RESUMEN
We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13-1.27), P = 7.7 x 10(-9)) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11-1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31-1.72) and 1.55 (1.23-1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.
Asunto(s)
Proteínas Portadoras/genética , Diabetes Mellitus Tipo 2/genética , Resistencia a la Insulina/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple , Adulto , Glucemia/metabolismo , Estudios de Casos y Controles , Estudios Transversales , Femenino , Frecuencia de los Genes , Genoma Humano , Humanos , Insulina/metabolismo , Secreción de Insulina , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Factores de Transcripción TCF/genética , Proteína 1 Similar al Factor de Transcripción 7 , Proteína 2 Similar al Factor de Transcripción 7RESUMEN
Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions, with African American men having among the highest worldwide incidence and mortality rates. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered, accounts for about 11%-13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%-4%) susceptibility variant in individuals of European descent that happens to be very common (approximately 42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.
Asunto(s)
Cromosomas Humanos Par 8/genética , Ligamiento Genético , Predisposición Genética a la Enfermedad/genética , Variación Genética , Neoplasias de la Próstata/genética , Negro o Afroamericano , Europa (Continente) , Genómica/métodos , Haplotipos/genética , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Estados Unidos , Población BlancaRESUMEN
We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.
Asunto(s)
Cromosomas Humanos Par 17 , Diabetes Mellitus Tipo 2/genética , Factor Nuclear 1-beta del Hepatocito/genética , Neoplasias de la Próstata/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.
Asunto(s)
Población Negra/genética , Neoplasias de la Próstata/genética , Población Blanca/genética , Alelos , Humanos , Masculino , Repeticiones de Microsatélite/genética , Polimorfismo de Nucleótido SimpleRESUMEN
A refined physical map of chromosome 17q21.31 uncovered a 900-kb inversion polymorphism. Chromosomes with the inverted segment in different orientations represent two distinct lineages, H1 and H2, that have diverged for as much as 3 million years and show no evidence of having recombined. The H2 lineage is rare in Africans, almost absent in East Asians but found at a frequency of 20% in Europeans, in whom the haplotype structure is indicative of a history of positive selection. Here we show that the H2 lineage is undergoing positive selection in the Icelandic population, such that carrier females have more children and have higher recombination rates than noncarriers.
Asunto(s)
Inversión Cromosómica , Cromosomas Humanos Par 17 , Selección Genética , Población Blanca/genética , Femenino , Frecuencia de los Genes , Haplotipos , Humanos , Islandia , Datos de Secuencia Molecular , Filogenia , Mapeo Físico de Cromosoma , Polimorfismo Genético , Recombinación GenéticaRESUMEN
A major task in human genetics is to understand the nature of the evolutionary processes that have shaped the gene pools of contemporary populations. Ancient DNA studies have great potential to shed light on the evolution of populations because they provide the opportunity to sample from the same population at different points in time. Here, we show that a sample of mitochondrial DNA (mtDNA) control region sequences from 68 early medieval Icelandic skeletal remains is more closely related to sequences from contemporary inhabitants of Scotland, Ireland, and Scandinavia than to those from the modern Icelandic population. Due to a faster rate of genetic drift in the Icelandic mtDNA pool during the last 1,100 years, the sequences carried by the first settlers were better preserved in their ancestral gene pools than among their descendants in Iceland. These results demonstrate the inferential power gained in ancient DNA studies through the application of population genetics analyses to relatively large samples.
Asunto(s)
ADN Mitocondrial/química , Evolución Molecular , Pool de Genes , Genética de Población , Geografía , Humanos , Islandia , Análisis de Secuencia de ADNRESUMEN
The alpha(V) integrins are key receptors involved in mediating cell migration and angiogenesis. In age-related macular degeneration (AMD) and diabetic retinopathy, angiogenesis plays a critical role in the loss of vision. These ocular vasculopathies might be treatable with a suitable alpha(V) antagonist, and an oral drug would offer a distinct advantage over current therapies. (3,S,beta,S)-1,2,3,4-Tetrahydro-beta-[[1-[1-oxo-3-(1,5,6,7-tetrahydro-1,8-naphthyridin-2-yl)propyl]-4-piperidinyl]methyl]-3-quinolinepropanoic acid (JNJ-26076713) is a potent, orally bioavailable, nonpeptide alpha(V) antagonist derived from the arginine-glycine-asparagine binding motif in the matrix protein ligands (e.g., vitronectin). This compound inhibits alpha(V)beta(3) and alpha(V)beta(5) binding to vitronectin in the low nanomolar range, it has excellent selectivity over integrins alpha(IIb)beta(3) and alpha(5)beta(1), and it prevents adhesion to human, rat, and mouse endothelial cells. JNJ-26076713 blocks cell migration induced by vascular endothelial growth factor, fibroblast growth factor (FGF), and serum, and angiogenesis induced by FGF in the chick chorioallantoic membrane model. JNJ-26076713 is the first alpha(V) antagonist reported to inhibit retinal neovascularization in an oxygen-induced model of retinopathy of prematurity after oral administration. In diabetic rats, orally administered JNJ-26076713 markedly inhibits retinal vascular permeability, a key early event in diabetic macular edema and AMD. Given this profile, JNJ-26076713 represents a potential therapeutic candidate for the treatment of age-related macular degeneration, macular edema, and proliferative diabetic retinopathy.
Asunto(s)
Permeabilidad Capilar/fisiología , Diabetes Mellitus Experimental/metabolismo , Retinopatía Diabética/metabolismo , Integrina alfaV/metabolismo , Naftiridinas/administración & dosificación , Naftiridinas/farmacocinética , Quinolinas/administración & dosificación , Quinolinas/farmacocinética , Neovascularización Retiniana/metabolismo , Administración Oral , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacocinética , Animales , Disponibilidad Biológica , Permeabilidad Capilar/efectos de los fármacos , Línea Celular , Embrión de Pollo , Diabetes Mellitus Experimental/tratamiento farmacológico , Retinopatía Diabética/tratamiento farmacológico , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Naftiridinas/química , Embarazo , Quinolinas/química , Ratas , Ratas Long-Evans , Ratas Sprague-Dawley , Neovascularización Retiniana/tratamiento farmacológicoRESUMEN
Various 4-phenylpiperidine-benzoxazin-3-ones were synthesized and biologically evaluated as urotensin-II (U-II) receptor antagonists. Compound 12i was identified from in vitro evaluation as a low nanomolar antagonist against both rat and human U-II receptors. This compound showed in vivo efficacy in reversing the ear-flush response induced by U-II in rats.
Asunto(s)
Benzoxazinas/síntesis química , Piperidinas/síntesis química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Urotensinas/metabolismo , Animales , Benzoxazinas/farmacología , Células CHO , Cricetinae , Cricetulus , Humanos , Piperidinas/farmacología , Ratas , Receptores Acoplados a Proteínas G/fisiología , Relación Estructura-Actividad , Urotensinas/antagonistas & inhibidores , Urotensinas/fisiologíaRESUMEN
The large neuregulin 1 gene (NRG1) has been mapped to a 1.125 Mb region on chromosome 8p11-21. Three major forms of NRG1 (types I-III), all with distinct amino-termini encoded by unique 5'-exons, have been described. We report here the discovery of nine novel NRG1 exons, including six alternative 5'-exons, increasing the number of potential promoters in NRG1 from three to nine. The novel transcripts of NRG1 described here use the novel 5'-exons which are either coding or non-coding. The functional relevance of the predicted proteins they encode has not been evaluated. Three of the novel 5'-exons are well conserved in syntenic rat and mouse sequences; they encode proteins with novel amino-termini, here termed types IV-VI. NRG1 plays a central role in neural development and is most likely involved in regulation of synaptic plasticity, or how the brain responds or adapts to the environment. The unusually complex gene structure may facilitate spatial and temporal regulation of NRG1 expression, fine-tune NRG1 protein function at different stages during development of the nervous system, and adapt responses to the environment in the adult brain.
Asunto(s)
Empalme Alternativo , Proteínas del Tejido Nervioso/genética , Sitio de Iniciación de la Transcripción , Región de Flanqueo 5'/genética , Animales , Secuencia de Bases , Encéfalo/metabolismo , ADN Complementario/química , ADN Complementario/genética , Bases de Datos de Ácidos Nucleicos , Exones/genética , Humanos , Ratones , Neurregulina-1 , Ratas , Análisis de Secuencia de ADNRESUMEN
We have discovered two related chemical series of nonpeptide urotensin-II (U-II) receptor antagonists based on piperazino-phthalimide (5 and 6) and piperazino-isoindolinone (7) scaffolds. These structure types are distinctive from those of U-II receptor antagonist series reported in the literature. Antagonist 7a exhibited single-digit nanomolar potency in rat and human cell-based functional assays, as well as strong binding to the human U-II receptor. In advanced pharmacological testing, 7a blocked the effects of U-II in vitro in a rat aortic ring assay and in vivo in a rat ear-flush model. A discussion of U-II receptor antagonist pharmacophores is presented, and a specifically defined model is suggested from tricycle 13, which has a high degree of conformational constraint.
Asunto(s)
Isoindoles/química , Isoindoles/farmacología , Ftalimidas/química , Ftalimidas/farmacología , Piperazinas/química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , Células CHO , Cricetinae , Cricetulus , Ensayos Analíticos de Alto Rendimiento , Humanos , Isoindoles/síntesis química , Masculino , Ftalimidas/síntesis química , Piperazina , Ratas , Ratas WistarRESUMEN
An improved scale-up synthesis was required for the alpha(V)beta(3)/alpha(V)beta(5) integrin antagonist 1, which had demonstrated oral efficacy in eye disease models of angiogenesis and vascular permeability. A stereodefined, quinoline-substituted, unsaturated ester was conveniently prepared by a Suzuki-Miyaura coupling to facilitate exploration of multiple methods of asymmetric reduction. The catalytic chiral hydrogenation of the corresponding unsaturated acid (Z-5b) with a ruthenium-based metal precursor and the (R)-XylPhanePhos ligand proved particularly efficient and economical. The resulting (3S)-quinoline-containing intermediate was reduced to an equal mixture of tetrahydroquinoline diastereomers. The undesired diastereomer could be recycled to the desired one by an oxidation/reduction protocol. The absolute stereochemistry of 1 was established as 3S,3'S by a combination of X-ray diffraction and chemical means.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Integrinas/antagonistas & inhibidores , Naftiridinas/síntesis química , Quinolinas/síntesis química , Receptores de Vitronectina/antagonistas & inhibidores , Naftiridinas/química , Naftiridinas/farmacología , Quinolinas/química , Quinolinas/farmacología , Estereoisomerismo , Difracción de Rayos XRESUMEN
We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 x 10(-13) and 7.7 x 10(-9), respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease.
Asunto(s)
Cromosomas Humanos Par 2 , Cromosomas Humanos X , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/genética , Estudios de Casos y Controles , Frecuencia de los Genes , Pruebas Genéticas , Humanos , Islandia , Desequilibrio de Ligamiento , Masculino , Países Bajos , España , Suecia , Estados UnidosRESUMEN
One of the key problems in the study of ancient DNA is that of authenticating sequences obtained from PCR amplifications of highly degraded samples. Contamination of ancient samples and postmortem damage to endogenous DNA templates are the major obstacles facing researchers in this task. In particular, the authentication of sequences obtained from ancient human remains is thought by many to be rather challenging. We propose a novel approach, based on the c statistic, that can be employed to help identify the sequence motif of an endogenous template, based on a sample of sequences that reflect the nucleotide composition of individual template molecules obtained from ancient tissues (such as cloned products from a PCR amplification). The c statistic exploits as information the most common form of postmortem damage observed among clone sequences in ancient DNA studies, namely, lesion-induced substitutions caused by cytosine deamination events. Analyses of simulated sets of templates with miscoding lesions and real sets of clone sequences from the literature indicate that the c-based approach is highly effective in identifying endogenous sequence motifs, even when they are not present among the sampled clones. The proposed approach is likely to be of general use to researchers working with DNA from ancient tissues, particularly from human remains, where authentication of results has been most challenging.
Asunto(s)
Daño del ADN , ADN/análisis , Mitocondrias/genética , Modelos Estadísticos , Cambios Post Mortem , ADN/metabolismo , Interpretación Estadística de Datos , Humanos , Mitocondrias/metabolismoRESUMEN
Oxovanadium complexes with H(2)bzimpy (2,6-bis[benzimidazol-2'-yl]pyridine) and Me(2)bzimpy (2,6-bis[N'-methylbenzimidazol-2'-yl]pyridine), and H(3)ntb (tris[benzimidazol-2'-yl-methyl]amine) and Me(3)ntb (tris[N'-methylbenzimidazol-2'-yl-methyl]amine) have been synthesized. Dioxovanadium(V) and oxovanadium(IV) complexes prepared from H(2)bzimpy and Me(2)bzimpy are [V(V)O(2)(Hbzimpy)].1.25H(2)O (1), [V(V)O(2)(Me(2)bzimpy)](ClO(4)).H(2)O (3), [V(IV)O(H(2)bzimpy)(H(2)O)(2)](CF(3)SO(3))(2).2H(2)O (2), and [V(IV)O(Me(2)bzimpy)(H(2)O)(2)](CF(3)SO(3))(2) (4). H(3)ntb and Me(3)ntb afforded oxovanadium(IV) complexes, [V(IV)O(Hntb)].2MeOH (5), [V(IV)O(H(3)ntb)Cl]Cl.H(2)O (7), [V(IV)O(Me(3)ntb)SO(4)].H(2)O (9), [V(IV)O(Me(3)ntb)Cl]Cl.H(2)O (10), and mixed-valence complexes, [(H(3)ntb)V(IV)O(mu-O)V(V)O(H(3)ntb)](CF(3)SO(3))(3).2H(2)O (8) and [(Me(3)ntb)V(IV)O(mu-O)V(V)O(Me(3)ntb)](CF(3)SO(3))(3).3H(2)O (11). Crystal structures of 2, 7, and 11 are reported. The mixed-valence complexes, 8 and 11, show 15-line isotropic ESR spectra in fluid solutions at room temperature. These compounds also exhibit an intervalence transfer band around 1015 nm which is essentially independent of solvent, so these compounds are stable, mixed-valence species where the single unpaired electron is delocalized over the two vanadium centers at ambient temperature. With respect to one-electron reduction, the dioxovanadium(V) complexes are redox-potential equivalent with their monooxovanadium(IV) counterparts.
RESUMEN
The synthesis and SAR of a new class of piperidine-based alphavbeta3/alphavbeta5 integrin antagonists is described. Replacement of an amide bond in a prototype isonipecotamide by a C-C isostere, and adjustment of the spacer length between the carboxylic acid and basic moieties, led to low nanomolar antagonists of alphavbeta3 and/or alphavbeta5 integrins with excellent selectivity versus alpha(IIb)beta3.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Integrinas/antagonistas & inhibidores , Piperidinas/síntesis química , Propionatos/síntesis química , Receptores de Vitronectina/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Humanos , Integrina alfaVbeta3/metabolismo , Integrinas/metabolismo , Piperidinas/química , Piperidinas/farmacología , Propionatos/química , Propionatos/farmacología , Unión Proteica , Ratas , Receptores de Vitronectina/metabolismo , Relación Estructura-ActividadRESUMEN
Reduction of the quinoline ring in an alpha(v)beta(3) antagonist yielded a 1,2,3,4-tetrahydro derivative as two diastereomers, the four isomers of which were separated by sequential chiral HPLC. Two isomers had significant alpha(V)beta(3) antagonist activity with improved oral bioavailability, relative to the corresponding quinoline derivative.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Integrina alfaVbeta3/metabolismo , Quinolinas/química , Quinolinas/metabolismo , Administración Oral , Animales , Disponibilidad Biológica , Humanos , Quinolinas/administración & dosificación , RatasRESUMEN
The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.