13%) and DRB1*03 (14%) were more prevalent in ANCA-positive than -negative patients (43% vs 25%, P=.0012 and 43% vs 25%, P=.0015 respectively). The results were similar when restricting the analysis to pANCA-positive patients. In UC patients without liver disease, HLA-DRB1*03 was more prevalent in pANCA-positive compared with -negative patients (P=.03). CONCLUSIONS: Antineutrophil cytoplasmic antibodies identified PSC patients with particular clinical and genetic characteristics, suggesting that ANCA may mark a clinically relevant pathogenetic subgroup in the PSC-UC disease spectrum.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Colangite Esclerosante/sangue , Colangite Esclerosante/genética , Antígeno HLA-B27/genética , Cadeias HLA-DRB1/genética , Adolescente , Adulto , Idoso , Biomarcadores , Estudos de Casos e Controles , Estudos Transversais , Bases de Dados Factuais , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Genótipo , Humanos , Doenças Inflamatórias Intestinais/genética , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Noruega , Adulto Jovem
18.
Cancer Res ; 76(18): 5326-36, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27406829

RESUMO

By affecting immunological presentation, the presence of cytomegalovirus in some glioblastomas may impact progression. In this study, we examined a hypothesized role for natural killer (NK) cells in impacting disease progression in this setting. We characterized 108 glioblastoma patients and 454 healthy controls for HLA-A,-B,-C, NK-cell KIR receptors, and CMV-specific antibodies and correlated these metrics with clinical parameters. Exome sequences from a large validation set of glioblastoma patients and control individuals were examined from in silico databases. We demonstrated that the KIR allele KIR2DS4*00101 was independently prognostic of prolonged survival. KIR2DS4*00101 displayed 100% concordance with cognate HLA-C1 ligands in glioblastoma patients, but not controls. In the context of both HLA-C1/C2 ligands for the KIR2DS4 receptor, patient survival was further extended. Notably, all patients carrying KIR2DS4*00101 alleles were CMV seropositive, but not control individuals, and exhibited increased NK-cell subpopulations, which expressed the cytotoxicity receptors CD16, NKG2D, and CD94/NKG2C. Finally, healthy controls exhibited a reduced risk for developing glioblastoma if they carried two KIR2DS4*00101 alleles, where protection was greatest among Caucasian individuals. Our findings suggest that KIR2DS4*00101 may offer a molecular biomarker to identify intrinsically milder forms of glioblastoma. Cancer Res; 76(18); 5326-36. ©2016 AACR.


Assuntos
Biomarcadores Tumorais/imunologia , Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Células Matadoras Naturais/imunologia , Receptores KIR/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/virologia , Criança , Infecções por Citomegalovirus/complicações , Feminino , Citometria de Fluxo , Glioblastoma/mortalidade , Glioblastoma/virologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Modelos de Riscos Proporcionais , Adulto Jovem
19.
Hum Mol Genet ; 25(14): 3117-3124, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27199374

RESUMO

Genome-wide association studies (GWAS) have boosted our knowledge of genetic risk variants in autoimmune diseases (AIDs). Most risk variants are located within or near genes with immunological functions, and the majority is found to be non-coding, pointing towards a regulatory role. In this study, we performed a cis expression quantitative trait locus (eQTL) screen restricted to 353 AID associated risk variants selected from the GWAS catalog to investigate whether these single nucleotide polymorphisms (SNPs) influence gene expression in thymus. Genotypes were obtained by Immunochip (Ichip) and tested against expression of surrounding genes (±1 Mb) in human thymic tissue (n = 42). We identified eight significant eQTLs located within seven genetic regions (FCRL3, RNASET2, C2orf74, NPIPB8, SIRPG, SYS1 and AJ006998.2) where the expression was associated with AID risk SNPs at a study-wide level of significance (P < 2.7 × 10-5). In NPIPB8 and AJ006998.2, the eQTL signals appeared to be thymus-specific. Furthermore, many AID risk SNPs from GWAS have been subsequently fine-mapped in recent Ichip projects, and fine-mapped AID SNPs overlapped with the thymic eQTLs within RNASET2 and SIRPG Finally, in all the eQTL regions, except C2orf74, SNPs underlying the thymic eQTLs were predicted to interfere with transcription factors important in T cell development. Our study therefore reveals autoimmune risk variants that act as eQTLs in thymus, and suggest that thymic gene regulation may play a functional role at some AID risk loci.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença , Locos de Características Quantitativas/genética , Timo/metabolismo , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/patologia , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
20.
BMC Med Genet ; 17: 24, 2016 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-27005825

RESUMO

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children, the etiology of which involves a strong genetic component, but much of the underlying genetic determinants still remain unknown. Our aim was to identify novel genetic variants that predispose to JIA. METHODS: We performed a genome-wide association study (GWAS) and replication in a total of 1166 JIA cases and 9500 unrelated controls of European ancestry. Correlation of SNP genotype and gene expression was investigated. Then we conducted targeted resequencing of a candidate locus, among a subset of 480 cases and 480 controls. SUM test was performed to evaluate the association of the identified rare functional variants. RESULTS: The CXCR4 locus on 2q22.1 was found to be significantly associated with JIA, peaking at SNP rs953387. However, this result is subjected to subpopulation stratification within the subjects of European ancestry. After adjusting for principal components, nominal significant association remained (p < 10(-4)). Because of its interesting known function in immune regulation, we carried out further analyses to assess its relationship with JIA. Expression of CXCR4 was correlated with CXCR4 rs953387 genotypes in lymphoblastoid cell lines (p = 0.014) and T-cells (p = 0.0054). In addition, rare non-synonymous and stop-gain sequence variants in CXCR4, putatively damaging for CXCR4 function, were significantly enriched in JIA cases (p = 0.015). CONCLUSION: Our results suggest the association of CXCR4 variants with JIA, implicating that this gene may be involved in the pathogenesis of autoimmune disease. However, because this locus is subjected to population stratification within the subjects of European ancestry, additional replication is still necessary for this locus to be considered a true risk locus for JIA. This cell-surface chemokine receptor has already been targeted in other diseases and may serve as a tractable therapeutic target for a specific subset of pediatric arthritis patients with additional replication and functional validation of the locus.


Assuntos
Artrite Juvenil/genética , Predisposição Genética para Doença , Receptores CXCR4/genética , Adolescente , Sequência de Aminoácidos , Estudos de Casos e Controles , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Análise de Sequência de DNA
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