Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
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.

2.
J Food Biochem ; 43(3): e12770, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31353556

RESUMO

The soursop (Annona muricata L.) is a climacteric fruit that may undergo enzymatic browning during ripening, mainly by the activity of polyphenol oxidase (PPO). Soursop PPO was purified 160-fold by hydrophobic interaction and ion-exchange chromatography. The native structure has a molecular weight of 112 kDa corresponding to a dimeric structure. The protein has an optimum pH and temperature of 6.5 and 25°C, respectively; and activation energy of 40.97 kJ·mol-1 . The lowest Km value was observed for caffeic acid (0.47 mM); the best substrate was 4-methyl-catechol (1,067 U·mM-1  min-1 ). Inactivation assays showed that PPO was completely inactivated by tropolone, Na2 S2 O5 and ascorbic acid, and thermally at 55°C for <5 min, microwave exposure reduced activity to 57% at 70 W in 30 s and ultrasound treatment diminished activity to 43% at 120 W in 220 s. This study allows a better understanding of soursop PPO behavior and provides inactivation information. PRACTICAL APPLICATIONS: The conservation of fresh fruits is complicated due to the enzymatic reactions that are present in fruits, such as enzymatic browning. The enzymes responsible for these reactions can be inactivated by, different chemical compounds as well as by the use of emerging technologies, such as microwaves and sonication, which seek to satisfy the consumer needs to obtain fresh products with good nutritional characteristics and adequate safety.

3.
Ann Rheum Dis ; 78(8): 1127-1134, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31092410

RESUMO

OBJECTIVES: There is a need to identify effective treatments for rheumatic diseases, and while genetic studies have been successful it is unclear which genes contribute to the disease. Using our existing Capture Hi-C data on three rheumatic diseases, we can identify potential causal genes which are targets for existing drugs and could be repositioned for use in rheumatic diseases. METHODS: High confidence candidate causal genes were identified using Capture Hi-C data from B cells and T cells. These genes were used to interrogate drug target information from DrugBank to identify existing treatments, which could be repositioned to treat these diseases. The approach was refined using Ingenuity Pathway Analysis to identify enriched pathways and therefore further treatments relevant to the disease. RESULTS: Overall, 454 high confidence genes were identified. Of these, 48 were drug targets (108 drugs) and 11 were existing therapies used in the treatment of rheumatic diseases. After pathway analysis refinement, 50 genes remained, 13 of which were drug targets (33 drugs). However considering targets across all enriched pathways, a further 367 drugs were identified for potential repositioning. CONCLUSION: Capture Hi-C has the potential to identify therapies which could be repositioned to treat rheumatic diseases. This was particularly successful for rheumatoid arthritis, where six effective, biologic treatments were identified. This approach may therefore yield new ways to treat patients, enhancing their quality of life and reducing the economic impact on healthcare providers. As additional cell types and other epigenomic data sets are generated, this prospect will improve further.

4.
Scand J Immunol ; 89(5): e12753, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30710386

RESUMO

Over the past decade, genome-wide association studies have contributed a wealth of knowledge to our understanding of polygenic disorders such as rheumatoid arthritis. As the size of sample cohorts has improved so too have the computational and experimental methods used to robustly define variants associated with disease susceptibility. The challenge now remains to translate these findings into improved understanding of disease aetiology and patient care. Whilst much of the focus of translating the findings of genome-wide association studies has been on global analysis of all variants identified, careful functional study of individual disease susceptibility loci will be required in order to refine our understanding of how individual variants contribute to disease risk. Here, we present the argument behind such an approach and describe some of the novel tools being used to investigate risk loci. This includes the use of chromosomal conformation capture techniques and modifications of the CRISPR-Cas9 system, with several examples of their implementation being described.


Assuntos
Artrite Reumatoide/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Estudos de Associação Genética/métodos , Animais , Causalidade , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Humanos , Polimorfismo Genético
5.
BMC Med Genet ; 18(1): 107, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28974197

RESUMO

BACKGROUND: Osteoporosis individual susceptibility is determined by the interaction of multiple genetic variants and environmental factors. The aim of this study was to conduct SNP-SNP interaction analyses in candidate genes influencing heel quantitative ultrasound (QUS) parameter in early adulthood to identify novel insights into the mechanism of disease. METHODS: The study population included 575 healthy subjects (mean age 20.41; SD 2.36). To assess bone mass QUS was performed to determine Broadband ultrasound attenuation (BUA, dB/MHz). A total of 32 SNPs mapping to loci that have been characterized as genetic markers for QUS and/or BMD parameters were selected as genetic markers in this study. The association of all possible SNP pairs with QUS was assessed by linear regression and a SNP-SNP interaction was defined as a significant departure from additive effects. RESULTS: The pairwise SNP-SNP analysis showed multiple interactions. The interaction comprising SNPs rs9340799 and rs3736228 that map in the ESR1 and LRP5 genes respectively, revealed the lowest p value after adjusting for confounding factors (p-value = 0.001, ß (95% CI) = 14.289 (5.548, 23.029). In addition, our model reported others such as TMEM135-WNT16 (p = 0.007, ß(95%CI) = 9.101 (2.498, 15.704), ESR1-DKK1 (p = 0.012, ß(95%CI) = 13.641 (2.959, 24.322) or OPG-LRP5 (p = 0.012, ß(95%CI) = 8.724 (1.936, 15.512). However, none of the detected interactions remain significant considering the Bonferroni significance threshold for multiple testing (p<0.0001). CONCLUSION: Our analysis of SNP-SNP interaction in candidate genes of QUS in Caucasian young adults reveal several interactions, especially between ESR1 and LRP5 genes, that did not reach statistical significance. Although our results do not support a relevant genetic contribution of SNP-SNP epistatic interactions to QUS in young adults, further studies in larger independent populations would be necessary to support these preliminary findings.


Assuntos
Densidade Óssea/genética , Calcâneo/diagnóstico por imagem , Marcadores Genéticos/genética , Osteoporose/diagnóstico , Polimorfismo de Nucleotídeo Único , Ultrassonografia/métodos , Adulto , Remodelação Óssea , Receptor alfa de Estrogênio/genética , Feminino , Voluntários Saudáveis , Humanos , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Osteoporose/diagnóstico por imagem , Osteoporose/genética , Adulto Jovem
6.
Nat Rev Rheumatol ; 13(7): 421-432, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28569263

RESUMO

Susceptibility to rheumatic diseases, such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, juvenile idiopathic arthritis and psoriatic arthritis, includes a large genetic component. Understanding how an individual's genetic background influences disease onset and outcome can lead to a better understanding of disease biology, improved diagnosis and treatment, and, ultimately, to disease prevention or cure. The past decade has seen great progress in the identification of genetic variants that influence the risk of rheumatic diseases. The challenging task of unravelling the function of these variants is ongoing. In this Review, the major insights from genetic studies, gained from advances in technology, bioinformatics and study design, are discussed in the context of rheumatic disease. In addition, pivotal genetic studies in the main rheumatic diseases are highlighted, with insights into how these studies have changed the way we view these conditions in terms of disease overlap, pathways of disease and potential new therapeutic targets. Finally, the limitations of genetic studies, gaps in our knowledge and ways in which current genetic knowledge can be fully translated into clinical benefit are examined.


Assuntos
Mapeamento Cromossômico/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Doenças Reumáticas/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Humanos
7.
Genome Biol ; 17(1): 212, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27799070

RESUMO

BACKGROUND: The identification of causal genes from genome-wide association studies (GWAS) is the next important step for the translation of genetic findings into biologically meaningful mechanisms of disease and potential therapeutic targets. Using novel chromatin interaction detection techniques and allele specific assays in T and B cell lines, we provide compelling evidence that redefines causal genes at the 6q23 locus, one of the most important loci that confers autoimmunity risk. RESULTS: Although the function of disease-associated non-coding single nucleotide polymorphisms (SNPs) at 6q23 is unknown, the association is generally assigned to TNFAIP3, the closest gene. However, the DNA fragment containing the associated SNPs interacts through chromatin looping not only with TNFAIP3, but also with IL20RA, located 680 kb upstream. The risk allele of the most likely causal SNP, rs6927172, is correlated with both a higher frequency of interactions and increased expression of IL20RA, along with a stronger binding of both the NFκB transcription factor and chromatin marks characteristic of active enhancers in T-cells. CONCLUSIONS: Our results highlight the importance of gene assignment for translating GWAS findings into biologically meaningful mechanisms of disease and potential therapeutic targets; indeed, monoclonal antibody therapy targeting IL-20 is effective in the treatment of rheumatoid arthritis and psoriasis, both with strong GWAS associations to this region.


Assuntos
Artrite Reumatoide/genética , Estudo de Associação Genômica Ampla , Psoríase/genética , Receptores de Interleucina/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Linfócitos B/imunologia , Cromatina/genética , Cromossomos Humanos Par 6/genética , Predisposição Genética para Doença , Genoma Humano , Humanos , Polimorfismo de Nucleotídeo Único , Psoríase/imunologia , Psoríase/patologia , Linfócitos T/imunologia
8.
PLoS One ; 11(11): e0166923, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27861577

RESUMO

BACKGROUND: The chromosomal region 6q23 has been found to be associated with multiple sclerosis (MS) predisposition through genome wide association studies (GWAS). There are four independent single nucleotide polymorphisms (SNPs) associated with MS in this region, which spans around 2.5 Mb. Most GWAS variants associated with complex traits, including these four MS associated SNPs, are non-coding and their function is currently unknown. However, GWAS variants have been found to be enriched in enhancers and there is evidence that they may be involved in transcriptional regulation of their distant target genes through long range chromatin looping. AIM: The aim of this work is to identify causal disease genes in the 6q23 locus by studying long range chromatin interactions, using the recently developed Capture Hi-C method in human T and B-cell lines. Interactions involving four independent associations unique to MS, tagged by rs11154801, rs17066096, rs7769192 and rs67297943 were analysed using Capture Hi-C Analysis of Genomic Organisation (CHiCAGO). RESULTS: We found that the pattern of chromatin looping interactions in the MS 6q23 associated region is complex. Interactions cluster in two regions, the first involving the rs11154801 region and a second containing the rs17066096, rs7769192 and rs67297943 SNPs. Firstly, SNPs located within the AHI1 gene, tagged by rs11154801, are correlated with expression of AHI1 and interact with its promoter. These SNPs also interact with other potential candidate genes such as SGK1 and BCLAF1. Secondly, the rs17066096, rs7769192 and rs67297943 SNPs interact with each other and with immune-related genes such as IL20RA, IL22RA2, IFNGR1 and TNFAIP3. Finally, the above-mentioned regions interact with each other and therefore, may co-regulate these target genes. CONCLUSION: These results suggest that the four 6q23 variants, independently associated with MS, are involved in the regulation of several genes, including immune genes. These findings could help understand mechanisms of disease and suggest potential novel therapeutic targets.


Assuntos
Cromossomos Humanos Par 6 , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Esclerose Múltipla/genética , Linhagem Celular , Mapeamento Cromossômico , Biologia Computacional/métodos , Genômica/métodos , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
9.
Nat Commun ; 6: 10069, 2015 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-26616563

RESUMO

Genome-wide association studies have been tremendously successful in identifying genetic variants associated with complex diseases. The majority of association signals are intergenic and evidence is accumulating that a high proportion of signals lie in enhancer regions. We use Capture Hi-C to investigate, for the first time, the interactions between associated variants for four autoimmune diseases and their functional targets in B- and T-cell lines. Here we report numerous looping interactions and provide evidence that only a minority of interactions are common to both B- and T-cell lines, suggesting interactions may be highly cell-type specific; some disease-associated SNPs do not interact with the nearest gene but with more compelling candidate genes (for example, FOXO1, AZI2) often situated several megabases away; and finally, regions associated with different autoimmune diseases interact with each other and the same promoter suggesting common autoimmune gene targets (for example, PTPRC, DEXI and ZFP36L1).


Assuntos
Doenças Autoimunes/genética , Estudo de Associação Genômica Ampla/métodos , Adolescente , Doenças Autoimunes/metabolismo , Linfócitos B/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Linfócitos T/metabolismo
10.
J Agric Food Chem ; 62(40): 9832-40, 2014 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-25211397

RESUMO

Polyphenol oxidase (PPO) is an enzyme widely distributed in the plant kingdom that has been detected in most fruits and vegetables. PPO was extracted and purified from Manila mango (Mangifera indica), and its biochemical properties were studied. PPO was purified 216-fold by hydrophobic interaction and ion exchange chromatography. PPO was purified to homogeneity, and the estimated PPO molecular weight (MW) by SDS-PAGE was ≈31.5 kDa. However, a MW of 65 kDa was determined by gel filtration, indicating a dimeric structure for the native PPO. The isolated PPO showed the highest affinity to pyrogallol (Km = 2.77 mM) followed by 4-methylcatechol (Km = 3.14 mM) and catechol (Km = 15.14 mM). The optimum pH for activity was 6.0. PPO was stable in the temperature range of 20-70 °C. PPO activity was completely inhibited by tropolone, ascorbic acid, sodium metabisulfite, and kojic acid at 0.1 mM.


Assuntos
Catecol Oxidase/isolamento & purificação , Catecol Oxidase/metabolismo , Mangifera/enzimologia , Catecol Oxidase/antagonistas & inibidores , Catecóis/metabolismo , Cromatografia em Gel , Cromatografia por Troca Iônica , Inibidores Enzimáticos/farmacologia , Estabilidade Enzimática , Concentração de Íons de Hidrogênio , Peso Molecular , Proteínas de Plantas/isolamento & purificação , Proteínas de Plantas/metabolismo , Pirogalol/metabolismo , Especificidade por Substrato , Temperatura Ambiente
11.
Arthritis Rheumatol ; 66(1): 24-30, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24449572

RESUMO

OBJECTIVE: The number of confirmed rheumatoid arthritis (RA) loci currently stands at 32, but many lines of evidence indicate that expansion of existing genome-wide association studies (GWAS) enhances the power to detect additional loci. This study was undertaken to extend our previous RA GWAS in a UK cohort, adding more independent RA cases and healthy controls, with the aim of detecting novel association signals for susceptibility to RA in a homogeneous UK cohort. METHODS: A total of 3,223 UK RA cases and 5,272 UK controls were available for association analyses, with the extension adding 1,361 cases and 2,334 controls to the original GWAS data set. The genotype data for all RA cases were imputed using the Impute program version 2. After stringent quality control thresholds were applied, 3,034 cases and 5,271 controls (1,831,729 single-nucleotide polymorphisms [SNPs]) were available for analysis. Association testing was performed using Plink software. RESULTS: The analyses indicated a suggestive association with susceptibility to RA (P < 0.0001) for 6 novel RA loci that have been previously found to be associated with other autoimmune diseases; these 6 SNPs were genotyped in independent samples. Two of the associated loci were validated, one of which was associated with RA at genome-wide levels of significance in the combined analysis, identifying a novel RA locus at 22q12 (P = 6.9 × 10(-9) ). In addition, most of the previously known RA susceptibility loci were confirmed to be associated with RA, and for 16 of the loci, the strength of the association was increased. CONCLUSION: This study identified a new RA locus mapping to 22q12. These results support the notion that increasing the power of GWAS enhances novel gene discovery.


Assuntos
Artrite Reumatoide/genética , Cromossomos Humanos Par 22/genética , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Reino Unido
12.
Arthritis Rheum ; 65(12): 3058-62, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24022229

RESUMO

OBJECTIVE: A recent high-density fine-mapping (ImmunoChip) study of genetic associations in rheumatoid arthritis (RA) identified 14 risk loci with validated genome-wide significance, as well as a number of loci showing associations suggestive of significance (P = 5 × 10(-5) < 5 × 10(-8)), but these have yet to be replicated. The aim of this study was to determine whether these potentially significant loci are involved in the pathogenesis of RA, and to explore whether any of the loci are associated with a specific RA serotype. METHODS: A total of 16 single-nucleotide polymorphisms (SNPs) were selected for genotyping and association analyses in 2 independent validation cohorts, comprising 6,106 RA cases and 4,290 controls. A meta-analysis of the data from the original ImmunoChip discovery cohort and from both validation cohorts was carried out, for a combined total of 17,581 RA cases and 20,160 controls. In addition, stratified analysis of patient subsets, defined according to their anti-cyclic citrullinated peptide (anti-CCP) antibody status, was performed. RESULTS: A significant association with RA risk (P < 0.05) was replicated for 6 of the SNPs assessed in the validation cohorts. All SNPs in the validation study had odds ratios (ORs) for RA susceptibility in the same direction as those in the ImmunoChip discovery study. One SNP, rs72928038, mapping to an intron of BACH2, achieved genome-wide significance in the meta-analysis (P = 1.2 × 10(-8), OR 1.12), and a second SNP, rs911263, mapping to an intron of RAD51B, was significantly associated in the anti-CCP-positive RA subgroup (P = 4 × 10(-8), OR 0.89), confirming that both are RA susceptibility loci. CONCLUSION: This study provides robust evidence for an association of RA susceptibility with genes involved in B cell differentiation (BACH2) and DNA repair (RAD51B). The finding that the RAD51B gene exhibited different associations based on serologic subtype adds to the expanding knowledge base in defining subgroups of RA.


Assuntos
Artrite Reumatoide/genética , Fatores de Transcrição de Zíper de Leucina Básica/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
13.
BJU Int ; 111(7): 1148-55, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22985493

RESUMO

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The link between inflammation and cancer has long been reported and inflammation is thought to play a role in the pathogenesis of many cancers, including prostate cancer (PrCa). Over the last 5 years, genome-wide association studies (GWAS) have reported numerous susceptibility loci that predispose individuals to many different traits. The present study aims to ascertain if there are common genetic risk profiles that might predispose individuals to both PrCa and the autoimmune inflammatory condition, rheumatoid arthritis. These results could have potential public heath impact in terms of screening and chemoprevention. OBJECTIVES: To investigate if potential common pathways exist for the pathogenesis of autoimmune disease and prostate cancer (PrCa). To ascertain if the single nucleotide polymorphisms (SNPs) reported by genome-wide association studies (GWAS) as being associated with susceptibility to PrCa are also associated with susceptibility to the autoimmune disease rheumatoid arthritis (RA). MATERIALS AND METHODS: The original Wellcome Trust Case Control Consortium (WTCCC) UK RA GWAS study was expanded to include a total of 3221 cases and 5272 controls. In all, 37 germline autosomal SNPs at genome-wide significance associated with PrCa risk were identified from a UK/Australian PrCa GWAS. Allele frequencies were compared for these 37 SNPs between RA cases and controls using a chi-squared trend test and corrected for multiple testing (Bonferroni). RESULTS: In all, 33 SNPs were able to be analysed in the RA dataset. Proxies could not be located for the SNPs in 3q26, 5p15 and for two SNPs in 17q12. After applying a Bonferroni correction for the number of SNPs tested, the SNP mapping to CCHCR1 (rs130067) retained statistically significant evidence for association (P = 6 × 10(-4) ; odds ratio [OR] = 1.15, 95% CI: 1.06-1.24); this has also been associated with psoriasis. However, further analyses showed that the association of this allele was due to confounding by RA-associated HLA-DRB1 alleles. CONCLUSIONS: There is currently no evidence that SNPs associated with PrCa at genome-wide significance are associated with the development of RA. Studies like this are important in determining if common genetic risk profiles might predispose individuals to many diseases, which could have implications for public health in terms of screening and chemoprevention.


Assuntos
Artrite Reumatoide/genética , Frequência do Gene/genética , Cadeias HLA-DRB1/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Artrite Reumatoide/epidemiologia , Austrália/epidemiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Razão de Chances , Neoplasias da Próstata/epidemiologia , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes , Reino Unido/epidemiologia
14.
J Rheumatol ; 39(9): 1781-5, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22798268

RESUMO

OBJECTIVE: Recent studies have identified 6q23 as an important susceptibility locus for rheumatoid arthritis (RA), with risk alleles at 3 single-nucleotide polymorphisms combining to give an effect size greater than that of these markers individually. We investigated whether these polymorphisms are also associated with disease severity measured by radiological damage. METHODS: We studied 927 patients from a cross-sectional RA cohort. Median Larsen scores (LS) read from radiographs taken at study entry were compared by genotype at rs6920220, rs13207033, and rs5029937 according to a dominant model using negative binomial regression with stratification for autoantibody status. RESULTS: Median LS was associated with genotype at rs6920220 [LS 31 GG vs 36 GA/AA (p=0.02) in cyclic citrullinated peptide+ (CCP) RA] and rs13020220 [LS 37 GG vs 29 GA/AA (p=0.02) in CCP+ RA] only in autoantibody-positive RA, with no association at rs5029937. Association was stronger for these markers in combination [LS 28 vs 42 for lowest vs highest risk genotype combination in rheumatoid factor positivity (p=0.007), LS 28 vs 37 for anti-CCP+ (p=0.01)]. CONCLUSION: Established RA risk markers at 6q23 are associated also with radiographic severity in autoantibody-positive RA; as for susceptibility, the association for these markers in combination is stronger than that for markers alone.


Assuntos
Artrite Reumatoide/genética , Autoanticorpos/genética , Cromossomos Humanos Par 6 , Loci Gênicos , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Estudos Transversais , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Índice de Gravidade de Doença
15.
Int J Epidemiol ; 41(5): 1376-82, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22825589

RESUMO

BACKGROUND: Genetic differences between men and women may contribute to sex differences in prevalence and progression of many common complex diseases. Using the WTCCC GWAS, we analysed whether there are sex-specific differences in effect size estimates at 142 established loci for seven complex diseases: rheumatoid arthritis, type 1 diabetes (T1D), Crohn's disease, type 2 diabetes (T2D), hypertension, coronary artery disease and bipolar disorder. METHODS: For each Single nucleotide polymorphism (SNP), we calculated the per-allele odds ratio for each sex and the relative odds ratios (RORs; the effect size is higher in men with ROR greater than one). RORs were then meta-analysed across loci within each disease and across diseases. RESULTS: For each disease, summary RORs were not different from one, but there was between-SNP heterogeneity in the RORs for T1D and T2D. Four loci in T1D, three in Crohn's disease and three in T2D showed differences in the genetic effect between men and women (P<0.05). We probed these differences in additional independent replication samples for T1D and T2D. The differences remained for the T1D loci CTSH, 17q21 and 20p13 and the T2D locus BCL11A, when WTCCC data and replication data were meta-analysed. Only CTSH showed different genetic effect between men and women in the replication data alone. CONCLUSION: Our results exclude the presence of large and frequent differences in the effect size estimates between men and women for the established loci in the seven common diseases explored. Documenting small differences in genetic effects between men and women requires large studies and systematic evaluation.


Assuntos
Doença Crônica/epidemiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Caracteres Sexuais , Artrite Reumatoide/genética , Transtorno Bipolar/genética , Doença da Artéria Coronariana/genética , Doença de Crohn/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Hipertensão/genética , Masculino , Polimorfismo de Nucleotídeo Único , Fatores Sexuais
16.
J Food Sci ; 77(4): C359-65, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22515234

RESUMO

Polyphenol oxidase (PPO) is the enzyme responsible for quality loss in most fruits and vegetables. Quality loss is mainly because of oxidative chemical reactions which generate the darkening of tissues. Mamey fruit (Pouteria sapota) after harvesting suffers a rapid quality decay trough activation of PPO. However, PPO may be inactivated in situ by chemical or thermal treatment. In food processing, microwave treatment (MT) has been used recently as an alternative for PPO inactivation. In this study, it was observed that mamey fruit pulp subjected to a gently MT resulted in a higher PPO activity as the generated heat induced in situ the increase in PPO activity. In contrast, PPO was completely inactivated after long MT by using a high microwave power. Temperature in mamey pulp after MT reached a maximum of 79 °C; although PPO was active up to 60 °C. PPO was completely inactivated when conventional blanching treatment was performed but required a higher temperature (92 °C/300 s). The optimum energy intensity (E(opt)) for PPO inactivation by MT was 0.51 kJ/g or 937 W/165 s. Under this condition, the remaining PPO activity was inversely proportional to energy intensity (E). Interestingly, MT resulted in a negligible damage in microstructure of mamey pulp, although blanching treatment resulted in large damaging effects on tissue organization and shape. Therefore, MT is proposed as an effective way to completely inactivate PPO without causing any significant damage to fruit tissues and shape; as preservation of color, flavor, and taste would be favored.


Assuntos
Catecol Oxidase/efeitos da radiação , Irradiação de Alimentos , Frutas/enzimologia , Frutas/efeitos da radiação , Micro-Ondas , Pouteria/enzimologia , Pouteria/efeitos da radiação , Catecol Oxidase/metabolismo , Parede Celular/efeitos da radiação , Parede Celular/ultraestrutura , Proteínas na Dieta/metabolismo , Proteínas na Dieta/efeitos da radiação , Irradiação de Alimentos/efeitos adversos , Frutas/ultraestrutura , Temperatura Alta/efeitos adversos , Microscopia Eletrônica de Varredura , Micro-Ondas/efeitos adversos , Pigmentação/efeitos da radiação , Proteínas de Plantas/metabolismo , Proteínas de Plantas/efeitos da radiação , Pouteria/ultraestrutura , Controle de Qualidade , Fatores de Tempo
17.
Open Access Rheumatol ; 3: 31-46, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-27790002

RESUMO

The study of complex genetics in autoimmune diseases has progressed at a tremendous pace over the last 4 years, as a direct result of the enormous gains made by genome wide association studies (GWAS). Novel genetic findings are continuously being reported alongside the rapid development of genetic technologies, sophisticated statistical analysis, and larger sample collections. It is now becoming clear that multiple genes contribute to disease risk in many complex genetic disorders including rheumatoid arthritis (RA) and that there are common genetic risk factors that underlie a spectrum of autoimmune diseases. This review details the current genetic landscape of RA, and describes what GWAS has taught us in terms of missing heritability, subsets of disease, existence of genetic heterogeneity, and shared autoimmune risk loci. Finally, this review addresses the initial challenges faced in translating the wealth of genetic findings into determining the biological mechanisms that contribute to the relationship between genotype and phenotype. Unraveling the mechanism of how genes directly influence the cause of RA will lead to a better understanding of the disease and will ultimately have a direct clinical impact, informing the development of new therapies that can be utilized in the treatment of RA.

18.
Ann Rheum Dis ; 70(9): 1641-4, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21623003

RESUMO

OBJECTIVES: To investigate a shared genetic aetiology for skin involvement in psoriasis and psoriatic arthritis (PsA) by genotyping single-nucleotide polymorphisms (SNPs), reported to be associated in genome-wide association studies of psoriasis, in patients with PsA. METHODS: SNPs with reported evidence for association with psoriasis were genotyped in a PsA case and control collection from the UK and Ireland. Genotype and allele frequencies were compared between PsA cases and controls using the Armitage test for trend. RESULTS: Seven SNPs mapping to the IL1RN, TNIP1, TNFAIP3, TSC1, IL23A, SMARCA4 and RNF114 genes were successfully genotyped. The IL23A and TNIP1 genes showed convincing evidence for association (rs2066808, p = 9.1×10(-7); rs17728338, p = 3.5×10(-5), respectively) whilst SNPs mapping to the TNFAIP3, TSC1 and RNF114 genes showed nominal evidence for association (rs610604, p = 0.03; rs1076160, p = 0.03; rs495337, p = 0.0025). No evidence for association with IL1RN or SMARCA4 was found but the power to detect association was low. CONCLUSIONS: SNPs mapping to previously reported psoriasis loci show evidence for association to PSA, thus supporting the hypothesis that the genetic aetiology of skin involvement is the same in both PsA and psoriasis.


Assuntos
Artrite Psoriásica/genética , Proteínas de Ligação a DNA/genética , Subunidade p19 da Interleucina-23/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Psoríase/genética , Adulto Jovem
19.
Ann Rheum Dis ; 70(3): 463-8, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21068098

RESUMO

BACKGROUND: Evidence is beginning to emerge that there may be susceptibility loci for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) that are common to both diseases. OBJECTIVE: To investigate single nucleotide polymorphisms that have been reported to be associated with SLE in a UK cohort of patients with RA and controls. METHODS: 3962 patients with RA and 9275 controls were included in the study. Eleven SNPs mapping to confirmed SLE loci were investigated. These mapped to the TNFSF4, BANK1, TNIP1, PTTG1, UHRF1BP1, ATG5, JAZF1, BLK, KIAA1542, ITGAM and UBE2L3 loci. Genotype frequencies were compared between patients with RA and controls using the trend test. RESULTS: The SNPs mapping to the BLK and UBE2L3 loci showed significant evidence for association with RA. Two other SNPs, mapping to ATG5 and KIAA1542, showed nominal evidence for association with RA (p=0.02 and p=0.02, respectively) but these were not significant after applying a Bonferroni correction. Additionally, a significant global enrichment in carriage of SLE alleles in patients with RA compared with controls (p=9.1×10(-7)) was found. Meta-analysis of this and previous studies confirmed the association of the BLK and UBE2L3 gene with RA at genome-wide significance levels (p<5×10(-8)). Together, the authors estimate that the SLE and RA overlapping loci, excluding HLA-DRB1 alleles, identified so far explain ∼5.8% of the genetic susceptibility to RA as a whole. CONCLUSION: The findings confirm the association of the BLK and UBE2L3 loci with RA, thus adding to the list of loci showing overlap between RA and SLE.


Assuntos
Artrite Reumatoide/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino
20.
Phytochemistry ; 72(1): 82-8, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21087780

RESUMO

While a long shelf life for fruit products is highly desired, enzymatic browning is the main cause of quality loss in fruits and is therefore a main problem for the food industry. In this study polyphenol oxidase (PPO), the main enzyme responsible for browning was isolated from mamey fruit (Pouteria sapota) and characterized biochemically. Two isoenzymes (PPO 1 and PPO 2) were obtained upon ammonium sulfate precipitation and hydrophobic and ion exchange chromatography; PPO 1 was purified up to 6.6-fold with 0.28% yield, while PPO 2 could not be characterized as enzyme activity was completely lost after 24 h of storage. PPO 1 molecular weight was estimated to be 16.1 and 18 kDa by gel filtration and SDS-PAGE, respectively, indicating that the native state of the PPO 1 is a monomer. The optimum pH for PPO 1 activity was 7. The PPO 1 was determined to be maximum thermally stable up to 35°C. Kinetic constants for PPO 1 were K(m)=44 mM and K(m)=1.3 mM using catechol and pyrogallol as substrate, respectively. The best substrates for PPO 1 were pyrogallol, 4-methylcatechol and catechol, while ascorbic acid and sodium metabisulfite were the most effective inhibitors.


Assuntos
Catecol Oxidase/metabolismo , Frutas/enzimologia , Pouteria/enzimologia , Ácido Ascórbico/farmacologia , Catecol Oxidase/antagonistas & inibidores , Catecol Oxidase/isolamento & purificação , Catecóis/metabolismo , Cromatografia por Troca Iônica , Eletroforese em Gel de Poliacrilamida , Concentração de Íons de Hidrogênio , Isoenzimas/isolamento & purificação , Isoenzimas/metabolismo , México , Peso Molecular , Pirogalol/metabolismo , Sulfitos/farmacologia , Termodinâmica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA