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1.
J Proteome Res ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31747749

RESUMO

N-glycosylation profile of total human plasma proteins could be a useful biomarker for various pathological states. Reliable high-throughput methods for such profiling have been developed. However, studies of relative importance of genetic and environmental factors in regulation of plasma N glycome are scarce. The aim of our study was to determine the role of genetic factors in phenotypic variation of plasma N glycan profile through the estimates of its heritability. Thirty-nine total plasma N glycome traits were analysed in 2816 individuals from the TwinsUK dataset. For the majority of the traits, high heritability estimates (>50%) were obtained pointing at a significant contribution of genetic factors in plasma N-glycome variation, especially for glycans mostly attached to immunoglobulins. We have also found several structures with higher environmental contribution to their variation.

2.
Sci Rep ; 9(1): 16302, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31705029

RESUMO

Asthma and hypertension are complex diseases coinciding more frequently than expected by chance. Unraveling the mechanisms of comorbidity of asthma and hypertension is necessary for choosing the most appropriate treatment plan for patients with this comorbidity. Since both diseases have a strong genetic component in this article we aimed to find and study genes simultaneously associated with asthma and hypertension. We identified 330 shared genes and found that they form six modules on the interaction network. A strong overlap between genes associated with asthma and hypertension was found on the level of eQTL regulated genes and between targets of drugs relevant for asthma and hypertension. This suggests that the phenomenon of comorbidity of asthma and hypertension may be explained by altered genetic regulation or result from drug side effects. In this work we also demonstrate that not only drug indications but also contraindications provide an important source of molecular evidence helpful to uncover disease mechanisms. These findings give a clue to the possible mechanisms of comorbidity and highlight the direction for future research.

3.
Am J Hum Genet ; 105(4): 788-802, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564434

RESUMO

Age-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 65. It causes social isolation and depression and has recently been identified as a risk factor for dementia. The genetic risk factors and underlying pathology of ARHI are largely unknown, meaning that targets for new therapies remain elusive, yet heritability estimates range between 35% and 55%. We performed genome-wide association studies (GWASs) for two self-reported hearing phenotypes, using more than 250,000 UK Biobank (UKBB) volunteers aged between 40 and 69 years. Forty-four independent genome-wide significant loci (p < 5E-08) were identified, considerably increasing the number of established trait loci. Thirty-four loci are novel associations with hearing loss of any form, and only one of the ten known hearing loci has a previously reported association with an ARHI-related trait. Gene sets from these loci are enriched in auditory processes such as synaptic activities, nervous system processes, inner ear morphology, and cognition, while genetic correlation analysis revealed strong positive correlations with multiple personality and psychological traits for the first time. Immunohistochemistry for protein localization in adult mouse cochlea implicate metabolic, sensory, and neuronal functions for NID2, CLRN2, and ARHGEF28. These results provide insight into the genetic landscape underlying ARHI, opening up novel therapeutic targets for further investigation. In a wider context, our study also highlights the viability of using self-report phenotypes for genetic discovery in very large samples when deep phenotyping is unavailable.

4.
BMC Med Genet ; 20(Suppl 1): 47, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30967134

RESUMO

BACKGROUND: Hyperprolactinemia (HPRL) is a classical side effect of antipsychotic drugs primarily attributed to blockade of dopamine D2 receptors (DRD2s) on the membranes of lactotroph cells within the pituitary gland. Certain antipsychotic drugs, e.g. risperidone, are more likely to induce HPRL because of relative accumulation within the adenohypophysis. Nevertheless, due to competition for pituitary DRD2s by high dopamine levels may limit antipsychotic-induced HPRL. Moreover, the activity of prolactin-producing lactotrophs also depends on other hormones which are regulated by the extra-pituitary activity of dopamine receptors, dopamine transporters, enzymes of neurotransmitter metabolism and other factors. Polymorphic variants in the genes coding for these receptors and proteins can have functional significance and influence on the development of hyperprolactinemia. METHODS: A set of 41 SNPs of genes for dopamine receptors DRD1, DRD2, DRD3, DRD4, the dopamine transporter SLC6A3 and dopamine catabolizing enzymes MAOA and MAOB was investigated in a population of 446 Caucasians (221 males/225 females) with a clinical diagnosis of schizophrenia (according to ICD-10: F20) with and without HPRL who were treated with classical and/or atypical antipsychotic drugs. Additive genetic model was tested and the analysis was carried out in the total group and in subgroup stratified by the use of risperidone/paliperidone. RESULTS: One statistically significant association between polymorphic variant rs1799836 of MAOB gene and HPRL in men was found in the total group. Furthermore, the rs40184 and rs3863145 variants in SLC6A3 gene appeared to be associated with HPRL in the subgroup of patients using the risperidone/paliperidone, but not with HPRL induced by other antipsychotic drugs. CONCLUSIONS: Our results indicate that genetic variants of MAOB and SLC6A3 may have consequences on the modulation of prolactin secretion. A further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed.

5.
Pain ; 160(6): 1361-1373, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30747904

RESUMO

Back pain (BP) is a common condition of major social importance and poorly understood pathogenesis. Combining data from the UK Biobank and CHARGE consortium cohorts allowed us to perform a very large genome-wide association study (total N = 509,070) and examine the genetic correlation and pleiotropy between BP and its clinical and psychosocial risk factors. We identified and replicated 3 BP-associated loci, including one novel region implicating SPOCK2/CHST3 genes. We provide evidence for pleiotropic effects of genetic factors underlying BP, height, and intervertebral disk problems. We also identified independent genetic correlations between BP and depression symptoms, neuroticism, sleep disturbance, overweight, and smoking. A significant enrichment for genes involved in the central nervous system and skeletal tissue development was observed. The study of pleiotropy and genetic correlations, supported by the pathway analysis, suggests at least 2 strong molecular axes of BP genesis, one related to structural/anatomical factors such as intervertebral disk problems and anthropometrics, and another related to the psychological component of pain perception and pain processing. These findings corroborate with the current biopsychosocial model as a paradigm for BP. Overall, the results demonstrate BP to have an extremely complex genetic architecture that overlaps with the genetic predisposition to its biopsychosocial risk factors. The work sheds light on pathways of relevance in the prevention and management of low BP.

6.
PLoS One ; 14(2): e0212464, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30794634

RESUMO

Bone mineral density (BMD) and lipid levels are two of the most extensively studied risk factors for common diseases of aging, such as cardiovascular disease (CVD) and osteoporosis (OP). These two risk factors are also correlated with each other, but little is known about the molecular mechanisms behind this correlation. Recent studies revealed that circulating levels of several metabolites involved in the biosynthesis of androsterone correlate significantly with BMD and have the capacity to affect cholesterol and lipids levels. A main aim of the present study was to investigate the hypothesis that androsterone-related metabolites could provide a link between CVD and OP, as a common cause of lipid levels and BMD. The present study employed data from the NIHR BRC TwinsUK BioResource, comprising 1909 and 1994 monozygotic and dizygotic twin pairs, respectively, to address the causal relationships among BMD and lipids, and their associated metabolites, using reciprocal causation twin modelling, as well as Mendelian randomization (MR) using large publicly-available GWAS datasets on lipids and BMD, in conjunction with TwinsUK metabolite data. While results involving the twin modelling and MR analyses with metabolites were unable to establish a causal link between metabolite levels and either lipids or BMD, MR analyses of BMD and lipids suggest that lipid levels have a causal impact on BMD, which is consistent with findings from clinical trials of lipid-lowering drugs, which have also increased BMD.


Assuntos
Densidade Óssea/fisiologia , Lipídeos/sangue , Androsterona/metabolismo , Densidade Óssea/genética , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Causalidade , Estudo de Associação Genômica Ampla , Humanos , Lipídeos/genética , Osteoporose/etiologia , Osteoporose/genética , Osteoporose/metabolismo , Fenótipo , Fatores de Risco , Gêmeos Dizigóticos , Gêmeos Monozigóticos , Reino Unido
7.
World J Biol Psychiatry ; : 1-6, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30623717

RESUMO

OBJECTIVES: Acetylcholine M (muscarinic) receptors are possibly involved in tardive dyskinesia (TD). The authors tried to verify this hypothesis by testing for possible associations between two muscarinic receptor genes (CHRM1 and CHRM2) polymorphisms and TD in patients with schizophrenia. METHODS: A total of 472 patients with schizophrenia were recruited. TD was assessed cross-sectionally using the Abnormal Involuntary Movement Scale. Fourteen allelic variants of CHRM1 and CHRM2 were genotyped using Applied Biosystems amplifiers (USA) and the MassARRAY System by Agena Bioscience. RESULTS: The prevalence of the rs1824024*GG genotype of the CHRM2 gene was lower in TD patients compared to the group without it (χ2 = 6.035, p = 0.049). This suggested that this genotype has a protective effect for the development of TD (OR = 0.4, 95% CI: 0.19-0.88). When age, gender, duration of schizophrenia and dosage of antipsychotic treatment were added as covariates in regression analysis, the results did not reach statistical significance. CONCLUSIONS: This study did identify associations between CHRM2 variations and TD; the results of logistic regression analysis with covariates suggest that the association is, however, likely to be secondary to other concomitant factors.

8.
J Integr Bioinform ; 15(4)2018 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-30530896

RESUMO

Comorbidity, a co-incidence of several disorders in an individual, is a common phenomenon. Their development is governed by multiple factors, including genetic variation. The current study was set up to look at associations between isolated and comorbid diseases of bronchial asthma and hypertension, on one hand, and single nucleotide polymorphisms associated with regulation of gene expression (eQTL), on the other hand. A total of 96 eQTL SNPs were genotyped in 587 Russian individuals. Bronchial asthma alone was found to be associated with rs1927914 (TLR4), rs1928298 (intergenic variant), and rs1980616 (SERPINA1); hypertension alone was found to be associated with rs11065987 (intergenic variant); rs2284033 (IL2RB), rs11191582 (NT5C2), and rs11669386 (CARD8); comorbidity between asthma and hypertension was found to be associated with rs1010461 (ANG/RNASE4), rs7038716, rs7026297 (LOC105376244), rs7025144 (intergenic variant), and rs2022318 (intergenic variant). The results suggest that genetic background of comorbidity of asthma and hypertension is different from genetic backgrounds of both diseases manifesting isolated.


Assuntos
Asma/patologia , Biologia Computacional/métodos , Hipertensão Essencial/patologia , Redes Reguladoras de Genes , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Adulto , Idoso , Asma/epidemiologia , Asma/genética , Comorbidade , Hipertensão Essencial/epidemiologia , Hipertensão Essencial/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Federação Russa/epidemiologia
9.
Sci Rep ; 8(1): 16630, 2018 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-30413780

RESUMO

Modic change (MC) is considered an independent risk factor for low back pain (LBP) but its aetiology remains unclear. In this cross-sectional, large-scale population-based study we sought to characterise associations between endplate defect (ED) and MC in a population sample of broad age range. The study population consisted of 831 twin volunteers (including 4155 discs and 8310 endplates) from TwinsUK. Lumbar T2-weighted MR images were coded for ED and MC. Total endplate (TEP) score was calculated at each intervertebral disc while receiver operating curves (ROC) were calculated to define critical endplate values predictive of MC. MC was detected in 32.1% of the subjects, with a significantly higher prevalence at lower lumbar levels (3.5% at L1/2-L3/4 vs. 15.9% at L4/5-L5/S1, p < 0.001). TEP score was strongly and independently associated with MC at each lumbar level (risk estimates from 1.49 to 2.44; all p ≤ 0.001) after adjustment for age, sex, BMI and twin pairing. ROC analysis showed a TEP score cut-off of 6 above which there was a significantly higher prevalence of MC. In conclusion, ED were strongly associated with MC at every lumbar level. These findings support the hypothesis that endplate defect is a major initiating factor for the cascade of events that may include disc degeneration (DD) and MC.

10.
Curr Mol Biol Rep ; 4(4): 143-150, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30464887

RESUMO

Purpose of Review: This review aims to highlight recent advances in understanding the genetic basis of intervertebral disc degeneration (IDD). Recent Findings: It has been known for some time that IDD is highly heritable. Recent studies, and in particular the availability of agnostic techniques such as genome-wide association studies, have identified new variants in a variety of genes which contribute to the risk of IDD and to back pain. Summary: A variety of genetic variants are involved in IDD. Some are shared with variants predisposing to back pain, but few have been identified reliably in either phenotype. Further research is required to explain fully the high heritability and how the genetic variants influence cell biology to lead to IDD.

11.
Pain ; 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30371560

RESUMO

Studies have shown that moderate alcohol consumption is strongly associated with reduced reporting of chronic widespread pain (CWP). The study designs used however are prone to confounding and are not able to establish the direction of causality. The current study overcomes these problems by using the Mendelian randomisation design to determine the effect of alcohol consumption on the likelihood of reporting CWP. The UK Biobank recruited 500,000 participants aged between 40 and 69 years. Data collected included questions on chronic pain and alcohol consumption, and biological samples providing genotypic information. Alcohol consumption was categorised as 'weekly consumption' or 'non or infrequent'. Participants were classified by genotype according to alleles of the rs1229984 SNP, either 'GG' or 'AA/AG'. CWP was defined as pain all over the body for more than 3 months that interfered with activities. Associations between genotype, CWP and alcohol consumption were tested by logistic regression. Instrumental variable analysis was used to calculate the causal effect of weekly alcohol consumption on CWP. Persons with 'GG' genotype had an increased risk of CWP (odds ratio, OR 1.17, 99% confidence interval CI 1.01-1.35) and were more likely to consume alcohol weekly (OR 1.76, 1.70-1.81) compared to those with 'AA/AG' genotype. Weekly consumption of alcohol was associated with reduced risk of CWP (OR 0.33, 0.31-0.35), but instrumental variable analysis did not show a causal effect of alcohol consumption on reducing CWP (OR 1.29, 0.96-1.74). An interpretation of observational population studies as showing a protective effect of alcohol on CWP is not supported.

12.
PLoS Genet ; 14(9): e1007601, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30261039

RESUMO

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10-8. Suggestive (p<5×10-7) and genome-wide significant (p<5×10-8) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10-10). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10-11), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10-19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10-13), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10-10). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

13.
J Pharm Pharm Sci ; 21(1): 340-346, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30075828

RESUMO

PURPOSE: Parkinson's disease (PD), a common neurodegenerative disorder, is usually treated with Levodopa (L-DOPA). The use of this drug, however, is severely limited by the development of side effects of the motor system: Levodopa-induced dyskinesia (LID). The aim of this study is to investigate the association between seven COMT gene single-nucleotide polymorphisms (SNPs) and the development of LID in patients with PD. METHODS: 232 Caucasian patients with PD were investigated. 212 patients with PD received Levodopa therapy. Dyskinesia was assessed with the use of the Abnormal Involuntary Movement Scale (AIMS).  Genotyping was carried out on seven SNPs of the COMT gene (rs4680, rs6269, rs4633, rs4818, rs769224, rs165774, rs174696) using a real-time PCR method, and blind to the clinical status of the subjects. RESULTS: We found association between four SNPs, rs165774, rs4818, rs4633, rs4680, and LID. When the duration of disease was added as a covariate in regression analysis, however, the results did not reach statistical significance. Only the additive model for rs165774 was found to be close to be statistical significance (OR = 1.627 [0.976-2.741], permutation p = 0.057). CONCLUSIONS: The results failed to clearly support a contribution of the studied polymorphisms; this may be related to a dominant relationship with the disease duration confounding the effect on the prevalence of LID.

14.
Spine (Phila Pa 1976) ; 43(21): 1496-1501, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29847371

RESUMO

STUDY DESIGN: Longitudinal study of spine magnetic resonance imaging (MRI) in a large-scale population-based study. OBJECTIVE: To determine the order of appearance of degenerative change in vertebral bodies and intervertebral discs. We also sought to define the influence of endplate defect on low back pain (LBP) and to determine whether there is a genetic influence on endplate defect. SUMMARY OF BACKGROUND DATA: Endplate defect is a magnetic resonance imaging trait, found to be associated with intervertebral disc degeneration. There is a lack of understanding regarding the mechanism underlying lumbar disc degeneration (LDD). Recent attention has shifted to vertebral endplate defects and their role in spine degeneration pathology. METHODS: Individuals from the TwinsUK spine study having longitudinal T2-weighted lumbar MR scans at baseline (n = 996) and a decade later (n = 438) were included. LDD, vertebral endplate defect by calculating a total endplate score, and Modic change (MC) were assessed using standard techniques. Mixed-effects models were used to determine the association between the features of spine pathology, adjusted for covariates. Endplate defect heritability was estimated using variance component analysis. RESULTS: Significant association was found between endplate defect, LDD, MRI features of LDD and MC was observed. Endplate defect was associated with severe disabling LBP (P ≤ 0.013) in multivariate analysis. An association between disc degeneration (DD) at baseline and MC at follow-up was shown at upper lumbar levels. Total endplate score was heritable with estimated additive genetic component A = 55.3% (95% CI 43.0-65.4). CONCLUSION: Endplate defect, LDD, and MC are all independent risk factors for episodes of severe and disabling LBP. Longitudinal analysis showed DD is followed by MC. Endplate defect has significant heritability of 55%. However, whether endplate defect triggers DD or these pathological changes occur concurrently could not be conclusively determined. LEVEL OF EVIDENCE: 2.

15.
PLoS One ; 13(4): e0196279, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29698501

RESUMO

BACKGROUND: Raynaud's phenomenon (RP) describes the phenomenon of recurrent vasospasm of digital arteries, associated with skin colour changes: pallor, cyanosis and erythema. Twin studies have indicated a genetic predisposition for RP; however, the precise aetiology of RP remains unknown. It is thought that genetic variation in temperature-responsive or vasospastic genes might underlie RP so performed a candidate gene study in a large, population based sample. We assessed the association between RP and single nucleotide polymorphisms (SNPs) in the TRPA1, TRPM8, CALCA, CALCB and NOS1 genes. METHODS: Analysis included a total of 4276 individuals from the TwinsUK database. RP status had been determined using validated, self-administered questionnaires and was diagnosed in 640 individuals (17.6%). 66 tag SNPs across the candidate genes were tested for association with RP status using a linear regression model, accounting for covariates. Adjustment was made for multiple testing. RegulomeDB and GTEx databases were used to assess possible functional effects of the polymorphisms. RESULTS: Nominally significant associations between RP and four SNPs in NOS1 and one in CALCB were identified. After permutation testing, rs527590 SNP in NOS1 passed the significance threshold. RegulomeDB scores indicated an unlikely functional effect of this variant, while the survey of the GTEx database found the SNP and several variants in linkage disequilibrium to be cis-eQTLs in skin. CONCLUSION: Results indicate that RP is associated with variation in gene NOS1. This finding may be related to the observation that the significant SNP in NOS1 is known to exhibit functional influence on the gene expression.


Assuntos
Predisposição Genética para Doença , Óxido Nítrico Sintase Tipo I/genética , Polimorfismo de Nucleotídeo Único , Doença de Raynaud/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Peptídeo Relacionado com Gene de Calcitonina/genética , Doenças em Gêmeos , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Pele/patologia , Canal de Cátion TRPA1/genética , Canais de Cátion TRPM/genética , Temperatura Ambiente , Adulto Jovem
16.
BMC Med Genomics ; 11(Suppl 1): 15, 2018 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-29504915

RESUMO

BACKGROUND: Hypertension and bronchial asthma are a major issue for people's health. As of 2014, approximately one billion adults, or ~ 22% of the world population, have had hypertension. As of 2011, 235-330 million people globally have been affected by asthma and approximately 250,000-345,000 people have died each year from the disease. The development of the effective treatment therapies against these diseases is complicated by their comorbidity features. This is often a major problem in diagnosis and their treatment. Hence, in this study the bioinformatical methodology for the analysis of the comorbidity of these two diseases have been developed. As such, the search for candidate genes related to the comorbid conditions of asthma and hypertension can help in elucidating the molecular mechanisms underlying the comorbid condition of these two diseases, and can also be useful for genotyping and identifying new drug targets. RESULTS: Using ANDSystem, the reconstruction and analysis of gene networks associated with asthma and hypertension was carried out. The gene network of asthma included 755 genes/proteins and 62,603 interactions, while the gene network of hypertension - 713 genes/proteins and 45,479 interactions. Two hundred and five genes/proteins and 9638 interactions were shared between asthma and hypertension. An approach for ranking genes implicated in the comorbid condition of two diseases was proposed. The approach is based on nine criteria for ranking genes by their importance, including standard methods of gene prioritization (Endeavor, ToppGene) as well as original criteria that take into account the characteristics of an associative gene network and the presence of known polymorphisms in the analysed genes. According to the proposed approach, the genes IL10, TLR4, and CAT had the highest priority in the development of comorbidity of these two diseases. Additionally, it was revealed that the list of top genes is enriched with apoptotic genes and genes involved in biological processes related to the functioning of central nervous system. CONCLUSIONS: The application of methods of reconstruction and analysis of gene networks is a productive tool for studying the molecular mechanisms of comorbid conditions. The method put forth to rank genes by their importance to the comorbid condition of asthma and hypertension was employed that resulted in prediction of 10 genes, playing the key role in the development of the comorbid condition. The results can be utilised to plan experiments for identification of novel candidate genes along with searching for novel pharmacological targets.

17.
Nat Genet ; 50(1): 42-53, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29273806

RESUMO

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

18.
Spine (Phila Pa 1976) ; 43(6): 412-419, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28749857

RESUMO

STUDY DESIGN: Cross-sectional study of spine magnetic resonance in a population, predominantly female, sample. OBJECTIVE: To determine the relationship between vertebral endplate defect and intervertebral disc degeneration (DD) in general population. SUMMARY OF BACKGROUND DATA: Precise understanding of the mechanisms leading to DD development is lacking. In a degenerating disc, mechanical and structural changes lead to further worsening of disc integrity. Increasing attention has been paid to vertebral endplate defects as having a possible role in the etiopathogenesis of DD. METHODS: The study population comprised 831 twin volunteers from TwinsUK (mean age 54 ±â€Š8 yr, 95.8% female). Lumbar T2-weighted magnetic resonance images were coded for endplate defects from 8310 endplates into six grades. Total endplate score (TEP score) was achieved by summing both endplate defect grades from the same disc level. DD was evaluated using two different classifications; Pfirrmann grading, and a quantitative trait for DD based on a 4-point grading system. Multivariable regression analysis was used to determine relationships between the traits of interest and the known risk factors for DD, age, and body mass index (BMI). A receiver operator curve for TEP score predicting DD was generated, and survival analysis paired with Cox proportional hazards models analysis performed. RESULTS: There was statistically significant association between DD and age and BMI. These associations lost significance when TEP score was included as predictor in multivariable model. TEP score was strongly and independently associated at every lumbar disc level with DD (Pfirmann P≤0.001; 4-point grading systems P < 1e-16). A cut-off point score of 5 for TEP score was found above which there was a higher DD prevalence. Across all age subgroups, probabilities of having DD were significantly increased in those considered TEP score positive (≥5). CONCLUSION: Our large, population-based study has shown that endplate defect was strongly and independently associated with DD at every lumbar disc level. These results provide a mechanism by which increasing age and BMI predispose to DD. LEVEL OF EVIDENCE: 2.


Assuntos
Degeneração do Disco Intervertebral/cirurgia , Disco Intervertebral/cirurgia , Vértebras Lombares/cirurgia , Região Lombossacral/cirurgia , Adulto , Idoso , Feminino , Humanos , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/patologia , Vértebras Lombares/patologia , Região Lombossacral/patologia , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores de Risco , Adulto Jovem
19.
Biochim Biophys Acta Mol Basis Dis ; 1864(2): 601-606, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29197660

RESUMO

BACKGROUND: Fatigue is a sensation of unbearable tiredness that frequently accompanies chronic widespread musculoskeletal pain (CWP) and inflammatory joint disease. Its mechanisms are poorly understood and there is a lack of effective biomarkers for diagnosis and onset prediction. We studied the circulating metabolome in a population sample characterised for CWP to identify biomarkers showing specificity for fatigue. MATERIAL AND METHODS: Untargeted metabolomic profiling was conducted on fasting plasma and serum samples of 1106 females with and without CWP from the TwinsUK cohort. Linear mixed-effects models accounting for covariates were used to determine relationships between fatigue and metabolites. Receiver operating curve (ROC)-analysis was used to determine predictive value of metabolites for fatigue. RESULTS: While no association between fatigue and metabolites was identified in twins without CWP (n=711), in participants with CWP (n=395), levels of eicosapentaenoate (EPA) ω-3 fatty acid were significantly reduced in those with fatigue (ß=-0.452±0.116; p=1.2×10-4). A significant association between fatigue and two other metabolites also emerged when BMI was excluded from the model: 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF), and C-glycosyltryptophan (p=1.5×10-4 and p=3.1×10-4, respectively). ROC analysis has identified a combination of 15 circulating metabolites with good predictive potential for fatigue in CWP (AUC=75%; 95% CI 69-80%). CONCLUSION: The results of this agnostic metabolomics screening show that fatigue is metabolically distinct from CWP, and is associated with a decrease in circulating levels of EPA. Our panel of circulating metabolites provides the starting point for a diagnostic test for fatigue in CWP.


Assuntos
Dor Crônica/sangue , Fadiga/sangue , Metaboloma , Adulto , Idoso , Área Sob a Curva , Biomarcadores , Proteína C-Reativa/química , Dor Crônica/diagnóstico , Dor Crônica/terapia , Estudos de Coortes , Doenças em Gêmeos , Ácido Eicosapentaenoico/sangue , Fadiga/diagnóstico , Fadiga/terapia , Ácidos Graxos Ômega-3/sangue , Feminino , Furanos/sangue , Furanos/química , Glicosilação , Humanos , Inflamação , Modelos Lineares , Pessoa de Meia-Idade , Dor Musculoesquelética/patologia , Propionatos/sangue , Propionatos/química , Curva ROC , Fatores de Risco , Triptofano/química , Reino Unido
20.
J Integr Bioinform ; 15(4)2018 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-30864351

RESUMO

Comorbid states of diseases significantly complicate diagnosis and treatment. Molecular mechanisms of comorbid states of asthma and hypertension are still poorly understood. Prioritization is a way for identifying genes involved in complex phenotypic traits. Existing methods of prioritization consider genetic, expression and evolutionary data, molecular-genetic networks and other. In the case of molecular-genetic networks, as a rule, protein-protein interactions and KEGG networks are used. ANDSystem allows reconstructing associative gene networks, which include more than 20 types of interactions, including protein-protein interactions, expression regulation, transport, catalysis, etc. In this work, a set of genes has been prioritized to find genes potentially involved in asthma and hypertension comorbidity. The prioritization was carried out using well-known methods (ToppGene and Endeavor) and a cross-talk centrality criterion, calculated by analysis of associative gene networks from ANDSystem. The identified genes, including IL1A, CD40LG, STAT3, IL15, FAS, APP, TLR2, C3, IL13 and CXCL10, may be involved in the molecular mechanisms of comorbid asthma/hypertension. An analysis of the dynamics of the frequency of mentioning the most priority genes in scientific publications revealed that the top 100 priority genes are significantly enriched with genes with increased positive dynamics, which may be a positive sign for further studies of these genes.


Assuntos
Asma/genética , Biomarcadores/análise , Biologia Computacional/métodos , Redes Reguladoras de Genes , Hipertensão/genética , Asma/epidemiologia , Comorbidade , Mineração de Dados , Alemanha/epidemiologia , Humanos , Hipertensão/epidemiologia , Software
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