RESUMEN
Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10-8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.
Asunto(s)
Endometriosis/genética , Leiomioma/genética , Neoplasias Uterinas/genética , Adulto , Proteínas de la Ataxia Telangiectasia Mutada/genética , Endometriosis/epidemiología , Femenino , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Leiomioma/complicaciones , Leiomioma/epidemiología , Análisis de la Aleatorización Mendeliana , Menorragia/etiología , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Modelos de Riesgos Proporcionales , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Transducción de Señal , Telomerasa/genética , Neoplasias Uterinas/complicaciones , Neoplasias Uterinas/epidemiología , Población Blanca/genéticaRESUMEN
We conducted a genome-wide meta-analysis of cognitive empathy using the 'Reading the Mind in the Eyes' Test (Eyes Test) in 88,056 research volunteers of European Ancestry (44,574 females and 43,482 males) from 23andMe Inc., and an additional 1497 research volunteers of European Ancestry (891 females and 606 males) from the Brisbane Longitudinal Twin Study. We confirmed a female advantage on the Eyes Test (Cohen's d=0.21, P<2.2 × 10-16), and identified a locus in 3p26.1 that is associated with scores on the Eyes Test in females (rs7641347, Pmeta=1.58 × 10-8). Common single nucleotide polymorphisms explained 5.8% (95% CI: 4.5%-7.2%; P=1.00 × 10-17) of the total trait variance in both sexes, and we identified a twin heritability of 28% (95% CI: 13%-42%). Finally, we identified significant genetic correlation between the Eyes Test and anorexia nervosa, openness (NEO-Five Factor Inventory), and different measures of educational attainment and cognitive aptitude.
Asunto(s)
Empatía/genética , Empatía/fisiología , Adulto , Anciano , Anorexia Nerviosa/genética , Cognición/fisiología , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Trastornos Mentales/genética , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores Sexuales , Gemelos , Población Blanca/genéticaRESUMEN
Intra-abdominal cystic lymphangiomas are rare, benign congenital tumors that often present with vague symptoms, making diagnosis difficult. We report a case of a 4-year-old patient who presented to the emergency department with nonspecific abdominal pain. Her diagnosis of intra-abdominal cystic lymphangioma was facilitated by point-of-care ultrasonography.
Asunto(s)
Linfangioma Quístico/diagnóstico por imagen , Neoplasias Retroperitoneales/diagnóstico por imagen , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Linfangioma Quístico/diagnóstico , Sistemas de Atención de Punto , Neoplasias Retroperitoneales/diagnóstico , Tomografía Computarizada por Rayos X , UltrasonografíaRESUMEN
The main genetic determinant of soluble interleukin 6 receptor (sIL-6R) levels is the missense variant rs2228145 that maps to the cleavage site of IL-6R. For each Ala allele, sIL-6R serum levels increase by ≈ 20 ng ml(-1) and asthma risk by 1.09-fold. However, this variant does not explain the total heritability for sIL-6R levels. Additional independent variants in IL6R may therefore contribute to variation in sIL-6R levels and influence asthma risk. We imputed 471 variants in IL6R and tested these for association with sIL-6R serum levels in 360 individuals. An intronic variant (rs12083537) was associated with sIL-6R levels independently of rs4129267 (P=0.0005), a proxy single-nucleotide polymorphism for rs2228145. A significant and consistent association for rs12083537 was observed in a replication panel of 354 individuals (P=0.033). Each rs12083537:A allele increased sIL-6R serum levels by 2.4 ng ml(-1). Analysis of mRNA levels in two cohorts did not identify significant associations between rs12083537 and IL6R transcription levels. On the other hand, results from 16,705 asthmatics and 30,809 controls showed that the rs12083537:A allele increased asthma risk by 1.04-fold (P=0.0419). Genetic risk scores based on IL6R regulatory variants may prove useful in explaining variation in clinical response to tocilizumab, an anti-IL-6R monoclonal antibody.
Asunto(s)
Asma/genética , Polimorfismo de Nucleótido Simple , Receptores de Interleucina-6/genética , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Interleucina-6/metabolismoRESUMEN
This study evaluated association between common and rare sequence variants in 10 nicotinic acetylcholine receptor subunit genes and the severity of nausea 21 days after initiating the standard, Food and Drug Administration-approved varenicline regimen for smoking cessation. A total of 397 participants from a randomized clinical effectiveness trial with complete clinical and DNA resequencing data were included in the analysis (mean age=49.2 years; 68.0% female). Evidence for significant association between common sequence variants in CHRNB2 and nausea severity was obtained after adjusting for age, gender and correlated tests (all P(ACT)<0.05). Individuals with the minor allele of CHRNB2 variants experienced less nausea than did those without the minor allele, consistent with previously reported findings for CHRNB2 and the occurrence of nausea and dizziness as a consequence of first smoking attempt in adolescents, and with the known neurophysiology of nausea. As nausea is the most common reason for discontinuance of varenicline, further pharmacogenetic investigations are warranted.
Asunto(s)
Benzazepinas/efectos adversos , Náusea/genética , Quinoxalinas/efectos adversos , Receptores Nicotínicos/genética , Benzazepinas/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Agonistas Nicotínicos/efectos adversos , Quinoxalinas/uso terapéutico , Cese del Hábito de Fumar , VareniclinaRESUMEN
Global patterns of human DNA sequence variation (haplotypes) defined by common single nucleotide polymorphisms (SNPs) have important implications for identifying disease associations and human traits. We have used high-density oligonucleotide arrays, in combination with somatic cell genetics, to identify a large fraction of all common human chromosome 21 SNPs and to directly observe the haplotype structure defined by these SNPs. This structure reveals blocks of limited haplotype diversity in which more than 80% of a global human sample can typically be characterized by only three common haplotypes.
Asunto(s)
Cromosomas Humanos Par 21/genética , Haplotipos/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Polimorfismo de Nucleótido Simple/genética , Algoritmos , Alelos , Animales , Etnicidad/genética , Frecuencia de los Genes/genética , Variación Genética/genética , Genoma Humano , Humanos , Células Híbridas/metabolismo , Mutación/genética , Grupos Raciales/genética , Distribución Aleatoria , Sensibilidad y EspecificidadRESUMEN
Allometric equations can be useful in comparative physiology in a number of ways, not the least of which include assessing whether a particular species deviates from the norm for its size and phylogenetic group with respect to some specific physiological process or determining how differences in design among groups may be reflected in differences in function. The allometric equations for respiratory variables in birds were developed 30 yr ago by Lasiewski and Calder and presented as "preliminary" because they were based on a small number of species. With the expanded data base now available to reconstruct these allometries and the call for taking account of the nonindependence of species in this process through a phylogenetically independent contrasts (PIC) approach, we have developed new allometric equations for respiratory variables in birds using both the traditional and PIC approaches. On the whole, the new equations agree with the old ones with only minor changes in the coefficients, and the primary difference between the traditional and PIC approaches is in the broader confidence intervals given by the latter. We confirm the lower VE/VO2 ratio for birds compared to mammals and observe a common scaling of inspiratory flow and oxygen consumption for birds as has been reported for mammals. Use of allometrics and comparisons among avian groups are also discussed.
Asunto(s)
Aves/fisiología , Modelos Teóricos , Filogenia , Respiración , Animales , Biometría , Mamíferos , Consumo de Oxígeno , Pruebas de Función RespiratoriaRESUMEN
Nonparametric sib-pair analysis was performed on the Collaborative Study on the Genetics of Alcoholism data set. Concordant and discordant pair groups were examined using the ASPEX package of programs. Allele sharing and multipoint lod scores for six comparison groups were obtained. Sharing and lod score patterns were not consistent with a simple genetic interpretation.
Asunto(s)
Alcoholismo/genética , Ligamiento Genético , Alcoholismo/epidemiología , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Genotipo , Humanos , Escala de Lod , Núcleo Familiar , Programas Informáticos , Estadísticas no ParamétricasRESUMEN
Chromosomal region 15q11-q13 has been implicated to harbor a susceptibility gene or genes underlying autism. Evidence has been derived from the existence of cytogenetic anomalies in this region associated with autism, and the report of linkage in a modest collection of multiplex families. Most recently, linkage disequilibrium with the marker GABRB3-155CA2 in the candidate locus GABRB3, located in this region, has been reported. We searched for linkage using eight microsatellite markers located in this region of chromosome 15 in 147 affected sib-pairs from 139 multiplex autism families. We also tested for linkage disequilibrium in the same set of families with the same markers. We found no evidence for excess allele sharing (linkage) for the markers in this region. Also, we found no evidence of linkage disequilibrium, including for the locus GABRB3-155CA2. Thus, it appears that the role of this region of chromosome 15 is minor, at best, in the majority of individuals with autism.
Asunto(s)
Trastorno Autístico/genética , Cromosomas Humanos Par 15 , Ligamiento Genético , Desequilibrio de Ligamiento , Repeticiones de Microsatélite , Adolescente , Adulto , Alelos , Niño , Preescolar , Familia , Femenino , Genotipo , Humanos , MasculinoRESUMEN
We have conducted a genome screen of autism, by linkage analysis in an initial set of 90 multiplex sibships, with parents, containing 97 independent affected sib pairs (ASPs), with follow-up in 49 additional multiplex sibships, containing 50 ASPs. In total, 519 markers were genotyped, including 362 for the initial screen, and an additional 157 were genotyped in the follow-up. As a control, we also included in the analysis unaffected sibs, which provided 51 discordant sib pairs (DSPs) for the initial screen and 29 for the follow-up. In the initial phase of the work, we observed increased identity by descent (IBD) in the ASPs (sharing of 51.6%) compared with the DSPs (sharing of 50.8%). The excess sharing in the ASPs could not be attributed to the effect of a small number of loci but, rather, was due to the modest increase in the entire distribution of IBD. These results are most compatible with a model specifying a large number of loci (perhaps >/=15) and are less compatible with models specifying
Asunto(s)
Trastorno Autístico/genética , Ligamiento Genético , Herencia Multifactorial , Adolescente , Adulto , Niño , Preescolar , Cromosomas Humanos/genética , Femenino , Genotipo , Humanos , Pruebas de Inteligencia , Desequilibrio de Ligamiento , Masculino , Análisis por Apareamiento , Repeticiones de Microsatélite , Modelos Genéticos , Datos de Secuencia Molecular , Núcleo Familiar , Factores Sexuales , Distribuciones EstadísticasRESUMEN
Several studies have suggested a role for the histocompatibility complex of loci (HLA) in the genetic susceptibility to autism. We have tested this hypothesis by linkage analysis using genetic marker loci in the HLA region on chromosome 6p in multiplex families with autism. We have examined sharing of alleles identical by descent in 97 affected sib pairs from 90 families. Results demonstrate no deviation from the null expectation of 50% sharing of alleles in this region; in fact, for most marker loci, the observed sharing was less than 50%. Thus, it is unlikely that loci in this region contribute to the genetic etiology of autism to any significant extent in our families.
Asunto(s)
Trastorno Autístico/genética , Ligamiento Genético/genética , Antígenos HLA/genética , Adolescente , Adulto , Alelos , Niño , Preescolar , Aberraciones Cromosómicas/genética , Trastornos de los Cromosomas , Cromosomas Humanos Par 6/genética , Femenino , Marcadores Genéticos/fisiología , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Análisis por Apareamiento , Reacción en Cadena de la PolimerasaRESUMEN
During the past decade, the genetics of type 1 (insulin-dependent) diabetes mellitus (IDDM) has been studied extensively and the disorder has become a paradigm for genetically complex diseases. Previous genome screens and studies focused on candidate genes have provided evidence for genetic linkage between polymorphic DNA markers and 15 putative IDDM susceptibility loci, designated IDDM1-IDDM15. We have carried out a second-generation screen of the genome for linkage and analysed the data by multipoint linkage methods. An initial panel of 212 affected sibpairs (ASPs) was genotyped for 438 markers spanning all autosomes, and an additional 467 ASPs were used for follow-up genotyping. Other than the well-established linkage with the HLA region at chromosome 6p21.3, there was only one region, located on chromosome 1q and not previously reported, where the log likelihood ratio (lod) was greater than 3. Lods between 1.0 and 1.8 were found in six other regions, three of which have been reported in other studies. Another reported region, on chromosome 6q and loosely linked to HLA, also had an elevated lod. Little or no support was found for most reported IDDM loci (lods were less than 1), despite larger sample sizes in the present study.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Pruebas Genéticas , Mapeo Cromosómico , Ligamiento Genético , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genoma Humano , HumanosRESUMEN
The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.
Asunto(s)
Esclerosis Múltiple/genética , Mapeo Cromosómico , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 2 , Cromosomas Humanos Par 3 , Cromosomas Humanos Par 5 , Cromosomas Humanos Par 6 , Femenino , Humanos , Desequilibrio de Ligamiento , Complejo Mayor de Histocompatibilidad , Masculino , Linaje , Cromosoma XRESUMEN
Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is a common disorder of middle-aged individuals characterized by high blood glucose levels which, if untreated, can cause serious medical complications and lead to early death. Genetic factors play an important role in determining susceptibility to this disorder. However, the number of genes involved, their chromosomal location and the magnitude of their effect on NIDDM susceptibility are unknown. We have screened the human genome for susceptibility genes for NIDDM using non-and quasi-parametric linkage analysis methods in a group of Mexican American affected sib pairs. One marker, D2S125, showed significant evidence of linkage to NIDDM and appears to be a major factor affecting the development of diabetes mellitus in Mexican Americans. We propose that this locus be designated NIDDM1.
Asunto(s)
Cromosomas Humanos Par 2 , Diabetes Mellitus Tipo 2/genética , Americanos Mexicanos/genética , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/etnología , Ligamiento Genético , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Japón , Población BlancaRESUMEN
With a simple lattice model and sequence design algorithm, we can design sequences to fit arbitrary compact globular structures. We judged the success of the design algorithm by performing exhaustive conformational searches to determine if a designed sequence's lowest energy conformation matched the target for which it was designed. Designed sequences tend to be much better optimized for their targets than a natural sequence is optimized for its lowest energy model conformation. We examined the effect of varying the number of available amino acid types on the success of the design method. It was more difficult but not impossible to successfully design discriminating sequences using fewer amino acid types.
Asunto(s)
Algoritmos , Secuencia de Aminoácidos , Modelos Moleculares , Conformación Proteica , Datos de Secuencia Molecular , Pliegue de Proteína , Proteínas Ribosómicas/química , TermodinámicaRESUMEN
The clinical medical students on the Cambridge Community-Based Clinical Course (CCBCC) derive part of their training by taking part in consultations between patients and their general practitioners. Patients' attitudes to this arrangement and their support for student training in a general practice setting are an important factor in the development of community-based education. A postal questionnaire seeking information from patients achieved an 84% response rate. Both the numerical results and the patients' comments are presented. Patients proved generally supportive of the community-based course and some identified positive benefits to themselves from this provision. The large majority of patients did not mind the presence of medical students during consultations, although there are some areas in which patients are less willing to involve students.
Asunto(s)
Actitud , Medicina Clínica/educación , Educación de Pregrado en Medicina , Aceptación de la Atención de Salud , Centros Comunitarios de Salud , Inglaterra , HumanosRESUMEN
This paper reports on the establishment of the Cambridge Community-based Clinical Course and places on record details of the organization, goals and teaching arrangements of the course. It also identifies the main questions which are being addressed in the course and which must be answered before it will be clear whether such attachments are generally viable.
Asunto(s)
Medicina Comunitaria/educación , Educación de Pregrado en Medicina , Medicina Familiar y Comunitaria/educación , Curriculum , Inglaterra , Enseñanza/organización & administraciónRESUMEN
We present a low resolution lattice model for which we can exhaustively generate all possible compact backbone conformations for small proteins. Using simple structural and energetic criteria, for a variety of proteins, we can select for lattice structures that have significant similarities with their known native structures. Our energetic parameters are based on pairwise amino acid contact frequencies in a database of experimentally determined structures. A key step in our method involves the threading of a sequence onto every lattice model, such that a locally optimal pattern of tertiary interactions is formed. We evaluate our results against statistics collected for structures covering all of conformational space, and against statistics collected for permuted sequences. Despite the low resolution of the model, our low energy structures contain many native features. These results indicate that the overall pattern of hydrophobicity of a sequence significantly constrains the range of folds that sequence is likely to adopt.
Asunto(s)
Modelos Moleculares , Conformación Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Algoritmos , Animales , Proteínas Bacterianas/química , Calbindinas , Cristalografía por Rayos X , Bases de Datos Factuales , Ferredoxinas/química , Neurotoxinas/química , Proteínas de Plantas/química , Control de Calidad , Estándares de Referencia , Proteínas Represoras/química , Proteínas Ribosómicas/química , Rubredoxinas/química , Proteína G de Unión al Calcio S100/química , Inhibidores de Tripsina/química , Ubiquitinas/químicaRESUMEN
This study reports that corticotropin-releasing factor (CRF) expression within the inferior olivary complex (IOC) of the cat is increased 8 h after administration of the tremor-inducing beta-carboline harmaline. Following harmaline treatment, hybridization of an oligodeoxynucleotide complementary to CRF mRNA increased significantly in the dorsal accessory olive, subnuclei A and C of the medial accessory olive and the dorsal cap of Kooy, a subnucleus thought previously to be unresponsive physiologically to harmaline. At this early time point, greater increases in CRF mRNA hybridization were present in the caudal than the rostral IOC. These results support published reports that harmaline-mediated effects are more profound within the caudal than the rostral IOC, but also suggest that harmaline mediates cellular responses in inferior olivary neurons which are not related to activation of rhythmic firing.