RESUMEN
BACKGROUND: Few genome-wide association studies (GWAS) on Helicobacter pylori infection susceptibility have been conducted for admixed populations from developing countries. Here, we performed a GWAS to identify genetic factors associated with H. pylori serostatus in a cohort of admixed children from a large Latin American urban center. METHODS: A cross-sectional study involving 1161 children from 4 to 11 years old living in poor areas of Salvador, in northeastern Brazil. Logistic regression analysis was performed to detect associations between single-nucleotide variants (SNVs) and H. pylori seropositivity, assuming an additive genetic model. Enrichment analyses were conducted using the MAGMA v1.10 software. RESULTS: We found 22 SNVs to be suggestively associated (p < 10-5 ) with H. pylori seropositivity. The most suggestive SNV was the rs77955022 (p = 4.83e-07) located in an intronic region of EXOC3 at 5p15.33. The second most suggestively associated SNV was rs10914996 (p = 8.97e-07), located in an intergenic region at 1p34.3. Furthermore, we were able to replicate three SNVs (p < 0.05) in the Study of Health in Pomerania (SHIP) cohort: the rs2339212 and rs4795970, both located at 17q12 near TMEM132E, as well as the rs6595814, an intronic variant of FBN2 at 5q23.3. The enrichment analysis indicated the participation of genes and metabolic pathways related to the regulation of the digestive system and gastric acid secretion in the risk of seropositivity for H. pylori. CONCLUSIONS: Additional studies are required to validate these association findings in larger population samples and to get insight into the underlying physiological mechanisms.
Asunto(s)
Infecciones por Helicobacter , Helicobacter pylori , Humanos , Niño , Preescolar , Estudio de Asociación del Genoma Completo , Helicobacter pylori/genética , América Latina/epidemiología , Infecciones por Helicobacter/epidemiología , Estudios TransversalesRESUMEN
BACKGROUND: The dorsal cochlear nucleus (DCN) is a region known to integrate somatosensory and auditory inputs and is identified as a potential key structure in the generation of phantom sound perception, especially noise-induced tinnitus. Yet, how altered homeostatic plasticity of the DCN induces and maintains the sensation of tinnitus is not clear. Here, we chemogenetically decrease activity of a subgroup of DCN neurons, Ca2+/Calmodulin kinase 2 α (CaMKII α)-positive DCN neurons, using Gi-coupled human M4 Designer Receptors Exclusively Activated by Designer Drugs (hM4Di DREADDs), to investigate their role in noise-induced tinnitus. RESULTS: Mice were exposed to loud noise (9-11kHz, 90dBSPL, 1h, followed by 2h of silence), and auditory brainstem responses (ABRs) and gap prepulse inhibition of acoustic startle (GPIAS) were recorded 2 days before and 2 weeks after noise exposure to identify animals with a significantly decreased inhibition of startle, indicating tinnitus but without permanent hearing loss. Neuronal activity of CaMKII α+ neurons expressing hM4Di in the DCN was lowered by administration of clozapine-N-oxide (CNO). We found that acutely decreasing firing rate of CaMKII α+ DCN units decrease tinnitus-like responses (p = 3e -3, n = 11 mice), compared to the control group that showed no improvement in GPIAS (control virus; CaMKII α-YFP + CNO, p = 0.696, n = 7 mice). Extracellular recordings confirmed CNO to decrease unit firing frequency of CaMKII α-hM4Di+ mice and alter best frequency and tuning width of response to sound. However, these effects were not seen if CNO had been previously administered during the noise exposure (n = 6 experimental and 6 control mice). CONCLUSION: We found that lowering DCN activity in mice displaying tinnitus-related behavior reduces tinnitus, but lowering DCN activity during noise exposure does not prevent noise-induced tinnitus. Our results suggest that CaMKII α-positive cells in the DCN are not crucial for tinnitus induction but play a significant role in maintaining tinnitus perception in mice.
Asunto(s)
Núcleo Coclear , Acúfeno , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Núcleo Coclear/fisiología , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Ratones , Percepción , Acúfeno/etiologíaRESUMEN
AIMS: The relationship between adiponectin and type 2 diabetes mellitus (T2DM) is established; however the evidence on its role in high-density lipoprotein (HDL) functionality is still scant. The aim of this study was to assess the association of adiponectin with HDL functionality especially on the antioxidant capacity and HDL subfractions in individuals with T2DM. METHODS: This case-control study enrolled 356 individuals who were divided into two groups: diabetics [T2DM (nâ¯=â¯188)] and non-diabetic [nT2DM (nâ¯=â¯168)]. The association of adiponectin level on HDL functionality parameters was done in function of the cut-off point for adiponectin [percentile pâ¯<â¯75â¯=â¯12.9⯵g/mL versus pâ¯≥â¯75â¯=â¯12.9⯵g/mL] and multiple adjustments applied in the logistic regression models. RESULTS: Body mass index (BMI), waist circumference (WC) and body fat mass (FM) were higher in T2DM. The larger HDL particles (HDLLARGE) were lower in T2DM group in comparison with nT2DM (28.20% versus 30.40%; pâ¯=â¯0.016). Individuals with T2DM and simultaneous highest adiponectin (pâ¯≥â¯75) had 2.25 OR (95% CIâ¯=â¯1.03-4.91) and 5.14 OR (95% CIâ¯=â¯2.37-11.15) to present higher HDL-C and HDLLARGE concentrations. After adjustment for multiple confounders, high level of adiponectin was independently related with improvement of the HDL antioxidant capacity (ORâ¯=â¯2.78; 95% CIâ¯=â¯1.16-6.67). CONCLUSIONS: High adiponectin level associates with a lesser negative impact of T2DM on HDL functionality by increase in APO AI, particles size, and cholesterol content. On the same token, higher adiponectin was associated with greater odds to have high antioxidant capacity.
Asunto(s)
Adiponectina , Diabetes Mellitus Tipo 2 , Lipoproteínas HDL/sangre , Adiponectina/sangre , Antioxidantes , Estudios de Casos y Controles , HDL-Colesterol , Diabetes Mellitus Tipo 2/sangre , HumanosRESUMEN
A Th2 immune response is central to allergic airway inflammation, which afflicts millions worldwide. However, the mechanisms that augment GATA3 expression in an antigen-primed developing Th2 cell are not well understood. Here, we describe an unexpected role for Blimp-1, a transcriptional repressor that constrains autoimmunity, as an upstream promoter of GATA3 expression that is critical for Th2 cell development in the lung to inhaled but not systemically delivered allergens but is dispensable for TFH function and IgE production. Mechanistically, Blimp-1 acts through Bcl6, leading to increased GATA3 expression in lung Th2 cells. Surprisingly, the anti-inflammatory cytokine IL-10, but not the pro-inflammatory cytokines IL-6 or IL-21, is required via STAT3 activation to up-regulate Blimp-1 and promote Th2 cell development. These data reveal a hitherto unappreciated role for an IL-10-STAT3-Blimp-1 circuit as an initiator of an inflammatory Th2 response in the lung to allergens. Thus, Blimp-1 in a context-dependent fashion can drive inflammation by promoting rather than terminating effector T cell responses.
Asunto(s)
Alérgenos/inmunología , Asma/inmunología , Pulmón/inmunología , Pulmón/patología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Células Th2/inmunología , Animales , Asma/complicaciones , Diferenciación Celular , Factor de Transcripción GATA3/metabolismo , Inmunoglobulina E/metabolismo , Inflamación/patología , Interleucina-6/metabolismo , Interleucinas/metabolismo , Ganglios Linfáticos/metabolismo , Ratones Endogámicos C57BL , Especificidad de Órganos , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Pyroglyphidae/inmunología , Receptores de Interleucina-21/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
Gallstones Disease (GSD) is one of the most common digestive diseases requiring hospitalization and surgical procedures in the world. GSD has a high prevalence in populations with European or Amerindian ancestry (10-20%) and the influence of genetic factors is broadly acknowledged. However, known genetic variants do not entirely explain the disease heritability suggesting that additional genetic variants remain to be identified. Here, we examined the association of copy number variants (CNVs) with GSD in a sample of 4778 individuals (1929 GSD cases and 2849 controls) including two European cohorts from Germany (n = 3702) and one admixed Latin American cohort from Chile (n = 1076). We detected 2936 large and rare CNVs events (size > 100 kb, frequency < 1%). Case-control burden analysis and generalized linear regression models revealed significant association of CNVs with GSD in men, with the strongest effect observed with CNVs overlapping lipid metabolism genes (p-value = 6.54 × 10-4; OR = 2.76; CI 95% = 1.53-4.89). Our results indicate a clear link between CNVs and GSD in men and provides additional evidence that the genetic components of risk for GSD are complex, can be sex specific and include CNVs affecting genes involved in lipid metabolism.
Asunto(s)
Variaciones en el Número de Copia de ADN , Cálculos Biliares/genética , Metabolismo de los Lípidos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores SexualesRESUMEN
The hippocampus is an extended structure displaying heterogeneous anatomical cell layers along its dorsoventral axis. It is known that dorsal and ventral regions show different integrity when it comes to functionality, innervation, gene expression, and pyramidal cell properties. Still, whether hippocampal interneurons exhibit different properties along the dorsoventral axis is not known. Here, we report electrophysiological properties of dorsal and ventral oriens lacunosum moleculare (OLM) cells from coronal sections of the Chrna2-cre mouse line. We found dorsal OLM cells to exhibit a significantly more depolarized resting membrane potential compared to ventral OLM cells, while action potential properties were similar between the two groups. We found ventral OLM cells to show a higher initial firing frequency in response to depolarizing current injections but also to exhibit a higher spike-frequency adaptation than dorsal OLM cells. Additionally, dorsal OLM cells displayed large membrane sags in response to negative current injections correlating with our results showing that dorsal OLM cells have more hyperpolarization-activated current (Ih ) compared to ventral OLM cells. Immunohistochemical examination indicates the h-current to correspond to hyperpolarization-activated cyclic nucleotide-gated subunit 2 (HCN2) channels. Computational studies suggest that Ih in OLM cells is essential for theta oscillations in hippocampal circuits, and here we found dorsal OLM cells to present a higher membrane resonance frequency than ventral OLM cells. Thus, our results highlight regional differences in membrane properties between dorsal and ventral OLM cells allowing this interneuron to differently participate in the generation of hippocampal theta rhythms depending on spatial location along the dorsoventral axis of the hippocampus.
Asunto(s)
Potenciales de Acción/fisiología , Hipocampo/fisiología , Interneuronas/fisiología , Potenciales de la Membrana/fisiología , Receptores Nicotínicos/fisiología , Animales , Femenino , Masculino , Ratones , Ratones TransgénicosRESUMEN
Latin Americans and Chilean Amerindians have the highest prevalence of gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however, they only explain a small portion of the genetic component of the disease. Here, we performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Chilean Latinos with Mapuche Native American ancestry. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Top-10 candidate variants surpassing the suggestive cutoff of P < 1 × 10-5 in the discovery cohort were genotyped in an independent replication sample composed of 1,643 individuals. Variants with positive replication were further examined in two European GSD populations and a Chilean GBC cohort. We consistently replicated the association of ABCG8 gene with GSD (rs11887534, P = 3.24 × 10-8, OR = 1.74) and identified TRAF3 (rs12882491, P = 1.11 × 10-7, OR = 1.40) as a novel candidate gene for the disease in admixed Chilean Latinos. ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 was significantly decreased in gallbladder (P = 0.015) and duodenal mucosa (P = 0.001) of GSD individuals compared to healthy controls, where according to GTEx data in the small intestine, the presence of the risk allele contributes to the observed effect. We conclude that ABCG8 and TRAF3 genes are associated with GSD and GBC in admixed Latinos and that decreased TRAF3 levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.
Asunto(s)
Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/genética , Neoplasias de la Vesícula Biliar/etiología , Cálculos Biliares/genética , Indígenas Sudamericanos/genética , Polimorfismo de Nucleótido Simple , Factor 3 Asociado a Receptor de TNF/genética , Población Blanca/genética , Adulto , Anciano , Chile/etnología , Colecistectomía , Regulación hacia Abajo , Duodeno/química , Femenino , Vesícula Biliar/química , Neoplasias de la Vesícula Biliar/diagnóstico por imagen , Neoplasias de la Vesícula Biliar/etnología , Neoplasias de la Vesícula Biliar/cirugía , Cálculos Biliares/diagnóstico por imagen , Cálculos Biliares/etnología , Cálculos Biliares/cirugía , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , UltrasonografíaRESUMEN
Bipolar disorder (BD) is a major psychiatric illness affecting around 1% of the global population. BD is characterized by recurrent manic and depressive episodes, and has an estimated heritability of around 70%. Research has identified the first BD susceptibility genes. However, the underlying pathways and regulatory networks remain largely unknown. Research suggests that the cumulative impact of common alleles with small effects explains only around 25-38% of the phenotypic variance for BD. A plausible hypothesis therefore is that rare, high penetrance variants may contribute to BD risk. The present study investigated the role of rare, nonsynonymous, and potentially functional variants via whole exome sequencing in 15 BD cases from two large, multiply affected families from Cuba. The high prevalence of BD in these pedigrees renders them promising in terms of the identification of genetic risk variants with large effect sizes. In addition, SNP array data were used to calculate polygenic risk scores for affected and unaffected family members. After correction for multiple testing, no significant increase in polygenic risk scores for common, BD-associated genetic variants was found in BD cases compared to healthy relatives. Exome sequencing identified a total of 17 rare and potentially damaging variants in 17 genes. The identified variants were shared by all investigated BD cases in the respective pedigree. The most promising variant was located in the gene SERPING1 (p.L349F), which has been reported previously as a genome-wide significant risk gene for schizophrenia. The present data suggest novel candidate genes for BD susceptibility, and may facilitate the discovery of disease-relevant pathways and regulatory networks.
Asunto(s)
Trastorno Bipolar/genética , Proteína Inhibidora del Complemento C1/genética , Exoma , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Alelos , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/fisiopatología , Cuba , Familia , Femenino , Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Linaje , Penetrancia , Riesgo , Secuenciación del ExomaRESUMEN
Reprogramming of somatic cells into induced pluripotent stem cells (iPS) or directly into cells from a different lineage, including neurons, has revolutionized research in regenerative medicine in recent years. Mesenchymal stem cells are good candidates for lineage reprogramming and autologous transplantation, since they can be easily isolated from accessible sources in adult humans, such as bone marrow and dental tissues. Here, we demonstrate that expression of the transcription factors (TFs) SRY (sex determining region Y)-box 2 (Sox2), Mammalian achaete-scute homolog 1 (Ascl1), or Neurogenin 2 (Neurog2) is sufficient for reprogramming human umbilical cord mesenchymal stem cells (hUCMSC) into induced neurons (iNs). Furthermore, the combination of Sox2/Ascl1 or Sox2/Neurog2 is sufficient to reprogram up to 50% of transfected hUCMSCs into iNs showing electrical properties of mature neurons and establishing synaptic contacts with co-culture primary neurons. Finally, we show evidence supporting the notion that different combinations of TFs (Sox2/Ascl1 and Sox2/Neurog2) may induce multiple and overlapping neuronal phenotypes in lineage-reprogrammed iNs, suggesting that neuronal fate is determined by a combination of signals involving the TFs used for reprogramming but also the internal state of the converted cell. Altogether, the data presented here contribute to the advancement of techniques aiming at obtaining specific neuronal phenotypes from lineage-converted human somatic cells to treat neurological disorders.
RESUMEN
The authors evaluated the association of reduced bone stiffness of the calcaneus with clinical attachment loss (CAL) and tooth loss. The authors analyzed data from 4,678 subjects (2,384 women), aged 20 to 88 y, from the second follow-up of the population-based Study of Health in Pomerania (SHIP-2) and the baseline examination of the SHIP-Trend cohort. Bone stiffness, characterized by the stiffness index (SI) and the osteoporotic fracture risk (OFR), was assessed by quantitative ultrasound of the heel. SI and OFR were significantly associated with the mean CAL in women. While 1) the SI showed a significant association with the mean CAL and 2) the OFR with the median number of teeth in just the postmenopausal women, the OFR showed a significant association with mean CAL for both pre- and postmenopausal women. In postmenopausal women, a 10-unit increase in the SI was associated with a decrease in the mean CAL of 0.05 mm (95% confidence interval [CI]: -0.10 to 0.00; P = 0.046). Moreover, the adjusted median number of teeth was 21.4 (95% CI: 20.9 to 21.9) among the postmenopausal women with a low OFR, while it was 19.1 (95% CI: 17.8 to 20.3; P = 0.001) among the postmenopausal women with a high OFR. For the premenopausal women with a low OFR, the mean CAL was 1.60 mm (95% CI: 1.53 to 1.66), while for the premenopausal women with a high OFR, it was 2.24 mm (95% CI: 1.78 to 2.69; P = 0.006). Reduced bone stiffness was associated with clinical attachment and tooth loss in women but not in men.
Asunto(s)
Densidad Ósea , Calcáneo/diagnóstico por imagen , Calcáneo/patología , Pérdida de la Inserción Periodontal/epidemiología , Pérdida de Diente/epidemiología , Absorciometría de Fotón , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Alemania/epidemiología , Humanos , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Central neurons express a variety of neuronal types and ion channels that promote firing heterogeneity among their distinct neuronal populations. Action potential (AP) phasic firing, produced by low-threshold voltage-activated potassium currents (VAKCs), is commonly observed in mammalian brainstem neurons involved in the processing of temporal properties of the acoustic information. The avian caudomedial nidopallium (NCM) is an auditory area analogous to portions of the mammalian auditory cortex that is involved in the perceptual discrimination and memorization of birdsong and shows complex responses to auditory stimuli We performed in vitro whole-cell patch-clamp recordings in brain slices from adult zebra finches (Taeniopygia guttata) and observed that half of NCM neurons fire APs phasically in response to membrane depolarizations, while the rest fire transiently or tonically. Phasic neurons fired APs faster and with more temporal precision than tonic and transient neurons. These neurons had similar membrane resting potentials, but phasic neurons had lower membrane input resistance and time constant. Surprisingly phasic neurons did not express low-threshold VAKCs, which curtailed firing in phasic mammalian brainstem neurons, having similar VAKCs to other NCM neurons. The phasic firing was determined not by VAKCs, but by the potassium background leak conductances, which was more prominently expressed in phasic neurons, a result corroborated by pharmacological, dynamic-clamp, and modeling experiments. These results reveal a new role for leak currents in generating firing diversity in central neurons.
RESUMEN
BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is among the most frequently occurring congenital malformations worldwide. The number of genetic loci identified as being involved in NSCL/P etiology was recently increased by a large genome-wide meta-analysis of European and Asian samples. This meta-analysis confirmed all six previously recognized genetic susceptibility loci and identified six novel ones. METHODS: To investigate which of these 12 loci contribute to NSCL/P risk in an independent sample of distinct ethnicity, we performed a case-control association analysis in a sample of the Mesoamerican population. A total of 153 individuals with NSCL/P (cases) and 337 unaffected controls were included. Top single-nucleotide polymorphisms (SNPs) at 8 of the 12 loci (1p22.1, 1p36, 2p21, 3p11.1, 8q21.3, 13q31.1, 15q22, and 20q12) were analyzed using mass spectroscopy and restriction-length-fragment polymorphism analyses. In a previous study, we had analyzed the remaining four NSCL/P susceptibility regions (IRF6, 8q24, 10q25, and 17q22) in the same sample. RESULTS: Single-marker association analyses applying allelic, dominant, and recessive models revealed nominal significant associations for four of the eight loci, with two additional loci showing at least a trend of association in the hypothesized direction. CONCLUSION: In combination with results from our previous study using the same sample, our data suggest that the majority of the known NSCL/P susceptibility regions identified to date also confer risk for this malformation in the Mesoamerican population. Birth Defects Research (Part A) 100:43-47, 2014. © 2013 Wiley Periodicals, Inc.
Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Alelos , Estudios de Casos y Controles , Labio Leporino/etnología , Labio Leporino/patología , Fisura del Paladar/etnología , Fisura del Paladar/patología , Femenino , Frecuencia de los Genes , Marcadores Genéticos , Estudio de Asociación del Genoma Completo , Técnicas de Genotipaje , Humanos , Indígenas Sudamericanos , Patrón de Herencia , Masculino , Espectrometría de Masas , México , Modelos Genéticos , Polimorfismo de Longitud del Fragmento de Restricción , RiesgoRESUMEN
Synchronization among neurons is thought to arise from the interplay between excitation and inhibition; however, the connectivity rules that contribute to synchronization are still unknown. We studied these issues in hippocampal CA1 microcircuits using paired patch clamp recordings and real time computing. By virtually connecting a model interneuron with two pyramidal cells (PCs), we were able to test the importance of connectivity in synchronizing pyramidal cell activity. Our results show that a circuit with a nonreciprocal connection between pyramidal cells and no feedback from PCs to the virtual interneuron produced the greatest level of synchronization and mutual information between PC spiking activity. Moreover, we investigated the role of intrinsic membrane properties contributing to synchronization where the application of a specific ion channel blocker, ZD7288 dramatically impaired PC synchronization. Additionally, background synaptic activity, in particular arising from NMDA receptors, has a large impact on the synchrony observed in the aforementioned circuit. Our results give new insights to the basic connection paradigms of microcircuits that lead to coordination and the formation of assemblies.
Asunto(s)
Hipocampo/citología , Hipocampo/fisiología , Potenciales Postsinápticos Inhibidores/fisiología , Red Nerviosa/citología , Red Nerviosa/fisiología , Potenciales de Acción/fisiología , Animales , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , Células Piramidales/fisiologíaRESUMEN
Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all congenital malformations and has a multifactorial etiology. Findings in mice suggest that the v-ski sarcoma viral oncogene homolog (SKI) gene is a candidate gene for orofacial clefting. In humans, a significant association between rs2843159 within SKI and NSCL/P has been reported in patients from the Philippines and South America. In the South American patients, the association was driven by the subgroup of patients with non-syndromic cleft lip only (NSCLO). Here we investigated the association with rs2843159 in a Mayan Mesoamerican population (172 NSCL/P patients and 366 controls). In addition, we analyzed the phenotypic subgroups NSCLO and non-syndromic cleft of lip and palate (NSCLP). A trend towards association between rs2843159 and NSCL/P was observed in the Mayan cohort (P = 0.097), and we found a stronger association in the NSCLP subgroup (P = 0.072) despite a limited sample size. To investigate whether other common variants within the SKI gene contribute to NSCL/P susceptibility in European and Asian populations, we also analyzed genotypic data from two recent genome-wide association studies using set-based statistical approaches. These analyses detected a trend toward association in the European population. Our data provide limited support for the hypothesis that common SKI variants are susceptibility factors for NSCL/P.
Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Proteínas de Unión al ADN/genética , Indígenas Norteamericanos/genética , Proteínas Proto-Oncogénicas/genética , Pueblo Asiatico/genética , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , México , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
OBJECTIVE: To identify genetic and nongenetic risk factors that contribute to the severity of the bladder exstrophy-epispadias complex (BEEC). STUDY DESIGN: Patients with BEEC from North America (n = 167) and Europe (n = 274) were included. The following data were collected: associated anomalies, parental age at conception, mode of conception, periconceptional folic acid supplementation, maternal risk factors during pregnancy, and environmental risk factors. The patients were divided into 3 subgroups according to phenotype severity: (i) mild, epispadias (n = 43); (ii) intermediate, classic bladder exstrophy (n = 366); and (iii) severe, cloacal exstrophy (n = 31). These subgroups then were compared with identify factors that contribute to phenotype severity. RESULTS: Males were overrepresented in all subgroups. A relatively high prevalence of cleft lip, with or without cleft palate, was observed. Maternal smoking and medical radiation during the first trimester were associated with the severe cloacal exstrophy phenotype. Compliance with periconceptional folic acid supplementation was associated with the mildest phenotype (epispadias). CONCLUSIONS: Periconceptional folic acid supplementation appears to prevent the development of the severe phenotype of BEEC.
Asunto(s)
Extrofia de la Vejiga/epidemiología , Epispadias/epidemiología , Adulto , Antiácidos/uso terapéutico , Labio Leporino/epidemiología , Fisura del Paladar/epidemiología , Europa (Continente)/epidemiología , Femenino , Fertilización In Vitro/estadística & datos numéricos , Ácido Fólico/uso terapéutico , Humanos , Masculino , Edad Materna , Persona de Mediana Edad , América del Norte/epidemiología , Edad Paterna , Fenotipo , Embarazo , Primer Trimestre del Embarazo , Atención Prenatal , Radiografía/estadística & datos numéricos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Distribución por Sexo , Fumar/epidemiología , Inyecciones de Esperma Intracitoplasmáticas/estadística & datos numéricos , Encuestas y Cuestionarios , Complejo Vitamínico B/uso terapéuticoRESUMEN
BACKGROUND & AIMS: Genome-wide association studies have mapped loci that are associated with serum levels of bilirubin. Bilirubin is a major component of gallstones so we investigated whether these variants predict gallstone bilirubin content and overall risk for gallstones. METHODS: Loci that were identified in a meta-analysis to attain a genome-wide significance level of a P value less than 1.0×10(-7) (UGT1A1, SLCO1B1, LST-3TM12, SLCO1A2) were analyzed in 1018 individuals with known gallstone composition. Gallstone risk was analyzed in 2606 German choleystecomized individuals and 1121 controls and was replicated in 210 cases and 496 controls from South America. RESULTS: By using the presence of bilirubin as a phenotype, variants rs6742078 (UGT1A1; P = .003), rs4149056 (SLCO1B1; P = .003), and rs4149000 (SLCO1A2; P = .015) were associated with gallstone composition. In regression analyses, only UGT1A1 and SLCO1B1 were independently retained in the model. UGT1A1 (rs6742078; P = .018) was associated with overall gallstone risk. In a sex-stratified analysis, only male carriers of rs6742078 had an increased risk for gallstone disease (P = 2.1×10(-7); odds ratio(recessive), 2.34; P(women) = .47). The sex-specific association of rs6742078 was confirmed in samples from South America (P(men) = .046; odds ratio(recessive), 2.19; P(women) = .96). CONCLUSIONS: The UGT1A1 Gilbert syndrome variant rs6742078 is associated with gallstone disease in men; further studies are required regarding the sex-specific physiology of bilirubin and bile acid metabolism. Variants of ABCG8 and UGT1A1 are the 2 major risk factors for overall gallstone disease, they contribute a population attributable risk of 21.2% among men.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Bilirrubina/sangre , Cálculos Biliares , Enfermedad de Gilbert , Glucuronosiltransferasa/genética , Transportadores de Anión Orgánico/genética , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8 , Adulto , Femenino , Cálculos Biliares/epidemiología , Cálculos Biliares/genética , Cálculos Biliares/metabolismo , Predisposición Genética a la Enfermedad/epidemiología , Estudio de Asociación del Genoma Completo , Genotipo , Alemania/epidemiología , Enfermedad de Gilbert/epidemiología , Enfermedad de Gilbert/genética , Enfermedad de Gilbert/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Modelos Genéticos , Fenotipo , Valor Predictivo de las Pruebas , Factores de Riesgo , América del Sur/epidemiologíaRESUMEN
INTRODUCTION: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all birth defects. NSCL/P has a multifactorial etiology that includes both genetic and environmental factors. The IRF6 gene and three further susceptibility loci at 8q24, 10q25, and 17q22, which were identified by a recent genome-wide association scan (GWAS), are confirmed genetic risk factors for NSCL/P in patients of European descent. METHODS: A case-control association study was performed to investigate whether these four risk loci contribute to NSCL/P in a Mesoamerican population using four single nucleotide polymorphisms to represent IRF6 and the three novel susceptibility loci. A total of 149 NSCL/P patients and 303 controls of Mayan origin were included. RESULTS: Single marker analysis revealed a significant association between NSCL/P and risk variants in IRF6 and the 8q24 and 10q25 loci. In contrast to previous findings, the association at the 8q24 locus was driven solely by homozygote carriers of the risk allele. This suggests that this locus might act in a recessive manner in the Mayan population. No evidence for association was found at the 17q22 locus. This may have been attributable to the limited power of the sample. CONCLUSION: These results suggest that IRF6 and the 10q25 and 8q24 loci confer a risk for the development of NSCL/P in persons of Mayan origin.