RESUMEN
Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10-11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
Asunto(s)
Enfermedad , Frecuencia de los Genes , Fenotipo , Humanos , Persona de Mediana Edad , Enfermedad/genética , Estonia , Finlandia , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Metaanálisis como Asunto , Reino Unido , Población Blanca/genéticaRESUMEN
Acute kidney injury (AKI) is a syndrome that frequently affects the critically ill. Recently, an increased number of dinucleotide repeats in the HMOX1 gene were reported to associate with development of AKI in cardiac surgery. We aimed to test the replicability of this finding in a Finnish cohort of critically ill septic patients. This multicenter study was part of the national FINNAKI study. We genotyped 300 patients with severe AKI (KDIGO 2 or 3) and 353 controls without AKI (KDIGO 0) for the guanine-thymine (GTn) repeat in the promoter region of the HMOX1 gene. The allele calling was based on the number of repeats, the cut off being 27 repeats in the S-L (short to long) classification, and 27 and 34 repeats for the S-M-L2 (short to medium to very long) classification. The plasma concentrations of heme oxygenase-1 (HO-1) enzyme were measured on admission. The allele distribution in our patients was similar to that published previously, with peaks at 23 and 30 repeats. The S-allele increases AKI risk. An adjusted OR was 1.30 for each S-allele in an additive genetic model (95% CI 1.01-1.66; p = 0.041). Alleles with a repeat number greater than 34 were significantly associated with lower HO-1 concentration (p<0.001). In septic patients, we report an association between a short repeat in HMOX1 and AKI risk.
Asunto(s)
Lesión Renal Aguda/genética , Hemo-Oxigenasa 1/genética , Repeticiones de Minisatélite , Polimorfismo Genético , Sepsis/genética , Lesión Renal Aguda/enzimología , Lesión Renal Aguda/epidemiología , Anciano , Alelos , Estudios de Cohortes , Comorbilidad , Enfermedad Crítica , Femenino , Finlandia/epidemiología , Predisposición Genética a la Enfermedad , Genotipo , Hemo-Oxigenasa 1/sangre , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas , Estudios Prospectivos , Factores de Riesgo , Sepsis/enzimología , Sepsis/epidemiologíaRESUMEN
AIM: To replicate the genome-wide associations of the antihypertensive effects of bisoprolol and losartan in GENRES, using the Finnish patients of LIFE study. PATIENTS & METHODS: We analyzed association of four SNPs with atenolol and three SNPs with losartan response in 927 Finnish LIFE patients (467 for atenolol and 460 for losartan). RESULTS: rs2514036, a variation at a transcription start site of ACY3, was associated with blood pressure response to atenolol in men in LIFE. Response to bisoprolol was correlated to baseline plasma levels of N-acetylphenylalanine and phenylalanine (ACY3 substrate and end product, respectively) in GENRES study. NPHS1 variation rs3814995 was associated with losartan effect in LIFE. CONCLUSION: We provide support for two pharmacogenomic markers for beta-blockers and angiotensin receptor antagonists.
Asunto(s)
Amidohidrolasas/genética , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Variación Genética/genética , Proteínas de la Membrana/genética , Anciano , Anciano de 80 o más Años , Estudios Cruzados , Método Doble Ciego , Finlandia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Valor Predictivo de las Pruebas , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Identification of genetic markers of antihypertensive drug responses could assist in individualization of hypertension treatment. METHODS AND RESULTS: We conducted a genome-wide association study to identify gene loci influencing the responsiveness of 228 male patients to 4 classes of antihypertensive drugs. The Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study is a double-blind, placebo-controlled cross-over study where each subject received amlodipine, bisoprolol,hydrochlorothiazide, and losartan, each as a monotherapy, in a randomized order. Replication analyses were performed in 4 studies with patients of European ancestry (PEAR Study, N=386; GERA I and II Studies, N=196 and N=198; SOPHIA Study, N=372). We identified 3 single-nucleotide polymorphisms within the ACY3 gene that showed associations with bisoprolol response reaching genome-wide significance (P<5x10(-8))however, this could not be replicated in the PEAR Study using atenolol. In addition, 39 single-nucleotide polymorphisms showed P values of 10(-5) to 10(-7). The 20 top-associated single-nucleotide polymorphisms were different for each antihypertensive drug. None of these top single-nucleotide polymorphisms co-localized with the panel of >40 genes identified in genome-wide association studies of hypertension. Replication analyses of GENRES results provided suggestive evidence for a missense variant (rs3814995) in the NPHS1 (nephrin) gene influencing losartan response, and for 2 variants influencing hydrochlorothiazide response, located within or close to the ALDH1A3 (rs3825926) and CLIC5 (rs321329) genes. CONCLUSIONS: These data provide some evidence for a link between biology of the glomerular protein nephrin and antihypertensive action of angiotensin receptor antagonists and encourage additional studies on aldehyde dehydrogenasemediated reactions in antihypertensive drug action.
Asunto(s)
Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Proteínas de la Membrana/genética , Farmacogenética/métodos , Adulto , Aldehído Oxidorreductasas/genética , Amlodipino/uso terapéutico , Antihipertensivos/farmacología , Bencimidazoles/uso terapéutico , Compuestos de Bifenilo , Bisoprolol/uso terapéutico , Monitoreo Ambulatorio de la Presión Arterial , Canales de Cloruro/genética , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Hipertensión Esencial , Finlandia , Estudio de Asociación del Genoma Completo , Humanos , Hidroclorotiazida/uso terapéutico , Hipertensión/diagnóstico , Losartán/uso terapéutico , Masculino , Metaanálisis como Asunto , Proteínas de Microfilamentos/genética , Persona de Mediana Edad , Mutación Missense , Polimorfismo de Nucleótido Simple , Índice de Severidad de la Enfermedad , Tetrazoles/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Thiazide diuretics have been recommended as a first-line antihypertensive treatment, although the choice of 'the right drug in the individual essential hypertensive patient' remains still empirical. Essential hypertension is a complex, polygenic disease derived from the interaction of patient's genetic background with the environment. Pharmacogenomics could be a useful tool to pinpoint gene variants involved in antihypertensive drug response, thus optimizing therapeutic advantages and minimizing side effects. METHODS AND RESULTS: We looked for variants associated with blood pressure response to hydrochlorothiazide over an 8-week follow-up by means of a genome-wide association analysis in two Italian cohorts of never-treated essential hypertensive patients: 343 samples from Sardinia and 142 from Milan. TET2 and CSMD1 as plausible candidate genes to affect SBP response to hydrochlorothiazide were identified. The specificity of our findings for hydrochlorothiazide was confirmed in an independent cohort of essential hypertensive patients treated with losartan. Our best findings were also tested for replication in four independent hypertensive samples of European Ancestry, such as GENetics of drug RESponsiveness in essential hypertension, Genetic Epidemiology of Responses to Antihypertensives, NORdic DILtiazem intervention, Pharmacogenomics Evaluation of Antihypertensive Responses, and Campania Salute Network-StayOnDiur. We validated a polymorphism in CSMD1 and UGGT2. CONCLUSION: This exploratory study reports two plausible loci associated with SBP response to hydrochlorothiazide: TET2, an aldosterone-responsive mediator of αENaC gene transcription; and CSMD1, previously described as associated with hypertension in a case-control study.
Asunto(s)
Antihipertensivos/uso terapéutico , Proteínas de Unión al ADN/genética , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas/genética , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Adulto , Anciano , Aldosterona/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Estudios de Casos y Controles , Dioxigenasas , Hipertensión Esencial , Estudio de Asociación del Genoma Completo , Humanos , Italia , Losartán/uso terapéutico , Masculino , Persona de Mediana Edad , Farmacogenética , Sístole/genética , Proteínas Supresoras de Tumor , Población BlancaRESUMEN
OBJECTIVE: The aim of this study is to identify single-nucleotide polymorphisms (SNPs) influencing blood pressure (BP) response to the ß-blocker atenolol. METHODS: Genome-wide association analysis of BP response to atenolol monotherapy was performed in 233 white participants with uncomplicated hypertension in the pharmacogenomic evaluation of antihypertensive responses study. Forty-two polymorphisms with P less than 10 for association with either diastolic or systolic response to atenolol monotherapy were validated in four independent groups of hypertensive individuals (total nâ=â2114). RESULTS: In whites, two polymorphisms near the gene PTPRD (rs12346562 and rs1104514) were associated with DBP response to atenolol (Pâ=â3.2â×â10 and Pâ=â5.9â×â10, respectively) with directionally opposite association for response to hydrochlorothiazide in another group of 228 whites (Pâ=â0.0018 and Pâ=â0.00012). A different polymorphism (rs10739150) near PTPRD was associated with response to atenolol in 150 black hypertensive individuals (Pâ=â8.25â×â10). rs12346562 had a similar trend in association with response to bisoprolol (a different ß-blocker) in 207 Finnish men in the genetics of drug responsiveness in essential hypertension study. In addition, an intronic single-nucleotide polymorphism (rs4742610) in the PTPRD gene was associated with resistant hypertension in whites and Hispanics in the international verapamil SR trandolapril study (meta-analysis Pâ=â3.2â×â10). CONCLUSION: PTPRD was identified as a novel locus potentially associated with BP response to atenolol and resistant hypertension in multiple ethnic groups.
Asunto(s)
Antihipertensivos/uso terapéutico , Atenolol/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Hipertensión/tratamiento farmacológico , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/genética , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Anciano , Población Negra/genética , Hipertensión Esencial , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Hipertensión/genética , Masculino , Persona de Mediana Edad , Farmacogenética , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
OBJECTIVE: Generalized glucocorticoid resistance is characterized by impaired cortisol signaling, resulting from mutations of the glucocorticoid receptor (GR) gene NR3C1. The objective of our study was to identify the causative mutation in a patient with clinical manifestations compatible with generalized glucocorticoid resistance and to determine the functional consequences of the mutation. The possible occurrence of NR3C1 mutations in a selected group of hypertensive subjects with low plasma renin and aldosterone levels was also explored. PATIENTS: The proband, a male athlete, was diagnosed with hypertension associated with low plasma renin activity and low serum aldosterone concentration at the age of 27 years. Liddle's syndrome was suspected and the patient was treated with amiloride with initial success. Subsequent examinations revealed elevated serum cortisol and ACTH levels, with resistance to suppression with low doses of dexamethasone. After identification of an NR3C1 mutation in the proband, the available family members and 51 nonrelated hypertensive subjects with low plasma renin and aldosterone concentrations were also studied. RESULTS: A two-nucleotide deletion in exon 9α, predicted to cause a frameshift mutation (p.L773VfsX25) in the hormone-binding domain of the GR, was identified in the patient in a heterozygous form. Affected brother and father died of premature coronary heart disease. Functional studies in COS-1 cells showed that this mutation eliminates both ligand-binding and transactivation ability of the receptor. No pathogenic NR3C1 mutations were identified in 51 unrelated hypertensive patients with low plasma renin and aldosterone levels. CONCLUSION: We identified a novel frameshift mutation in NR3C1 as the cause of glucocorticoid resistance. The mutation eliminates the functional activity of the GR, as studied by in vitro experiments. Mutations in NR3C1 do not seem to be common causes for hypertension with low renin and aldosterone levels.
Asunto(s)
Aldosterona/sangre , Hipertensión/genética , Errores Innatos del Metabolismo/genética , Receptores de Glucocorticoides/genética , Renina/sangre , Adulto , Animales , Secuencia de Bases , Células COS , Enfermedad de la Arteria Coronaria/genética , Femenino , Mutación del Sistema de Lectura , Humanos , Masculino , Receptores de Glucocorticoides/deficiencia , Eliminación de SecuenciaRESUMEN
To identify novel genes influencing blood pressure response to thiazide diuretic therapy for hypertension, we conducted genome-wide association meta-analyses of ≈1.1 million single-nucleotide polymorphisms in a combined sample of 424 European Americans with primary hypertension treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses study (n=228) and the Genetic Epidemiology of Responses to Antihypertensive study (n=196). Polymorphisms associated with blood pressure response at P<10(-5) were tested for replication of the associations in independent samples of hydrochlorothiazide-treated European hypertensives. The rs16960228 polymorphism in protein kinase C, α replicated for same-direction association with diastolic blood pressure response in the Nordic Diltiazem study (n=420) and the Genetics of Drug Responsiveness in Essential Hypertension study (n=206), and the combined 4-study meta-analysis P value achieved genome-wide significance (P=3.3 × 10(-8)). Systolic or diastolic blood pressure responses were consistently greater in carriers of the rs16960228 A allele than in GG homozygotes (>4/4 mm Hg) across study samples. The rs2273359 polymorphism in the GNAS-EDN3 region also replicated for same-direction association with systolic blood pressure response in the Nordic Diltiazem study, and the combined 3-study meta-analysis P value approached genome-wide significance (P=5.5 × 10(-8)). The findings document clinically important effects of genetic variation at novel loci on blood pressure response to a thiazide diuretic, which may be a basis for individualization of antihypertensive drug therapy and identification of new drug targets.
Asunto(s)
Antihipertensivos/uso terapéutico , Diuréticos/uso terapéutico , Estudio de Asociación del Genoma Completo , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Polimorfismo de Nucleótido Simple , Adulto , Atenolol/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Cromosomas Humanos Par 17 , Femenino , Humanos , Hipertensión/genética , Masculino , Persona de Mediana Edad , Proteína Quinasa C-alfa/genética , Factores de Transcripción/genéticaRESUMEN
Large-scale genome-wide association studies (GWASs) have identified significant associations of common genetic variants with blood pressure (BP) levels. To obtain more evidence for the role of these variants in BP regulation, we studied their association with BP responses to four different antihypertensive drug monotherapies. We selected 19 single-nucleotide variants based on data from five GWASs. The study group consisted of more than 200 hypertensive Finnish men from the GENRES study. Ambulatory BP responses to 4-week treatments with losartan, bisoprolol, hydrochlorothiazide and amlodipine were the primary targets of the study. Secondarily, baseline indicators of the activity of the renin-angiotensin-aldosterone system were studied. After correction for multiple comparisons, the variant rs6749447 in the STK39 gene was significantly associated with BP responses. Thus, the minor rs6749447 allele was associated with a lower systolic and diastolic BP response to losartan (P=0.0005 and 0.0002, respectively). rs6749447 minor allele homozygotes had marginally higher serum aldosterone/plasma renin activity (PRA) ratios (P=0.04) than those without this allele. In a replication study on aldosterone and renin levels, another cohort of hypertensive patients (n=311) showed a similar trend. When the two cohorts were combined, the aldosterone level (P=0.02) and the aldosterone/PRA ratio (P=0.01) were higher in subjects homozygous for the minor rs6749447 allele than in other subjects. The present study shows that pharmacogenetic approaches may provide evidence that complements systematic genome-wide strategies by identifying gene loci that not only affect the BP level but also might modify its response to pharmacologic interventions.
Asunto(s)
Antihipertensivos/uso terapéutico , Monitoreo Ambulatorio de la Presión Arterial , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Losartán/uso terapéutico , Proteínas Serina-Treonina Quinasas/genética , Adulto , Alelos , Amlodipino/farmacología , Amlodipino/uso terapéutico , Antihipertensivos/farmacología , Bisoprolol/farmacología , Bisoprolol/uso terapéutico , Genotipo , Humanos , Hidroclorotiazida/farmacología , Hidroclorotiazida/uso terapéutico , Losartán/farmacología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Two variants of the CYP2C9 gene, CYP2C9*2 and CYP2C9*3, have been indicated to have impaired enzyme function, and thus suspected to reduce the formation of the active metabolite of losartan. Cytochrome P450 (CYP) enzymes are also involved in eicosanoid biosynthesis and regulation of blood pressure (BP) and sodium homeostasis. METHODS: We studied the impact of these variants on BP response to losartan and three other antihypertensive drugs and on baseline indicators of the activity of the renin-angiotensin-aldosterone system. The participants were 217 moderately hypertensive Finnish men that participated in the double-blind, cross-over, placebo-controlled GENRES Study. RESULTS: BP responses to losartan did not differ between CYP2C9*2 or CYP2C9*3 allele carriers and CYP2C9*1*1 patients. A suggestive finding of less pronounced ambulatory BP response to losartan in CYP2C9*1*3 patients with low-normal kidney function was made. At baseline of the GENRES Study, CYP2C9*1*3 patients had significantly lower plasma renin activity and aldosterone levels than CYP2C9*1*1 patients (both P values 0.004). In a replication study in patients with treatment-resistant hypertension, men with CYP2C9*3 allele also had lower plasma renin activity (P = 0.03) and aldosterone levels (P = 0.18). In addition, these men had attenuated renin and aldosterone responses in captopril challenge test (P = 0.29 and 0.006, respectively). CONCLUSION: The CYP2C9*3 allele was associated with lower activity of the renin-angiotensin-aldosterone system in hypertensive men, which may reflect a more efficient sodium reabsorption capacity. CYP2C9*2 and CYP2C9*3 alleles do not influence the antihypertensive effect of losartan in men with essential hypertension and normal kidney function.