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1.
Alzheimers Dement ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31495601

RESUMO

INTRODUCTION: Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. METHODS: 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. RESULTS: A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. DISCUSSION: The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.

2.
Diabetes Ther ; 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31410711

RESUMO

The prevalence of type 2 diabetes continues to increase, along with a proliferation of glucose-lowering treatment options. There is universal agreement in the clinical community for the use of metformin as the first-line glucose-lowering therapy for the majority of patients. However, controversy exists regarding the choice of second-line therapy once metformin is no longer effective. The most recent treatment consensus focuses on the presence of cardiovascular disease, heart failure or kidney disease as a determinant of therapy choice. The majority of patients in routine practice, however, do not fall into such categories. Heart failure and kidney disease represent significant clinical and cost considerations in patients with type 2 diabetes and have a close pathophysiological association. Recent data has illustrated that sodium-glucose transporter 2 (SGLT2) inhibitor therapy can reduce the burden of heart failure and the progression of renal disease across a wide range of patients including those with and without established disease, supported by an increased understanding of the mechanistic effects of these agents. Furthermore, there is growing evidence to illustrate the overall safety profile of this class of agents and support the benefit-risk profile of SGLT2 inhibitors as a preferred option following metformin monotherapy failure, with respect to both kidney disease progression and heart failure outcomes.

3.
Alzheimers Dement ; 15(6): 776-787, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31047856

RESUMO

INTRODUCTION: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a "Holy Grail" of AD research and intensively sought; however, there are no well-established plasma markers. METHODS: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. RESULTS: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOε4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). DISCUSSION: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation.

4.
BMC Res Notes ; 10(1): 559, 2017 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-29110694

RESUMO

BACKGROUND: There is uncertainty regarding how stable complement analytes are during long-term storage at - 80 °C. As part of our work program we have measured 17 complement biomarkers (C1q, C1 inhibitor, C3, C3a, iC3b, C4, C5, C9, FB, FD, FH, FI, TCC, Bb, sCR1, sCR2, Clusterin) and the benchmark inflammatory marker C-reactive protein (CRP) in a large set of plasma samples (n = 720) that had been collected, processed and subsequently stored at - 80 °C over a period of 6.6-10.6 years, prior to laboratory analysis. The biomarkers were measured using solid-phase enzyme immunoassays with a combination of multiplex assays using the MesoScale Discovery Platform and single-plex enzyme-linked immunosorbent assays (ELISAs). As part of a post hoc analysis of extrinsic factors (co-variables) affecting the analyses we investigated the impact of freezer storage time on the values obtained for each complement analyte. RESULTS: With the exception of five analytes (C4, C9, sCR2, clusterin and CRP), storage time was significantly correlated with measured plasma concentrations. For ten analytes: C3, FI, FB, FD, C5, sCR1, C3a, iC3b, Bb and TCC, storage time was positively correlated with concentration and for three analytes: FH, C1q, and C1 inhibitor, storage time was negatively correlated with concentration. CONCLUSIONS: The results suggest that information on storage time should be regarded as an important co-variable and taken into consideration when analysing data to look for associations of complement biomarker levels and disease or other outcomes.


Assuntos
Biomarcadores/sangue , Proteínas do Sistema Complemento/metabolismo , Congelamento , Humanos , Valores de Referência , Fatores de Tempo
5.
J Alzheimers Dis ; 56(1): 25-36, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27911318

RESUMO

Plasma biomarkers to aid the early diagnosis of Alzheimer's disease (AD) or to monitor disease progression have long been sought and continue to be widely studied. Biomarkers that correlate with AD polygenic risk score, a measure of the polygenic architecture of the disease and highly predictive of AD status, would be excellent candidates. Therefore, we undertook a preliminary study to assess the association of plasma inflammatory biomarkers with an overall AD polygenic risk score as well as with an inflammation-specific AD polygenic risk score in a sample set of 93 AD cases. We measured five complement biomarkers [complement receptor 1 (CR1), clusterin, complement component 9 (C9), C1 inhibitor (C1inh), terminal complement complex (TCC)] and the benchmark inflammatory marker C-reactive protein (CRP). Plasma clusterin level showed an association with overall AD polygenic risk score, while clusterin, C1inh, and CRP levels each displayed some association with the inflammatory-specific AD polygenic risk score. The results suggest that elevated plasma levels of inflammatory biomarkers, including complement proteins, associate with polygenic risk scores in AD, further strengthening the link between genetic and biomarker disease predictors and indicating a potential role for these markers in disease prediction and patient stratification in AD.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/complicações , Biomarcadores/sangue , Citocinas/sangue , Inflamação/etiologia , Doença de Alzheimer/genética , Proteína C-Reativa/metabolismo , Clusterina/sangue , Proteína Inibidora do Complemento C1/metabolismo , Progressão da Doença , Feminino , Humanos , Inflamação/sangue , Masculino , Herança Multifatorial/genética , Testes Neuropsicológicos , Receptores de Complemento/sangue , Fatores de Risco , Estatística como Assunto , Estatísticas não Paramétricas
6.
Pediatr Allergy Immunol ; 26(3): 262-271, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25779902

RESUMO

BACKGROUND: There is strong evidence to support a genetic predisposition to eczema and more recently studies have suggested that probiotics might be used to prevent eczema by modifying the expression of putative allergy-associated genes. The aim of this present study was to investigate whether two probiotics, Lactobacillus rhamnosus HN001 (HN001) and Bifidobacterium animalis subsp. lactis HN019 (HN019), can modify the known genetic predisposition to eczema conferred by genetic variation in the Toll-like receptor (TLR) genes in a high-risk infant population. METHODS: We selected 54 SNPs in the Toll-like receptor genes. These SNPs were analysed in 331 children of sole European ancestry as part of a double-blind, randomized, placebo-controlled trial examining the effects of HN001 and HN019 supplementation on eczema development and atopic sensitization. RESULTS: The data showed that 26 TLR SNPs interacted with HN001 resulting in a significantly reduced risk of eczema, 18 for eczema severity as defined by SCORAD ≥ 10 and 20 for atopic sensitization compared to placebo. There were only two SNPs that interacted with HN019 resulting in a reduced risk of eczema, eczema severity or atopy. CONCLUSIONS: This is the first study to show that the negative impact of specific TLR genotypes may be positively affected by probiotic supplementation. HN001 exhibits a much stronger effect than HN019 in this respect.


Assuntos
Bifidobacterium/imunologia , Dermatite Atópica/tratamento farmacológico , Eczema/dietoterapia , Grupo com Ancestrais do Continente Europeu , Lactobacillus rhamnosus/imunologia , Probióticos/administração & dosagem , Receptores Toll-Like/genética , Pré-Escolar , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Suplementos Nutricionais , Método Duplo-Cego , Eczema/genética , Eczema/imunologia , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Efeito Placebo , Polimorfismo de Nucleotídeo Único , Gravidez , Risco
7.
Cognition ; 132(3): 461-70, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24955500

RESUMO

Maternal stress during pregnancy has been associated with a range of adverse outcomes in offspring and the catechol-O-methyltransferase (COMT) gene has been linked to differential susceptibility to the consequences of antenatal stress. This study examined two functional polymorphisms of the COMT gene (rs4680 and rs165599) in relation to maternal perceived stress and childhood cognitive performance. Data from the longitudinal Auckland Birthweight Collaborative (ABC) study was used. Maternal perceived stress over the prior month was measured at birth, 3.5 and 7years. Full-Scale IQ (FSIQ) was measured at ages 7 and 11. At age 11, a total of 546 DNA samples were collected from the child participants. Data were subjected to a series of split-plot ANCOVAs with birthweight for gestational age and maternal school leaving age as covariates. There were direct effects of maternal stress during the last month of pregnancy on offspring FSIQ at ages 7 and 11years. A significant interaction revealed that children exposed to high maternal antenatal stress had significantly lower FSIQ scores at both 7 and 11years of age than those exposed to low stress, only when they were carriers of the rs165599 G allele. At each age, this difference was of approximately 5 IQ points. The G allele of the rs165599 polymorphism may confer genetic susceptibility to negative cognitive outcomes arising from exposure to antenatal stress. This finding highlights the need to consider gene-environment interactions when investigating the outcomes of antenatal stress exposure.


Assuntos
Catecol O-Metiltransferase/genética , Inteligência/genética , Polimorfismo de Nucleotídeo Único , Efeitos Tardios da Exposição Pré-Natal/psicologia , Estresse Psicológico/psicologia , Criança , Feminino , Interação Gene-Ambiente , Humanos , Testes de Inteligência , Estudos Longitudinais , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética
8.
BMC Med Genet ; 14: 10, 2013 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-23339409

RESUMO

BACKGROUND: Children born small-for-gestational-age (SGA) are at increased risk of developing obesity and metabolic diseases later in life, a risk which is magnified if followed by accelerated postnatal growth. We investigated whether common gene variants associated with adult obesity were associated with increased postnatal growth, as measured by BMI z-score, in children born SGA and appropriate for gestational age (AGA) in the Auckland Birthweight Collaborative. METHODS: A total of 37 candidate SNPs were genotyped on 547 European children (228 SGA and 319 AGA). Repeated measures of BMI (z-score) were used for assessing obesity status, and results were corrected for multiple testing using the false discovery rate. RESULTS: SGA children had a lower BMI z-score than non-SGA children at assessment age 3.5, 7 and 11 years. We confirmed 27 variants within 14 obesity risk genes to be individually associated with increasing early childhood BMI, predominantly in those born AGA. CONCLUSIONS: Genetic risk variants are less important in influencing early childhood BMI in those born SGA than in those born AGA, suggesting that non-genetic or environmental factors may be more important in influencing childhood BMI in those born SGA.


Assuntos
Recém-Nascido Pequeno para a Idade Gestacional , Obesidade/genética , Criança , Predisposição Genética para Doença , Humanos , Recém-Nascido , Nova Zelândia , Polimorfismo de Nucleotídeo Único
9.
Nutrients ; 4(9): 1247-59, 2012 09.
Artigo em Inglês | MEDLINE | ID: mdl-23112913

RESUMO

New Zealand has one of the highest incidence rates of Crohn's Disease (CD), whilst the serum selenium status of New Zealanders is amongst the lowest in the world. A prospective case-control study in Auckland, New Zealand considered serum selenium as a potential CD risk factor. Serum selenium levels were significantly lower in CD patients compared to controls (101.8 ± 1.02 vs. 111.1 ± 1.01 ng/mL) (p = 5.91 × 10(-8)). Recent detailed studies in the United Kingdom have suggested an optimal serum level around 122 ng/mL, making the average CD patient in New Zealand selenium deficient. Of the 29 single nucleotide polymorphisms (SNPs) tested, 13 were found to significantly interact with serum selenium on CD. After adjustment for multiple testing, a significant interaction with serum selenium on CD was found for three SNPs, namely rs17529609 and rs7901303 in the gene SEPHS1, and rs1553153 in the gene SEPSECS. These three SNPs have not been reported elsewhere as being significantly associated with selenium or CD. It is unclear as to whether lower selenium levels are a cause or an effect of the disease.


Assuntos
Doença de Crohn/sangue , Doença de Crohn/epidemiologia , Selênio/sangue , Selenoproteínas/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Doença de Crohn/genética , Grupo com Ancestrais do Continente Europeu , Predisposição Genética para Doença , Humanos , Incidência , Lactente , Nova Zelândia/epidemiologia , Estado Nutricional , Razão de Chances , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Selenoproteínas/metabolismo , Fumar , Inquéritos e Questionários , Adulto Jovem
10.
ISRN Gastroenterol ; 2012: 826323, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22701800

RESUMO

DNase1 has been implicated in a number of immune disorders and is an excellent candidate gene for Crohn's disease (CD). We investigated whether DNase1 SNPs rs1053874 and rs8176938 were associated with CD in a well-characterized New Zealand dataset consisting of 447 cases and 716 controls. Furthermore, we measured serum DNase1 activity levels in a number of CD patients and controls. We did not find any evidence of association for either DNase1 genetic variation or DNase1 activity levels with CD. The lack of association indicates that DNase1 does not play a significant role in predisposing to CD in the New Zealand population.

11.
Gastroenterol Res Pract ; 2012: 715309, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22536218

RESUMO

The gene ULK1 is an excellent candidate for Crohn's disease (CD) due to its role in autophagy. A recent study provided evidence for the involvement of ULK1 in the pathogenesis of CD (Henckaerts et al., 2011). We attempted to validate this association, using a candidate gene SNP study of ULK1 in CD. We identified tagging SNPs and genotyped these SNPs using the Sequenom platform in a Caucasian New Zealand dataset consisting of 406 CD patients and 638 controls. In this sample, we were able to demonstrate an association between CD and several different ULK1 SNPs and haplotypes. Phenotypic analysis showed an association with age of diagnosis 17-40 years and inflammatory behaviour. The findings of this study provide evidence to suggest that genetic variation in ULK1 may play a role in interindividual differences in CD susceptibility and clinical outcome.

12.
Hum Immunol ; 73(4): 416-20, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22342453

RESUMO

Toll-like receptors (TLRs) play an important role in the induction and regulation of the innate immune system and have been implicated in both infectious and inflammatory diseases. Recently the first association of TLR10 with Crohn's disease (CD) was reported. Here, we attempted to validate this association, using a candidate gene single nucleotide polymorphism (SNP) study of TLR10 in CD. We identified tagging SNPs, and genotyped these SNPs in a Caucasian New Zealand dataset consisting of 406 CD patients and 638 controls. In this sample, we were able to demonstrate an association between CD and several different TLR10 SNPs and haplotypes. Phenotypic analysis showed an association with early age at first diagnosis, inflammatory and ileocolonic CD behavior, requirement of bowel resection, and extra intestinal manifestations. This study provides evidence to suggest that genetic variation in TLR10 plays a role in interindividual differences in CD susceptibility and clinical outcome.


Assuntos
Doença de Crohn/genética , Polimorfismo de Nucleotídeo Único , Receptor 10 Toll-Like/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Fenótipo , Adulto Jovem
13.
J Negat Results Biomed ; 11: 8, 2012 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-22284420

RESUMO

Metallothioneins (MTs) are excellent candidate genes for Inflammatory Bowel Disease (IBD) and have previously been shown to have altered expression in both animal and human studies of IBD. This is the first study to examine genetic variants within the MT genes and aims to determine whether such genetic variants have an important role in this disease. 28 tag SNPs in genes MT1 (subtypes A, B, E, F, G, H, M, X), MT2, MT3 and MT4 were selected for genotyping in a well-characterized New Zealand dataset consisting of 406 patients with Crohn's Disease and 638 controls. We did not find any evidence of association for MT genetic variation with CD. The lack of association indicates that genetic variants in the MT genes do not play a significant role in predisposing to CD in the New Zealand population.


Assuntos
Doença de Crohn/genética , Predisposição Genética para Doença , Metalotioneína/genética , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Nova Zelândia
14.
Dev Med Child Neurol ; 54(2): 148-54, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22070166

RESUMO

AIM: The functional polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene was analysed to determine its association with maternal stress and childhood total difficulties. METHOD: Data were collected at birth from a group of infants who were born small for gestational age and a group who were born at an appropriate size for gestational age and had been enrolled in the Auckland Birthweight Collaborative Study. Children were followed up at the ages of 1 year, 3 years 6 months, 7 years, and 11 years. At the age of 11 years, DNA samples were collected from 546 children (270 females, 276 males): 227 children born small for gestational age and 319 children born at an appropriate size for gestational age. The main independent variable was perceived maternal stress at birth and at 7 and 11 years of age, assessed using the total difficulties scale of the Strength and Difficulties Questionnaire. IQ was assessed at the age of 7 years. RESULTS: Met/Met homozygotes were at a significantly increased risk of behavioural and emotional problems at the ages of 7 (p=0.002) and 11 years (p=0.003), relative to either heterozygous or homozygous carriers of the Val158Met polymorphism, but only when they were exposed to maternal stress in utero. Met/Met homozygotes had, on average, IQ scores that were four points higher than those of Val/Val homozygotes (p=0.010). INTERPRETATION: These findings emphasize the potential long-term consequences of prenatal stress for genetically susceptible individuals during neurodevelopment in utero. Our findings add to the general understanding of the aetiology and developmental nature of childhood emotional and behavioural problems.


Assuntos
Catecol O-Metiltransferase/genética , Transtornos do Comportamento Infantil/genética , Metionina/genética , Polimorfismo de Nucleotídeo Único/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Valina/genética , Fatores Etários , Criança , Transtornos do Comportamento Infantil/etiologia , Pré-Escolar , Feminino , Genótipo , Humanos , Inteligência , Estudos Longitudinais , Masculino , Relações Mãe-Filho , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética
15.
J Alzheimers Dis ; 28(2): 377-87, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22027014

RESUMO

Rare mutations in AßPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AßPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Presenilina-1/genética , Presenilina-2/genética , Proteínas tau/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Metanálise como Assunto , Razão de Chances
16.
Curr Diab Rep ; 12(1): 88-92, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22139555

RESUMO

The prevalence of type 2 diabetes (T2D) is increasing significantly in the pediatric population. A strong family history of the disease suggests the involvement of genetic factors for diabetes development, but defining the molecular genetics of T2D in children is difficult due to a low number of subjects and the lack of robust diagnostic criteria. Thus, genetic studies of T2D have been carried out almost exclusively in adults. In this review, the genetics of T2D is summarized and options for discovering the missing heritability explored. The review concludes with a discussion of future research that will be required for determining genetic risk factors for pediatric T2D.


Assuntos
Diabetes Mellitus Tipo 2/genética , Obesidade/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Adolescente , Diabetes Mellitus Tipo 2/epidemiologia , Saúde da Família , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Nova Zelândia/epidemiologia , Obesidade/epidemiologia , Prevalência , Fatores de Risco
17.
J Pediatr Genet ; 1(2): 103-13, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27625810

RESUMO

Being born small for gestational age (SGA) is a putative risk factor for the development of later cognitive and psychiatric health problems. While the inter-uterine environment has been shown to play an important role in predicting birth weight, little is known about the genetic factors that might be important. Here we test the hypothesis that neurotransmitter-regulating genes implicated in psychiatric disorders previously shown to be associated with SGA (such as attention-deficit hyperactivity disorder) are themselves predictive of SGA. DNA was collected from 227 SGA and 319 appropriate for gestational age children taking part in the Auckland Birthweight Collaborative Study. Candidate single nucleotide polymorphisms in genes regulating activity within dopamine, serotonin, glutamate and gamma-aminobutyric acid pathways were genotyped. Multiple regression analysis, controlling for potentially confounding factors, supported nominally significant associations between SGA and single nucleotide polymorphisms in COMT, HTR2A, SLC1A1 and SLC6A1. This is the first evidence that genes implicated in psychiatric disorders previously linked to SGA status themselves predict SGA. This highlights the possibility that the link between SGA and psychiatric disorders such as attention-deficit hyperactivity disorder may in part be genetically determined - that SGA marks pre-existing genetic risk for later problems.

18.
Hum Immunol ; 72(11): 1117-27, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21925226

RESUMO

Increased production of matrix metalloproteinases (MMPs) plays an important role in tissue damage in inflammatory bowel disease (IBD). Genetically encoded variation between individuals in MMP production may therefore contribute to disease onset, type, or severity. We undertook an extensive candidate gene single nucleotide polymorphism (SNP) study of MMP-1, -2, -3, -7, -8, -9, -10, -12, -13, and -14 and tissue inhibitor of metalloproteinases (TIMPs)-1, -3, and -4 in ulcerative colitis (UC). We identified tagging SNPs across these genes, and genotyped these SNPs in a Caucasian New Zealand dataset consisting of 419 UC patients and 907 controls. SNPs in a number of MMP genes were associated with UC. After correcting for multiple testing SNPs in MMP-3, MMP-8, MMP-10, and MMP-14 remained significant in their associations with UC. In a second study, using samples from a Dutch cohort, most of the significant findings in the New Zealand cohort were not replicated. However, data from an international meta-analysis provide some support for the initial findings. In conclusion, this study provides preliminary evidence to suggest that genetic variation in the MMPs may play a role in interindividual differences in UC susceptibility and clinical outcome. Further studies are needed in other cohorts to determine the robustness of these observations in different populations.


Assuntos
Colite Ulcerativa/genética , Grupo com Ancestrais do Continente Europeu , Metaloproteinases da Matriz/genética , Adulto , Idoso , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/imunologia , Colite Ulcerativa/fisiopatologia , Progressão da Doença , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Nova Zelândia , Polimorfismo de Nucleotídeo Único
19.
BMC Res Notes ; 4: 253, 2011 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-21777433

RESUMO

BACKGROUND: Several lines of evidence suggest a possible functional role of Matrix metalloproteinase -2 (MMP-2) in obesity. The aim of this study was to evaluate the role of MMP-2 promoter polymorphisms in percentage body fat (PBF) as a measure of childhood obesity in a New Zealand population. FINDINGS: 546 samples from the Auckland Birthweight Collaborative (ABC) study were genotyped for the three MMP-2 promoter SNPs -1306 C/T (rs243865), -1575G/A (rs243866) and -790 T/G (rs243864) using the Sequenom genotyping platform. The results demonstrated that an MMP-2 promoter haplotype is associated with PBF in New Zealand 7 year old children. CONCLUSION: We have previously determined that environmental factors are associated with differences in PBF in this study group, and now we have demonstrated a possible genetic contribution.

20.
Hum Immunol ; 72(5): 431-5, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21354456

RESUMO

Interleukin (IL)-10 has important effects in immunoregulation and inflammation, and previous studies have provided evidence for the involvement of IL-10 in the pathogenesis of Crohn's disease (CD). In this study, we investigated whether genetic variants of the IL-10 gene were associated with CD in a New Zealand population. Three single nucleotide polymorphisms (SNPs) in the promoter region of IL-10 (rs1800871, rs1800872, and rs1800896) and a flanking SNP, rs3024505, were genotyped in a well-characterized New Zealand dataset consisting of 342 CD cases and 610 controls. Furthermore, we measured serum IL-10 levels in a number of the CD patients and controls and examined whether a relationship existed between these polymorphisms and serum IL-10 levels. We demonstrated an association with CD for SNPs rs3024505 and rs1800896, and phenotypic analysis indicated an association of rs3024505 with an early age at first diagnosis, stricturing CD behavior, and requirement for bowel resection. We also observed that IL-10 concentration was significantly higher in CD patients than in the controls and that the T allele of rs1800896, the A allele of rs1800871, and the T allele of rs1800872 were associated with increased serum IL-10 levels.


Assuntos
Doença de Crohn/genética , Doença de Crohn/imunologia , Interleucina-10/metabolismo , Adolescente , Adulto , Idade de Início , Doença de Crohn/sangue , Doença de Crohn/epidemiologia , Doença de Crohn/fisiopatologia , Progressão da Doença , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Interleucina-10/genética , Nova Zelândia , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética
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