RESUMEN
OBJECTIVES: The aims of the study were: (i) to extend our linkage analysis of chromosome 1q microsatellite markers in predominantly migraine with aura pedigrees and (ii) to test the novel FHM-2 ATP1A2 gene for involvement in these migraine affected pedigrees and a previous pedigree (MF14) showing evidence of linkage of markers to C1q31. METHODS: A chromosome 1 scan (31 markers) was performed in 21 multiplex pedigrees affected predominantly with migraine with aura (MA). The known FHM-2 ATP1A2 gene mutations were tested, by sequencing, for the involvement in MA and migraine without aura (MO) in these pedigrees. Sequencing was performed in the coding areas of the ATP1A2 gene through three MA individuals from MF14. RESULTS: Evidence for linkage was obtained at C1q23 to markers spanning the ATP1A2 gene. However, testing of the known ATP1A2 gene mutations (for FHM) in common migraine probands of pedigrees showing excess allele sharing was negative. Sequencing of the entire coding areas of the gene through all the three MA affected from MF14 was also negative for mutations. DISCUSSION: Microsatellite markers on chromosome 1q23 show evidence of excess allele sharing in MA and some MO pedigrees, suggesting linkage to the common forms of migraine and the presence of a susceptibility gene in this region. The FHM-2 (ATP1A2 gene) does not seem to be involved in the common types of migraine. Despite certain clinical characteristics, the genetic correlation between FHM and familial typical migraine remains unclear. Several candidate genes lie within the C1q23 and C1q31 cytogenetic regions; therefore, further studies are needed.
Asunto(s)
Cromosomas Humanos Par 1 , Repeticiones de Microsatélite/genética , Trastornos Migrañosos/genética , Mutación , ATPasa Intercambiadora de Sodio-Potasio/genética , Mapeo Cromosómico/métodos , Análisis Mutacional de ADN/métodos , Humanos , LinajeRESUMEN
Migraine is a prevalent neurovascular disease with a significant genetic component. Linkage studies have so far identified migraine susceptibility loci on chromosomes 1, 4, 6, 11, 14, 19 and X. We performed a genome-wide scan of 92 Australian pedigrees phenotyped for migraine with and without aura and for a more heritable form of "severe" migraine. Multipoint non-parametric linkage analysis revealed suggestive linkage on chromosome 18p11 for the severe migraine phenotype (LOD*=2.32, P=0.0006) and chromosome 3q (LOD*=2.28, P=0.0006). Excess allele sharing was also observed at multiple different chromosomal regions, some of which overlap with, or are directly adjacent to, previously implicated migraine susceptibility regions. We have provided evidence for two loci involved in severe migraine susceptibility and conclude that dissection of the "migraine" phenotype may be helpful for identifying susceptibility genes that influence the more heritable clinical (symptom) profiles in affected pedigrees. Also, we concluded that the genetic aetiology of the common (International Headache Society) forms of the disease is probably comprised of a number of low to moderate effect susceptibility genes, perhaps acting synergistically, and this effect is not easily detected by traditional single-locus linkage analyses of large samples of affected pedigrees.
Asunto(s)
Cromosomas Humanos Par 18 , Perfilación de la Expresión Génica , Genómica , Migraña sin Aura/genética , Ligamiento Genético , Predisposición Genética a la Enfermedad , Humanos , Linaje , FenotipoRESUMEN
The Low-Density Lipoprotein Receptor (LDLR) gene is a cell surface receptor that plays an important role in cholesterol homeostasis. We investigated the (TA)n polymorphism in exon 18 of the LDLR gene on chromosome 19p13.2 performing an association analysis in 244 typical migraine-affected patients, 151 suffering from migraine with aura (MA), 96 with migraine without aura (MO) and 244 unaffected controls. The populations consisted of Caucasians only, and controls were age- and sex-matched. The results showed no significant difference between groups for allele frequency distributions of the (TA)n polymorphism even after separation of the migraine-affected individuals into subgroups of MA and MO affected patients. This is in contradiction to Mochi et al. who found a positive association of this variant with MO. Our study discusses possible differences between the two studies and extends this research by investigating circulating cholesterol levels in a migraine-affected population.
Asunto(s)
Colesterol/metabolismo , Trastornos Migrañosos/genética , Trastornos Migrañosos/metabolismo , Polimorfismo Genético , Receptores de LDL/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Niño , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Trastornos Migrañosos/clasificación , Migraña con Aura/genética , Migraña con Aura/metabolismo , Repeticiones de Minisatélite/genética , Factores de Riesgo , Población BlancaRESUMEN
Essential hypertension is a common multifactorial trait that results in a significantly increased risk for heart attack and stroke. The condition has a genetic basis, although at present the number of genes is unknown. In order to identify such genes, we are utilising a linkage scanning approach using microsatellite markers and affected sibships. Here we provide evidence for the location of at least one hypertension susceptibility locus on chromosome 17. Analysis of 177 affected sibpairs gave evidence for significant excess allele sharing to D17S949 (SPLINK: P=0.0029; MAPMAKER SIBS: P=0.0033; ASPEX: P=0.0061; GENEHUNTER: P=0.0096; ANALYZE (SIBPAIR): P=0.0025) on 17q22-24, with significant allele sharing also indicated for an additional marker, D17S799 (SPLINK: P=0.025; MAPMAKER SIBS: P=0.025) located close to the centromere. Since these two genomic regions are well separated, our results indicate that there may be more than one chromosome 17 locus affecting human blood pressure. Moreover, further investigation of this chromosome, utilizing a polymorphism within the promoter of the iNOS candidate gene, NOS2A, revealed both increased allele sharing among sibpairs (SPLINK: P=0.02; ASPEX: P=0.00004) and positive association (P=0.034) of NOS2A to essential hypertension. Hence these results indicate that chromosome 17 and, more specifically, the NOS2A gene may play a role in human essential hypertension.
Asunto(s)
Cromosomas Humanos Par 17/genética , Predisposición Genética a la Enfermedad/genética , Hipertensión/genética , Óxido Nítrico Sintasa/genética , Alelos , Presión Sanguínea/genética , Índice de Masa Corporal , Femenino , Frecuencia de los Genes , Humanos , Hipertensión/enzimología , Escala de Lod , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo II , Núcleo Familiar , Mapeo Físico de CromosomaRESUMEN
Migraine is a debilitating disorder affecting approximately 12% of Caucasian populations. The disease has a large genetic component, although at present the type and number of genes involved is unclear. Candidate gene studies may be useful strategies for identifying genes involved in complex diseases such as migraine, especially if the gene being examined contributes only a minor effect to the overall phenotype. Nitric oxide (NO) is emerging as a key molecule affecting the pain associated with migraine. Since NO synthase (NOS) enzymes catalyze the synthesis of NO, the genes that code for these enzymes are good candidates for migraine molecular genetic analysis. This study investigated the role of a functionally relevant bi-allelic tetranucleotide polymorphism located in the promoter region of the human inducible nitric oxide synthase (iNOS) gene in migraine etiology. A large group of migraine affected individuals (n = 261) were genotyped and compared with an age- and sex-matched group of unaffected controls (n = 252). Results of a chi-squared analysis indicated that allele distributions for both migraine cases and controls were not significantly different (chi2 = 1.93, P = 0.16). These findings offer no evidence for an allelic association of the tested iNOS polymorphism with the common forms of the disease and therefore do not support a role for this gene in migraine pathogenesis.
Asunto(s)
Predisposición Genética a la Enfermedad , Trastornos Migrañosos/genética , Óxido Nítrico Sintasa/genética , Adulto , Alelos , Frecuencia de los Genes , Pruebas Genéticas , Genotipo , Humanos , Análisis por Apareamiento , Repeticiones de Microsatélite , Trastornos Migrañosos/clasificación , Óxido Nítrico Sintasa de Tipo II , Reacción en Cadena de la Polimerasa , Polimorfismo GenéticoRESUMEN
Typical migraine is a complex neurological disorder comprised of two main subtypes: migraine with (MA) and without aura (MO). The disease etiology is still unclear, but family studies provide strong evidence that defective genes play an important role. Familial hemiplegic migraine (FHM) is a very rare and severe subtype of MA. It has been proposed that FHM and MA may have a similar genetic etiology. Therefore, genetic studies on FHM provide a useful model for investigating the more prevalent types of typical migraine. FHM in some families has been shown to be caused by mutations in a brain-specific P/Q-type calcium channel alpha1 subunit gene (CACNA1A) on chromosome 19p13. There has also been a report of a CACNA1A mutation being associated with MA in a patient from a family with predominant FHM. We have previously demonstrated suggestive linkage of typical migraine in a large Australian family to the FHM region on chromosome 19p13. These findings suggest that CACNA1A may also be implicated in the etiology of typical migraine in this pedigree. To investigate this possibility, we sequenced two patients carrying the critical susceptibility haplotype surrounding CACNA1A. No disease-causing mutations or polymorphisms were revealed in any of the 47 exons screened. To determine whether the CACNA1A gene was implicated in typical migraine susceptibility in the general Caucasian population, we also analyzed 82 independent pedigrees and a large case control group. We did not detect any linkage or association in these groups and conclude that if CACNA1A plays a role in typical migraine, it does not confer a major effect on the disease.
Asunto(s)
Canales de Calcio/genética , Predisposición Genética a la Enfermedad/genética , Trastornos Migrañosos/genética , Alelos , Cromosomas Humanos Par 19/genética , ADN/química , ADN/genética , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Ligamiento Genético , Haplotipos , Humanos , Masculino , Repeticiones de Microsatélite , Linaje , Repeticiones de Trinucleótidos/genéticaAsunto(s)
Cisteína/genética , Demencia por Múltiples Infartos/genética , Mutación Missense/genética , Fenilalanina/genética , Proteínas Proto-Oncogénicas/genética , Adulto , Sustitución de Aminoácidos/genética , Australia , Humanos , Leucoencefalopatía Multifocal Progresiva/genética , Linaje , Receptor Notch3 , Receptores de Superficie Celular/genética , Receptores NotchRESUMEN
In a previous study we found evidence for an X-linked genetic component for familial typical migraine in two large Australian white pedigrees, designated MF7 and MF14. Significant excess allele sharing was indicated by nonparametric linkage (NPL) analysis using GENEHUNTER (P=0.031 and P=0.012, respectively), with a combined analysis of the two pedigrees showing further increased evidence for linkage, producing a maximum NPL score of 2.87 (P=0.011 ) at DXS 1123 on Xq27. The present study was aimed at refining the localization of the migraine X-chromosomal component by typing additional markers, performing haplotype analysis and applying a more powerful technique in the analysis of linkage data from these two pedigrees. Results from the haplotype analyses, coupled with linkage analyses that produced a peak GENEHUNTER-PLUS LOD* score of 2.388 (P=0.0005), provide compelling evidence for the presence of a migraine susceptibility locus on chromosome Xq24-28.
Asunto(s)
Ligamiento Genético , Trastornos Migrañosos/genética , Cromosoma X , Mapeo Cromosómico , Femenino , Marcadores Genéticos , Haplotipos , Humanos , Escala de Lod , Masculino , Migraña con Aura/genética , Migraña sin Aura/genética , Linaje , Recombinación GenéticaRESUMEN
OBJECTIVE: To determine whether a microsatellite polymorphism located towards the 3' end of the low density lipoprotein receptor gene (LDLR) is associated with obesity. DESIGN: A cross-sectional case-control study. SUBJECTS: One hundred and seven obese individuals, defined as a body mass index (BMI) > or = 26 kg/m2, and 163 lean individuals, defined as a BMI < 26 kg/m2. MEASUREMENTS: BMI, blood pressure, serum lipids, alleles of LDLR microsatellite (106 bp, 108 bp and 112 bp). RESULTS: There was a significant association between variants of the LDLR microsatellite and obesity, in the overall tested population, due to a contributing effect in females (chi 2 = 12.3, P = 0.002), but not in males (chi 2 = 0.3, P = 0.87). In females, individuals with the 106 bp allele were more likely to be lean, while individuals with the 112 bp and/or 108 bp alleles tended to be obese. CONCLUSIONS: These results suggest that in females, LDLR may play a role in the development of obesity.
Asunto(s)
Repeticiones de Microsatélite/genética , Obesidad/genética , Polimorfismo Genético/genética , Receptores de LDL/genética , Alelos , Análisis de Varianza , Índice de Masa Corporal , Estudios de Casos y Controles , Estudios Transversales , Femenino , Genotipo , Humanos , Hipertensión/genética , Lípidos/sangre , Masculino , Obesidad/sangre , Obesidad/complicacionesRESUMEN
Migraine shows strong familial aggregation. However, the number of genes involved in the disorder is unknown and not identified. Nitric oxide is involved in the central processing of pain stimuli and plays an important role in the regulation of basal or stimulated vasodilation. Nitric oxide synthase, which controls the synthesis of nitric oxide, could possibly be a cause, or candidate gene, in migraine etiology. In this study, we detected a polymorphism for endothelial nitric oxide synthase by polymerase chain reaction and tested this for association and linkage to migraine. Results from the study did not show an association of the nitric oxide synthase microsatellite when tested in 91 affected and 85 unaffected individuals. Using the FASTLINK program for parametric linkage analysis, the polymorphism did not show significant linkage to migraine when tested in four migraine pedigrees composed of 116 individuals, 52 affected. Total LOD scores excluded linkage up to 8.5 cM between the nitric oxide synthase polymorphism and migraine. Results using the nonparametric affected pedigree member form of analysis also did not support a role for this gene in migraine etiology.
Asunto(s)
Endotelio Vascular/enzimología , Genes , Ligamiento Genético , Trastornos Migrañosos/genética , Óxido Nítrico Sintasa/genética , Polimorfismo Genético , Alelos , Genotipo , Humanos , Escala de Lod , LinajeRESUMEN
5-Hydroxytryptamine (5HT), commonly known as serotonin, which predominantly serves as an inhibitory neurotransmitter in the brain, has long been implicated in migraine pathophysiology. This study tested an MspI polymorphism in the human 5HT2A receptor gene (HTR2A) and a closely linked microsatellite marker (D13S126), for linkage and association with common migraine. In the association analyses, no significant differences were found between the migraine and control populations for both the MspI polymorphism and the D13S126 microsatellite marker. The linkage studies involving three families comprising 36 affected members were analysed using both parametric (FASTLINK) and non-parametric (MFLINK and APM) techniques. Significant close linkage was indicated between the MspI polymorphism and the D13S126 microsatellite marker at a recombination fraction (theta) of zero (lod score = 7.15). Linkage results for the MspI polymorphism were not very informative in the three families, producing maximum and minimum lod scores of only 0.35 and -0.39 at recombination fractions (theta) of 0.2 and 0.00, respectively. However, linkage analysis between the D13S126 marker and migraine indicated significant non-linkage (lod < -2) up to a recombination fraction (theta) of 0.028. Results from this study exclude the HTR2A gene, which has been localized to chromosome 13q14-q21, for involvement with common migraine.
Asunto(s)
Trastornos Migrañosos/genética , Receptores de Serotonina/genética , Alelos , Cromosomas Humanos Par 13 , Femenino , Ligamiento Genético , Humanos , Masculino , Repeticiones de Microsatélite , Trastornos Migrañosos/metabolismo , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo GenéticoRESUMEN
1. The low density lipoprotein receptor is an important regulator of serum cholesterol which may have implications for the development of both hypertension and obesity. In this study, genotypes for a low density lipoprotein receptor gene (LDLR) dinucleotide polymorphism were determined in both lean and obese normotensive populations. 2. In previous cross-sectional association studies an ApaLI and a HincII polymorphism for LDLR were shown to be associated with obesity in essential hypertensives. However, these polymorphisms did not show an association with obesity in normotensives. 3. In contrast, this study reports that preliminary results for an LDLR microsatellite marker, located more towards the 3' end of the gene, show a significant association with obesity in the normotensive population studied. These results indicate that LDLR could play an important role in the development of obesity, which might be independent of hypertension.
Asunto(s)
Colesterol/sangre , Obesidad/etiología , Receptores de LDL/genética , Distribución de Chi-Cuadrado , Estudios Transversales , ADN Satélite/genética , Electroforesis en Gel de Poliacrilamida , Marcadores Genéticos , Genotipo , Humanos , Hipertensión/etiología , Hipertensión/fisiopatología , Obesidad/fisiopatología , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
PIP: The authors attempt to provide a comprehensive review of urbanization in three Melanesian countries (Papua New Guinea, the Solomon Islands, and Vanuatu) and in Fiji. The focus of the paper is on the development and perpetuation of various forms of inequality exemplified by Melanesian urbanization and its colonial origins.^ieng