RESUMEN
Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
Asunto(s)
Sitios Genéticos , Hipertensión/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Adulto , Anciano , Presión Sanguínea/genética , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , ATPasas Transportadoras de Calcio de la Membrana Plasmática/genética , Polimorfismo de Nucleótido Simple , Receptores del Factor Natriurético Atrial/genética , Análisis de Secuencia de ADNRESUMEN
Systemic lupus erythematosus (SLE) is an autoimmune disease which behaves as a complex genetic trait. At least 20 SLE risk susceptibility loci have been mapped using both candidate gene and genome-wide association strategies. The gene encoding the pro-inflammatory cytokine, IL18, has been reported as a candidate gene showing an association with SLE. This pleiotropic cytokine is expressed in a range of immune cells and has been shown to induce interferon-γ and tumour necrosis factor-α. Serum interleukin-18 has been reported to be elevated in patients with SLE. Here we aimed to densely map single nucleotide polymorphisms (SNPs) across IL18 to investigate the association across this locus. We genotyped 36 across IL18 by Illumina bead express in 372 UK SLE trios. We also genotyped these SNPs in a further 508 non-trio UK cases and were able to accurately impute a dense marker set across IL18 in WTCCC2 controls with a total of 258 SNPs. To improve the study's power, we also imputed a total of 158 SNPs across the IL18 locus using data from an SLE genome-wide association study and performed association testing. In total, we analysed 1818 cases and 10 770 controls in this study. Our large well-powered study (98% to detect odds ratio = 1.5, with respect to rs360719) showed that no individual SNP or haplotype was associated with SLE in any of the cohorts studied. We conclude that we were unable to replicate the SLE association with rs360719 located upstream of IL18. No evidence for association with any other common variant at IL18 with SLE was found.
Asunto(s)
Interleucina-18/genética , Lupus Eritematoso Sistémico/genética , Secuencia de Bases , Estudios de Casos y Controles , Estudios de Cohortes , Estudio de Asociación del Genoma Completo , Genotipo , Haplotipos , Humanos , Datos de Secuencia Molecular , Polimorfismo de Nucleótido SimpleRESUMEN
To understand the genetic predisposition to selective immunoglobulin A deficiency (IgAD), we performed a genome-wide association study in 430 affected individuals (cases) from Sweden and Iceland and 1,090 ethnically matched controls, and we performed replication studies in two independent European cohorts. In addition to the known association of HLA with IgAD, we identified association with a nonsynonymous variant in IFIH1 (rs1990760G>A, P = 7.3 x 10(-10)) which was previously associated with type 1 diabetes and systemic lupus erythematosus. Variants in CLEC16A, another known autoimmunity locus, showed suggestive evidence for association (rs6498142C>G, P = 1.8 x 10(-7)), and 29 additional loci were identified with P < 5 x 10(-5). A survey in IgAD of 118 validated non-HLA autoimmunity loci indicated a significant enrichment for association with autoimmunity loci as compared to non-autoimmunity loci (P = 9.0 x 10(-4)) or random SNPs across the genome (P < 0.0001). These findings support the hypothesis that autoimmune mechanisms may contribute to the pathogenesis of IgAD.
Asunto(s)
Autoinmunidad/genética , ARN Helicasas DEAD-box/genética , Deficiencia de IgA/genética , Alelos , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/genética , Estudios de Casos y Controles , Finlandia , Ligamiento Genético , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Islandia , Deficiencia de IgA/etiología , Deficiencia de IgA/inmunología , Helicasa Inducida por Interferón IFIH1 , Riesgo , España , Suecia , Estudios de Validación como AsuntoRESUMEN
Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 x 10(-8)): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P< or = 1 x 10(-5). A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 x 10(-3)) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.
Asunto(s)
Replicación del ADN , Proteínas de Unión al ADN/genética , Interleucina-10/genética , Lupus Eritematoso Sistémico/genética , Proteínas de Neoplasias/genética , Proteínas Represoras/genética , Proteínas Co-Represoras , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido Simple , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Factores de RiesgoRESUMEN
The QT interval, a measure of cardiac repolarization, predisposes to ventricular arrhythmias and sudden cardiac death (SCD) when prolonged or shortened. A common variant in NOS1AP is known to influence repolarization. We analyze genome-wide data from five population-based cohorts (ARIC, KORA, SardiNIA, GenNOVA and HNR) with a total of 15,842 individuals of European ancestry, to confirm the NOS1AP association and identify nine additional loci at P < 5 x 10(-8). Four loci map near the monogenic long-QT syndrome genes KCNQ1, KCNH2, SCN5A and KCNJ2. Two other loci include ATP1B1 and PLN, genes with established electrophysiological function, whereas three map to RNF207, near LITAF and within NDRG4-GINS3-SETD6-CNOT1, respectively, all of which have not previously been implicated in cardiac electrophysiology. These results, together with an accompanying paper from the QTGEN consortium, identify new candidate genes for ventricular arrhythmias and SCD.
Asunto(s)
Arritmias Cardíacas/genética , Variación Genética , Canales Iónicos/genética , Síndrome de QT Prolongado/genética , Mapeo Cromosómico , Canal de Potasio ERG1 , Electrocardiografía , Electrofisiología/métodos , Canales de Potasio Éter-A-Go-Go/genética , Corazón/fisiología , Corazón/fisiopatología , Humanos , Canal de Potasio KCNQ1/genética , Proteínas Musculares/genética , Canal de Sodio Activado por Voltaje NAV1.5 , Canales de Potasio de Rectificación Interna/genética , Reproducibilidad de los Resultados , Canales de Sodio/genéticaRESUMEN
To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.
Asunto(s)
Glucemia/genética , Ayuno/sangre , Polimorfismo de Nucleótido Simple/genética , Receptor de Melatonina MT2/genética , Receptores de Melatonina/genética , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatología , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Metaanálisis como Asunto , Sitios de Carácter Cuantitativo/genéticaRESUMEN
Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.