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1.
Pharmacogenomics J ; 20(3): 482-493, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31806883

RESUMO

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.


Assuntos
Negro ou Afro-Americano/genética , Diuréticos/sangue , Variação Genética/genética , Hipertensão/sangue , Hipertensão/genética , População Branca/genética , Diuréticos/efeitos adversos , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/tratamento farmacológico , Lipídeos/sangue
2.
Mol Psychiatry ; 21(5): 601-7, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26239294

RESUMO

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.


Assuntos
Negro ou Afro-Americano/genética , Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , Receptores Nicotínicos/genética , Tabagismo/etnologia , Tabagismo/genética , População Branca/genética , Adulto , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade
3.
Trop Anim Health Prod ; 29(2): 108-16, 1997 May.
Artigo em Inglês | MEDLINE | ID: mdl-9203313

RESUMO

Records from a large commercial Jersey herd covering the period 1980 to 1993 were used to estimate genetic and environmental trends in production traits, fertility traits and age at first calving. The farm is located in the upper midland agroecological zone of the Central Rift Valley in Kenya. The estimated annual genetic trends were 0.8 kg (milk yield), 0.003% (butterfat per cent), 0.09 kg (butter fat yield), 0 d (calving interval), -0.001 (number of services per conception), 0.22% (conception rate) and -0.5 d (age at first calving). All the traits studied showed an environmental trend in the desired direction: 14.6 kg (milk yield), 0.029% (butterfat per cent), 1.31 kg (butterfat yield), -2.52 d (calving interval), -0.62 (number of services per conception), 0.89% (conception rate), and -17 d (age at first calving). Despite great genetic variation in the production traits, the genetic trend in all traits was very small reflecting ineffective selection, whereas the results for the environmental trends indicate a substantial improvement in the management.


Assuntos
Criação de Animais Domésticos , Bovinos/genética , Meio Ambiente , Criação de Animais Domésticos/tendências , Animais , Cruzamento , Bovinos/metabolismo , Bovinos/fisiologia , Feminino , Variação Genética , Quênia , Lactação/genética , Lactação/fisiologia , Leite/química , Leite/metabolismo , Modelos Biológicos , Paridade , Gravidez , Taxa de Gravidez , Reprodutibilidade dos Testes , Reprodução/genética , Reprodução/fisiologia , Sensibilidade e Especificidade , Clima Tropical
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