RESUMEN
The aim of the present study was the identification of gene loci that contribute to the development and manifestation of behaviours related to acute and chronic alcohol exposure, as well as to alcohol withdrawal. For this purpose, we performed a serial behavioural phenotyping of 534 animals from the second filial (F2) generation of a C57BL/6J and C3H/HeJ mice intercross in paradigms with relevance to alcohol dependence. First, ethanol-induced hypothermia was determined in ethanol-naive animals. The mice then received an ethanol solution for several weeks as their only fluid source. Ethanol tolerance, locomotor activity and anxiety-related behaviours were evaluated. The ethanol was next withdrawn and the withdrawal severity was assessed. The ethanol-experienced animals were finally analysed in a two-bottle choice paradigm to determine ethanol preference and stress-induced changes in ethanol preference. The genotypes of these mice were subsequently assessed by microsatellite marker mapping. We genotyped 264 markers with an average marker distance of 5.56 cM, which represents a high-density whole genome coverage. Quantitative trait loci (QTL) were subsequently identified using univariate analysis performed with the R/qtl tool, which is an extensible, interactive environment for mapping QTL in experimental crosses. We found QTL that have already been published, thus validating the serial phenotyping protocol, and identified several novel loci. Our analysis demonstrates that the various responses to ethanol are regulated by independent groups of genes.
Asunto(s)
Etanol/farmacología , Repeticiones de Microsatélite/fisiología , Sitios de Carácter Cuantitativo/fisiología , Consumo de Bebidas Alcohólicas/genética , Animales , Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/genética , Conducta de Elección/efectos de los fármacos , Mapeo Cromosómico/métodos , Tolerancia a Medicamentos/genética , Femenino , Hibridación Genética , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Fenotipo , Síndrome de Abstinencia a Sustancias/genéticaRESUMEN
OBJECTIVE: Transforming growth factor-beta (TGF-ß) type 1 receptor (also known as activin receptor-like kinase 5, ALK5) is expressed in palatal tissue during embryogenesis. Experimental studies in transgenic mice with a genetic deletion of Alk5 showed that TGF-ß type 1 receptor is required for upper lip and midline fusion of the hard and soft palate. In humans, association of TGF-ß type 1 receptor gene (TGFBR1) and the development of non-syndromic cleft lip with or without cleft palate (NSCL/P) had been observed in a multiethnic sample of Chinese, Philippine, Indian and Turkish families. In order to re-evaluate the relevance of these findings, we carried out a family-based association study among 218 NSCL/P families of Central European descent. METHODS: Genomic DNA was obtained from peripheral blood of 218 complete parent-offspring triads with NSCL/P. The sample comprised 14 patients with cleft lip only (CLO) and 204 patients with cleft lip and palate (CLP). Genotyping and transmission disequilibrium test (TDT) were performed on all 218 triads with a total of 17 tagging single-nucleotide polymorphisms (SNPs). We also performed testing for extended haplotypes and a log-linear model by Weinberg was used to screen parent-of-origin effects. Furthermore the use of estimates for the relative risks (RR) of Weinberg's model was obtained. RESULTS: TDT analysis revealed no significant transmission distortion, neither at the level of individual markers nor at the level of haplotypes. Similarly negative results were obtained when we restricted our analysis to the subgroup of patients with CLP (n=204). Relative risk calculations (RR) of the children's and mothers' genotypes obtained negative results, after correction of p-values for multiple testing. Likewise application of Weinberg's log-linear model did not find any evidence for parent-of-origin effects in our sample. CONCLUSION: Despite the ample evidence supporting the role of TGF-ß type 1 receptor as a critically important and widespread morphogenetic regulator of craniofacial development in murine models, our results do not support TGFBR1 as major risk factor for NSCL/P in patients of Central European descent.
Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Predisposición Genética a la Enfermedad/epidemiología , Proteínas Serina-Treonina Quinasas/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Anomalías Múltiples/epidemiología , Anomalías Múltiples/cirugía , Animales , Animales Recién Nacidos , Labio Leporino/epidemiología , Labio Leporino/cirugía , Fisura del Paladar/epidemiología , Fisura del Paladar/cirugía , Estudios de Cohortes , Modelos Animales de Enfermedad , Europa (Continente)/epidemiología , Femenino , Regulación del Desarrollo de la Expresión Génica , Genética de Población , Humanos , Incidencia , Recién Nacido , Masculino , Ratones , Ratones Transgénicos , Linaje , Receptor Tipo I de Factor de Crecimiento Transformador beta , Medición de Riesgo , Especificidad de la Especie , SíndromeRESUMEN
OBJECTIVE: The 677C-->T allele in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been implicated in the etiology of nonsyndromic cleft lip and palate (CL/P). This study involved a family-based association study of the MTHFR polymorphism. PATIENTS/PARTICIPANTS: We examined 181 patients with CL/P of central European descent and their parents for this variant. RESULTS: The transmission disequilibrium test (TDT) did not confirm an association between the MTHFR 677C-->T polymorphism and nonsyndromic CL/P as previously suggested (p = .36). When comparing the offspring of mothers with periconceptional use of folate to those without, no statistically significant differences were found (p = .708). CONCLUSION: Our data suggest that the MTHFR 677C-->T polymorphism does not make a major contribution to the occurrence of CL/P among central Europeans.