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1.
Br J Dermatol ; 179(3): 717-723, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29851030

RESUMO

BACKGROUND: Eczema and asthma are chronic diseases with onset usually before the age of 5 years. More than 50% of individuals with eczema will develop asthma and/or other allergic diseases. Several loss-of-function mutations in filaggrin (FLG) have been identified in patients with eczema. However, the association of FLG with healthcare use is unknown. OBJECTIVES: To determine whether FLG mutations are associated with increased prescribing for eczema and asthma and whether increased prescribing is associated with increased healthcare costs. METHODS: A secondary analysis of BREATHE, a cross-sectional study of gene-environment associations with asthma severity, was undertaken. BREATHE data was collected for 1100 participants with asthma, in Tayside and Fife, Scotland during the period 2003-2005. Through collaboration with the Health Informatics Centre in Dundee, BREATHE was linked to accident and emergency, community prescribing and Scottish morbidity records. The data linkage allowed longitudinal exploration of associations between genetic variation and prescribing. RESULTS: An association was found between FLG mutations and increased prescribing for mild and moderate eczema, asthma-reliever medicine and asthma exacerbations. A strong association was found between FLG mutations and prescribing of emollients [incidence rate ratio (IRR) 2·19, 95% confidence interval (CI) 1·36-3·52], treatment for severe eczema (IRR 2·18, 95% CI 1·22-3·91) and a combination of a long-acting ß2 -agonist and corticosteroids (IRR 3·29, 95% CI 1·68-6·43). CONCLUSIONS: The presence of FLG mutations in this cohort is associated with increased prescribing for eczema and asthma. Randomized controlled trials are required to determine if these individuals could benefit from management strategies to reduce morbidity and treatment costs.


Assuntos
Asma/terapia , Doença Crônica/terapia , Eczema/terapia , Custos de Cuidados de Saúde/estatística & dados numéricos , Proteínas de Filamentos Intermediários/genética , Proteínas S100/genética , Adolescente , Adulto , Antiasmáticos/economia , Antiasmáticos/uso terapêutico , Asma/economia , Asma/genética , Criança , Pré-Escolar , Doença Crônica/economia , Estudos Transversais , Análise Mutacional de DNA , Prescrições de Medicamentos/estatística & dados numéricos , Eczema/economia , Eczema/genética , Emolientes/economia , Emolientes/uso terapêutico , Feminino , Proteínas Filagrinas , Predisposição Genética para Doença , Hospitalização/economia , Hospitalização/estatística & dados numéricos , Humanos , Mutação com Perda de Função , Masculino , Medicamentos sob Prescrição/economia , Medicamentos sob Prescrição/uso terapêutico , Escócia , Fatores de Tempo , Adulto Jovem
2.
Ann Oncol ; 29(5): 1292-1303, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29509840

RESUMO

Background: MSR1 repeats are a 36-38 bp minisatellite element that have recently been implicated in the regulation of gene expression, through copy number variation (CNV). Patients and methods: Bioinformatic and experimental methods were used to assess the distribution of MSR1 across the genome, evaluate the regulatory potential of such elements and explore the role of MSR1 elements in cancer, particularly non-familial breast cancer and prostate cancer. Results: MSR1s are predominately located at chromosome 19 and are functionally enriched in regulatory regions of the genome, particularly regions implicated in short-range regulatory activities (H3K27ac, H3K4me1 and H3K4me3). MSR1-regulated genes were found to have specific molecular roles, such as serine-protease activity (P = 4.80 × 10-7) and ion channel activity (P = 2.7 × 10-4). The kallikrein locus was found to contain a large number of MSR1 clusters, and at least six of these showed CNV. An MSR1 cluster was identified within KLK14, with 9 and 11 copies being normal variants. A significant association with the 9-copy allele and non-familial breast cancer was found in two independent populations (P = 0.004; P = 0.03). In the white British population, the minor allele conferred an increased risk of 1.21-3.51 times for all non-familial disease, or 1.7-5.3 times in early-onset disease. The 9-copy allele was also found to be associated with increased risk of prostate cancer in an independent population (odds ratio = 1.27-1.56; P =0.009). Conclusions: MSR1 repeats act as molecular switches that modulate gene expression. It is likely that CNV of MSR1 will affect risk of development of various forms of cancer, including that of breast and prostate. The MSR1 cluster at KLK14 represents the strongest risk factor identified to date in non-familial breast cancer and a significant risk factor for prostate cancer. Analysis of MSR1 genotype will allow development of precise stratification of disease risk and provide a novel target for therapeutic agents.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica/genética , Predisposição Genética para Doença , Repetições Minissatélites/genética , Neoplasias da Próstata/genética , Idade de Início , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Biologia Computacional , Variações do Número de Cópias de DNA , Feminino , Mutação em Linhagem Germinativa , Histonas/genética , Humanos , Calicreínas/genética , Masculino , Pessoa de Meia-Idade , Família Multigênica/genética , Neoplasias da Próstata/patologia , Medição de Risco/métodos
3.
Br J Dermatol ; 177(6): 1664-1670, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28672053

RESUMO

BACKGROUND: Diabetic foot ulcers (DFUs) are a devastating complication of diabetes. OBJECTIVES: To identify genetic contributors to the development of DFUs in the presence of peripheral neuropathy in a Scottish cohort with diabetes using a genome-wide association study. METHODS: A genome-wide association approach was applied. A case was defined as a person with diabetes (type 1 or type 2) who had ever had a foot ulcer (current or previous) in at least one foot, as well as a positive monofilament test result (i.e. evidence of peripheral neuropathy) recorded in their longitudinal e-health records. A control was defined as an individual with diabetes (type 1 or type 2) who has never been recorded as having a foot ulcer in either foot but who had a positive monofilament test result recorded in either foot in their longitudinal e-health records. RESULTS: There were 699 DFU cases and 2695 controls in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) dataset. The single-nucleotide polymorphism rs80028505 (Chr6p21·31) in MAPK14 reached genome-wide significance with a lowest P-value of 2·45 × 10-8 . The narrow-sense heritability of this phenotype is 0·06. CONCLUSIONS: We suggest that MAPK14 is associated with DFUs.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Pé Diabético/genética , Proteína Quinase 14 Ativada por Mitógeno/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino
5.
Pharmacogenomics J ; 16(3): 231-7, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26169577

RESUMO

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Tosse/induzido quimicamente , Tosse/genética , Proteínas Interatuantes com Canais de Kv/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Biologia Computacional , Tosse/etnologia , Bases de Dados Genéticas , Registros Eletrônicos de Saúde , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Razão de Chances , Fenótipo , Medição de Risco , Fatores de Risco , Escócia , Estados Unidos
6.
Clin Exp Allergy ; 45(6): 1051-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25616159

RESUMO

BACKGROUND: The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS. METHODS: We performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n = 357, age: 4-12 years, the Netherlands), BREATHE (n = 820, age: 3-22 years, UK) and Paediatric Asthma Gene Environment Study (n = 391, age: 2-16 years, UK). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n = 172, age: 5-12 years, USA), the Genes- environment and Mixture in Latino Americans II- study (n = 745, age: 8-21, USA) and the Pharmacogenetics of adrenal suppression cohort (n = 391, age: 5-18, UK) to test the robustness of the findings. Finally, all results were meta-analysed. RESULTS: Two SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year; OR = 1.22 (P = 0.013) and OR = 1.22 (P = 0.0017), respectively. CONCLUSION AND CLINICAL RELEVANCE: A novel susceptibility gene, ST13, coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.


Assuntos
Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/genética , Proteínas de Transporte/genética , Polimorfismo de Nucleotídeo Único , Proteínas Supressoras de Tumor/genética , Adolescente , Corticosteroides/administração & dosagem , Antiasmáticos/administração & dosagem , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Razão de Chances , Resultado do Tratamento , Adulto Jovem
7.
Eur J Pain ; 19(3): 392-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24974787

RESUMO

BACKGROUND: Neuropathic pain, caused by a lesion or a disease affecting the somatosensory system, is one of the most common complications in diabetic patients. The purpose of this study is to identify genetic factors contributing to this type of pain in a general diabetic population. METHOD: We accessed the Genetics of Diabetes Audit and Research Tayside (GoDARTS) datasets that contain prescription information and monofilament test results for 9439 diabetic patients, among which 6927 diabetic individuals were genotyped by Affymetrix SNP6.0 or Illumina OmniExpress chips. Cases of neuropathic pain were defined as diabetic patients with a prescription history of at least one of five drugs specifically indicated for the treatment of neuropathic pain and in whom monofilament test result was positive for sensory neuropathy in at least one foot. Controls were individuals who did not have a record of receiving any opioid analgesics. Imputation of non-genotyped SNPs was performed by IMPUTE2, with reference files from 1000 Genomes Phase I datasets. RESULTS: After data cleaning and relevant exclusions, imputed genotypes of 572 diabetic neuropathic pain cases and 2491 diabetic controls were used in the Fisher's exact test. We identified a cluster in the Chr8p21.3, next to GFRA2 with a lowest p-value of 1.77 × 10(-7) at rs17428041. The narrow-sense heritability of this phenotype was 11.00%. CONCLUSION: This genome-wide association study on diabetic neuropathic pain suggests new evidence for the involvement of variants near GFRA2 with the disorder, which needs to be verified in an independent cohort and at the molecular level.


Assuntos
Diabetes Mellitus Tipo 2/genética , Neuropatias Diabéticas/genética , Estudo de Associação Genômica Ampla , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Neuralgia/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Neuropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/etiologia , Humanos , Neuralgia/epidemiologia , Neuralgia/etiologia , Escócia/epidemiologia
8.
Clin Pharmacol Ther ; 96(4): 477-81, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24960520

RESUMO

Angioedema is a potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. To study the genetic etiology of this rare adverse event, international consortia and multicenter recruitment of patients are needed. To reduce patient heterogeneity, we have standardized the phenotype. In brief, it comprises swelling in the head and neck region that first occurs during treatment. It should not coincide with urticaria or have another likely cause such as hereditary angioedema.


Assuntos
Angioedema/induzido quimicamente , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Angioedema/classificação , Angioedema/epidemiologia , Bradicinina/metabolismo , Cabeça , Humanos , Pescoço , Fenótipo , Fatores de Risco
9.
Clin Pharmacol Ther ; 96(4): 470-6, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24897241

RESUMO

Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamente , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/classificação , Humanos , Doenças Musculares/classificação , Mialgia/induzido quimicamente , Mialgia/classificação , Miosite/induzido quimicamente , Miosite/classificação , Fenótipo , Rabdomiólise/induzido quimicamente , Rabdomiólise/classificação , Fatores de Risco , Terminologia como Assunto , Fatores de Tempo
10.
Clin Pharmacol Ther ; 95(3): 314-20, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24080640

RESUMO

The association of nonfunctional variants of the cholesteryl ester transfer protein (CETP) with efficacy of statins has been a subject of debate. We evaluated whether three functional CETP variants influence statin efficacy. The effect of CETP genotype on achieved levels of high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), and total cholesterol during statin treatment was estimated by meta-analysis of the linear regression outcomes of three studies (11,021 individuals). The effect of these single-nucleotide polymorphisms (SNPs) on statin response in protecting against myocardial infarction (MI) was estimated by meta-analysis of statin × SNP interaction terms from logistic regression in five studies (16,570 individuals). The enhancer SNP rs3764261 significantly increased HDLc by 0.02 mmol/l per T allele (P = 6 × 10(-5)) and reduced protection against MI by statins (interaction odds ratio (OR) = 1.19 per T allele; P = 0.04). Focusing on functional CETP variants, we showed that in carriers of the rs3764261 T variant, HDLc increased more during statin treatment, and protection against MI by statins appeared to be reduced as compared with those in noncarriers.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Proteínas de Transferência de Ésteres de Colesterol/genética , Colesterol/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Idoso , Doenças Cardiovasculares/tratamento farmacológico , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Ensaios Clínicos Controlados Aleatórios como Assunto , População Branca
11.
Diabet Med ; 30(10): 1230-5, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23586973

RESUMO

AIMS: To replicate the association of genetic variants with estimated glomerular filtration rate (GFR) and albuminuria, which has been found in recent genome-wide studies in patients with Type 2 diabetes. METHODS: We evaluated 16 candidate single nucleotide polymorphisms for estimated GFR in 3028 patients with Type 2 diabetes sampled from clinics across Tayside, Scotland, UK, who were included in the Genetics of Diabetes Audit and Research Tayside (GoDARTs) study. These single nucleotide polymorphisms were tested for their association with estimated GFR at entry to the study, with albuminuria, and with time to stage 3B chronic kidney disease (estimated GFR<45 ml/min/1.73 m(2)). We also stratified the effects on estimated GFR in patients with (n = 2096) and without albuminuria (n = 613). RESULTS: rs1260326 in GCKR (ß=1.30, P = 3.23E-03), rs17319721 in SHROOM3 (ß = -1.28, P-value = 3.18E-03) and rs12917707 in UMOD (ß = 2.0, P-value = 8.84E-04) were significantly associated with baseline estimated GFR. Analysis of effects on estimated GFR, stratified by albuminuria status, showed that in those without albuminuria (normoalbuminura; n = 613), UMOD had a significantly stronger effect on estimated GFR (ß(normo) = 4.03 ± 1.23 vs ß(albuminuria) = 1.72 ± 0.76, P = 0.002) compared with those with albuminuria, while GCKR (ß(normo) = 0.45 ± 0.89 vs ß(albuminuria) = 1.12 ± 0.55, P = 0.08) and SHROOM3 (ß(normo) = -0.07 ± 0.89 vs ß(albuminuria) = -1.43 ± 0.53, P = 0.003) had a stronger effect on estimated GFR in those with albuminuria. UMOD was also associated with a lower rate of transition to stage 3B chronic kidney disease (hazard ratio = 0.83[0.70, 0.99], P = 0.03). CONCLUSION: The genetic variants that regulate estimated GFR in the general population tend to have similar effects in patients with Type 2 diabetes and in this latter population, it is important to adjust for albuminuria status while investigating the genetic determinants of renal function.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Albuminúria , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Taxa de Filtração Glomerular/genética , Insuficiência Renal Crônica/genética , Uromodulina/genética , Albuminúria/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/fisiopatologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Reprodutibilidade dos Testes , Escócia/epidemiologia
12.
Diabetologia ; 55(7): 1971-7, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22453232

RESUMO

AIMS/HYPOTHESIS: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. METHODS: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) ≤ 7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. RESULTS: In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10(-6), respectively). CONCLUSIONS/INTERPRETATION: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.


Assuntos
Replicação do DNA/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Coortes , Replicação do DNA/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Feminino , Estudo de Associação Genômica Ampla , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Masculino , Metformina/farmacologia , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Resultado do Tratamento
13.
Allergy ; 66(12): 1546-52, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21958076

RESUMO

BACKGROUND: The T2206C FCER2 variant was found previously to be associated with IgE levels, exacerbation rates and decreased FCER2 expression in children on inhaled corticosteroids (ICS) participating in a clinical trial. This finding has not been replicated. We sought to replicate the association between the FCER2 gene and exacerbations in children with asthma. In addition, we tested the hypothesis that the T2206C variant may be associated with other markers of steroid resistance such as asthma symptom scores and asthma medication use. METHODS: The influence of the T2206C variant on asthma exacerbations (emergency department visits or hospitalization), symptoms scores and medication use was explored using data from two populations of asthmatic children using ICS: Pharmacogenetics of Asthma medication in Children: Medication with ANti-inflammatory effects study (n = 386) and BREATHE study (n = 939). RESULTS: The T2206C variant was associated with increased risk of asthma-related hospital visits in both cohorts (OR: 1.91, 95% CI: 1.08-3.40), and meta-analysis with previously published results was highly significant (OR: 2.38, 95% CI: 1.47-3.85, P = 0.0004). The FCER2 variant was also associated with increased risk of uncontrolled asthma measured by Asthma Control Questionnaire (OR: 2.64, 95% CI: 1.00-6.98) and was associated with increased daily steroid dose (OR: 2.46, 95% CI: 1.38-4.39). CONCLUSION: The association between the FCER2 T2206C variant and asthma-related hospitalizations in steroid-treated asthma appears robust and may also be associated with other indicators of lack of ICS efficacy such as asthma symptoms and a requirement for higher daily doses of ICS. Our results suggest that the FCER2 T2206C variant might be a useful pharmacogenetic predictor of steroid refractory patients.


Assuntos
Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/genética , Lectinas Tipo C/genética , Polimorfismo de Nucleotídeo Único , Receptores de IgE/genética , Adolescente , Corticosteroides/administração & dosagem , Criança , Pré-Escolar , Progressão da Doença , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Esteroides/uso terapêutico
14.
Diabetologia ; 54(1): 111-9, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20878384

RESUMO

AIMS/HYPOTHESIS: Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ~5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ~0.1%; T130I, MAF ~3.0%)-known to influence downstream HNF-4A target gene expression-are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis. METHODS: We genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls. RESULTS: We found no association between V255M and type 2 diabetes in either the initial (p = 0.28) or the expanded analysis (p = 0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08-1.28]; p = 1.5 × 10⁻4), which was strengthened in the meta-analysis (OR 1.20 [95% CI 1.10-1.30]; p = 2.1 × 10⁻5). CONCLUSIONS/INTERPRETATION: Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants.


Assuntos
Diabetes Mellitus Tipo 2/genética , Fator 4 Nuclear de Hepatócito/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
16.
Clin Pharmacol Ther ; 89(2): 210-6, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21178985

RESUMO

SLCO1B1 gene variants are associated with severe statin-induced myopathy. We examined whether these variants are also associated with general statin intolerance in a large population of patients with type 2 diabetes receiving statins as part of routine clinical care. A total of 4,196 individuals were genotyped for rs4149056 (Val174Ala) and rs2306283 (Asp130Asn). Intolerance was defined by serum biochemistry and also by discontinuation, switching, or reduction in dose of the prescribed statin drug. Ala174 was associated with higher intolerance (odds ratio = 2.05, P = 0.043), whereas Asp130 was associated with lower intolerance (odds ratio = 0.71, P = 0.026). Ala174 was associated with a lower low-density lipoprotein cholesterol (LDLc) response to statins (P = 0.01) whereas 130D was associated with a greater LDLc response to statins (P = 0.048), as previously reported; however, this association was no longer present when data for statin-intolerant individuals were removed from the analysis. This study suggests that common genetic variants selected for an extreme phenotype of statin-induced myopathy also predispose to more common milder statin intolerance and may, for this reason, impact lipid-lowering efficacy.


Assuntos
Diabetes Mellitus Tipo 2/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Transportadores de Ânions Orgânicos/genética , Idoso , LDL-Colesterol/sangue , Feminino , Genótipo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Modelos Logísticos , Masculino , Pessoa de Meia-Idade
17.
Diabetologia ; 53(1): 103-10, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19847392

RESUMO

AIMS/HYPOTHESIS: LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study was to establish the true contribution of this variant and common variants in LARS2 (MAF > 5%) to type 2 diabetes risk. METHODS: We combined genome-wide association data (n = 10,128) from the DIAGRAM consortium with independent data derived from a tagging single nucleotide polymorphism (SNP) approach in Dutch individuals (n = 999) and took forward two SNPs of interest to replication in up to 11,163 Dutch participants (rs17637703 and rs952621). In addition, because inspection of genome-wide association study data identified a cluster of low-frequency variants with evidence of type 2 diabetes association, we attempted replication of rs9825041 (a proxy for this group) and the previously identified H324Q variant in up to 35,715 participants of European descent. RESULTS: No association between the common SNPs in LARS2 and type 2 diabetes was found. Our replication studies for the two low-frequency variants, rs9825041 and H324Q, failed to confirm an association with type 2 diabetes in Dutch, Scandinavian and UK samples (OR 1.03 [95% CI 0.95-1.12], p = 0.45, n = 31,962 and OR 0.99 [0.90-1.08], p = 0.78, n = 35,715 respectively). CONCLUSIONS/INTERPRETATION: In this study, the largest study examining the role of sequence variants in LARS2 in type 2 diabetes susceptibility, we found no evidence to support previous data indicating a role in type 2 diabetes susceptibility.


Assuntos
Aminoacil-tRNA Sintetases/genética , Diabetes Mellitus Tipo 2/enzimologia , Estudo de Associação Genômica Ampla , Idoso , Substituição de Aminoácidos , Aminoacil-tRNA Sintetases/metabolismo , Índice de Massa Corporal , Estudos de Coortes , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Proteínas Mitocondriais/genética , Polimorfismo de Nucleotídeo Único
18.
Clin Pharmacol Ther ; 87(1): 52-6, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19794412

RESUMO

Sulfonylureas are metabolized mainly by the cytochrome p450 2C9 (CYP2C9) enzyme. Two CYP2C9 variants--*2 (Arg144Cys) and *3 (Ile359Leu)--are associated with reduced enzyme activity and impaired substrate metabolism. We identified 1,073 incident users of sulfonylureas in Tayside, Scotland, and assessed the impact of the combined CYP2C9*2 and CYP2C9*3 genotypes on early and sustained sulfonylurea response. We found that patients with two copies of a loss-of-function allele were 3.4 times (P = 0.0009) more likely to achieve a treatment hemoglobin A(1c) (HbA(1c)) level <7% than patients with two wild-type CYP2C9 alleles. This corresponds to a 0.5% (P = 0.003) greater reduction in HbA(1c) concentration. In addition, *2 and *3 allele carriers were less likely to experience treatment failure with sulfonylurea monotherapy (P = 0.04; per-allele hazard ratio 0.79; 95% confidence interval 0.63-0.99). In conclusion, CYP2C9 loss-of-function alleles are associated with greater response to sulfonylureas and decreased failure of therapy consistent with the pharmacokinetic role of CYP2C9.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Variação Genética/genética , Compostos de Sulfonilureia/uso terapêutico , Idoso , Alelos , Hidrocarboneto de Aril Hidroxilases/farmacocinética , Citocromo P-450 CYP2C9 , Bases de Dados Genéticas , Diabetes Mellitus Tipo 2/enzimologia , Feminino , Variação Genética/efeitos dos fármacos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escócia
19.
Diabet Med ; 26(5): 460-5, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19646183

RESUMO

AIMS: The Y402H variant of complement factor H (CFH) is associated with risk of age-related macular degeneration (ARMD). In common with ARMD, diabetic retinal disease also appears to involve complement activation. The aim was to investigate the impact of Y402H on both retinal pathologies in patients with Type 2 diabetes (T2DM) undergoing systematic eye screening. METHODS: Patients with T2DM (n = 2350) were genotyped for the CFH Y402H variant. The association of genotype with retinal disease was determined in both retrospective and prospective models. RESULTS: The retrospective study demonstrated that the HH genotype was associated with an age-adjusted odds ratio of 7.4 for ARMD (P = 2.9 x 10(-11)). In a longitudinal study in the disease-free cohort, the age-adjusted hazard ratio was 2.8 (P = 2.4 x 10(-7)). The life-time hazard ratio was 3.4 (P = 2.1 x 10(-16)). We found no association of Y402H with development of referable diabetic retinal disease. CONCLUSION: The ARMD-associated Y402H variant in CFH does not appear to be associated with diabetic retinal disease, although complement activation is involved in the pathoaetiology of both conditions.


Assuntos
Fator H do Complemento/genética , Diabetes Mellitus Tipo 2/genética , Retinopatia Diabética/genética , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/epidemiologia , Retinopatia Diabética/patologia , Métodos Epidemiológicos , Feminino , Genótipo , Humanos , Degeneração Macular/patologia , Masculino , Pessoa de Meia-Idade
20.
Allergy ; 64(2): 304-11, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19133922

RESUMO

BACKGROUND: Eczema is a common chronic inflammatory skin disorder which shows strong genetic predisposition. To identify new potential molecular determinants of the disease pathogenesis, we performed a gene expression study in an eczema mouse model. This analysis identified a marked down regulation of the cornulin gene (CRNN), a member of the epidermal differentiation complex, in the eczema-like skin. We then investigated CRNN as an eczema candidate gene and studied its polymorphism and the expression in the skin of eczema patients. METHODS: An eczema-like phenotype was induced in mice by allergen (Der p2) patching. Gene expression analysis was performed with the subtractive suppression hybridization method and validated by real time PCR and the transmission disequilibrium test was used to test for genetic associations in 406 multiplex eczema families. RESULTS: Der p 2 patched mice developed a localized eczema and a Th 2 skewed systemic response. Real time PCR analysis confirmed a down regulation of CRNN mRNA in eczema-like skin in the mouse model and in human eczema. The CRNN polymorphism rs941934 was significantly associated with atopic eczema in the genetic analysis (P = 0.006), though only as part of an extended haplotype including a known associated variant (2282del4) in the filaggrin gene. CONCLUSIONS: CRNN mRNA expression is decreased in eczematous skin. Further studies are needed to verify whether the associated cornulin polymorphism contribute to the genetic susceptibility in eczema.


Assuntos
Dermatite Atópica/genética , Regulação para Baixo/genética , Epiderme/imunologia , Predisposição Genética para Doença , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Adulto , Alérgenos/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Proteínas de Artrópodes , Citocinas/biossíntese , Citocinas/imunologia , Dermatite Atópica/imunologia , Epiderme/efeitos dos fármacos , Epiderme/patologia , Feminino , Proteínas Filagrinas , Expressão Gênica , Regulação da Expressão Gênica , Marcadores Genéticos , Genótipo , Haplótipos , Humanos , Imunoglobulina E/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Psoríase/diagnóstico , Psoríase/genética , Psoríase/imunologia
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