RESUMO
Hypokalemia is a recognized adverse effect of thiazide diuretic treatment. This phenomenon, which may impair insulin secretion, has been suggested to be a reason for the adverse effects on glucose metabolism associated with thiazide diuretic treatment of hypertension. However, the mechanisms underlying thiazide diuretic-induced hypokalemia are not well understood. In an effort to identify genes or genomic regions associated with potassium response to hydrochlorothiazide, without a priori knowledge of biologic effects, we performed a genome-wide association study and a multiethnic meta-analysis in 718 European- and African-American hypertensive participants from two different pharmacogenetic studies. Single-nucleotide polymorphisms rs10845697 (Bayes factor=5.560) on chromosome 12, near to the HEME binding protein 1 gene, and rs11135740 (Bayes factor=5.258) on chromosome 8, near to the Mitoferrin-1 gene, reached genome-wide association study significance (Bayes factor >5). These results, if replicated, suggest a novel mechanism involving effects of genes in the HEME pathway influencing hydrochlorothiazide-induced renal potassium loss.
Assuntos
Anti-Hipertensivos/uso terapêutico , Proteínas de Transporte/genética , Heme/genética , Hemeproteínas/genética , Hidroclorotiazida/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Potássio/metabolismo , Negro ou Afro-Americano/genética , Teorema de Bayes , Proteínas de Transporte de Cátions/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 8/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Proteínas Ligantes de Grupo Heme , Humanos , Hidroclorotiazida/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/genética , Hipertensão/metabolismo , Hipopotassemia/tratamento farmacológico , Hipopotassemia/genética , Hipopotassemia/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , População Branca/genéticaRESUMO
Hydrochlorothiazide (HCTZ) is one of the most widely prescribed antihypertensive medications. Although it is well known that HCTZ is associated with hyperglycemia and hypertriglyceridemia, the mechanisms underlying these adverse effects are not well understood. We performed a genome-wide association study and meta-analysis of the change in fasting plasma glucose and triglycerides in response to HCTZ from two different clinical trials: the Pharmacogenomic Evaluation of Antihypertensive Responses and the Genetic Epidemiology of Responses to Antihypertensive studies. Two single-nucleotide polymorphisms (rs12279250 and rs4319515 (r(2)=0.73)), located at 11p15.1 in the NELL1 gene, achieved genome-wide significance for association with change in fasting plasma triglycerides in African Americans, whereby each variant allele was associated with a 28 mg dl(-1) increase in the change in triglycerides. NELL1 encodes a cytoplasmic protein that contains epidermal growth factor-like repeats and has been shown to represses adipogenic differentiation. These findings may represent a novel mechanism underlying HCTZ-induced adverse metabolic effects.
Assuntos
Anti-Hipertensivos/efeitos adversos , Negro ou Afro-Americano/genética , Hidroclorotiazida/efeitos adversos , Hipertensão/tratamento farmacológico , Metabolismo dos Lipídeos/genética , Proteínas do Tecido Nervoso/genética , Adipogenia/genética , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Glicemia/análise , Proteínas de Ligação ao Cálcio , Estudo de Associação Genômica Ampla , Humanos , Hidroclorotiazida/administração & dosagem , Hidroclorotiazida/uso terapêutico , Hipertensão/genética , Hipertensão/metabolismo , Triglicerídeos/sangueRESUMO
Thiazide-induced potassium loss may contribute to new onset diabetes (NOD). KCNJ1 encodes a potassium channel and one study observed that a KCNJ1 single-nucleotide polymorphism (SNP) was associated with changes in fasting glucose (FG) during hydrochlorothiazide (HCTZ) treatment. We used linear regression to test association of KCNJ1 SNPs and haplotypes with FG changes during HCTZ treatment in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. We used logistic regression to test association of KCNJ1 variation with NOD in HCTZ-treated patients from the International Verapamil SR Trandolapril Study (INVEST). Multivariate regression analyses were performed by race/ethnicity with false discovery rate (FDR) correction. In PEAR blacks, a KCNJ1 SNP was associated with increased FG during HCTZ treatment (beta=8.47, P(FDR)=0.009). KCNJ1 SNPs and haplotypes were associated with NOD risk in all INVEST race/ethnic groups (strongest association: odds ratio 2.14 (1.31-3.53), P(FDR)=0.03). Our findings support that KCNJ1 variation is associated with HCTZ-induced dysglycemia and NOD.
