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B?rbel Maus Camille Jung Jestinah M. Mahachie John Jean-Pierre Hugot Emmanuelle Génin Kristel Van Steen 《PloS one》2013,8(10)
Complex human diseases commonly differ in their phenotypic characteristics, e.g., Crohn’s disease (CD) patients are heterogeneous with regard to disease location and disease extent. The genetic susceptibility to Crohn’s disease is widely acknowledged and has been demonstrated by identification of over 100 CD associated genetic loci. However, relating CD subphenotypes to disease susceptible loci has proven to be a difficult task. In this paper we discuss the use of cluster analysis on genetic markers to identify genetic-based subgroups while taking into account possible confounding by population stratification. We show that it is highly relevant to consider the confounding nature of population stratification in order to avoid that detected clusters are strongly related to population groups instead of disease-specific groups. Therefore, we explain the use of principal components to correct for population stratification while clustering affected individuals into genetic-based subgroups. The principal components are obtained using 30 ancestry informative markers (AIM), and the first two PCs are determined to discriminate between continental origins of the affected individuals. Genotypes on 51 CD associated single nucleotide polymorphisms (SNPs) are used to perform latent class analysis, hierarchical and Partitioning Around Medoids (PAM) cluster analysis within a sample of affected individuals with and without the use of principal components to adjust for population stratification. It is seen that without correction for population stratification clusters seem to be influenced by population stratification while with correction clusters are unrelated to continental origin of individuals. 相似文献
3.
Kristel Van Steen Nadia Tahri Geert Molenberghs 《Biometrical journal. Biometrische Zeitschrift》2004,46(2):187-202
Until recently, the most common parametric approaches to study the combined effects of several genetic polymorphisms located within a gene or in a small genomic region are, at the genotype level, logistic regressions and at the haplotype level, haplotype analyses. An alternative modeling approach, based on the case/control principle, is to regard exposures (e.g., genetic data such as derived from Single Nucleotide Polymorphisms – SNPs) as random and disease status as fixed and to use a marginal multivariate model that accounts for inter‐relationships between exposures. One such model is the multivariate Dale model. This model is based on multiple logistic regressions. That is why the model, applied in a case/control setting, leads to straightforward interpretations that are similar to those drawn in a classical logistic modeling framework. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim) 相似文献
4.
Synergism between thrombin and adrenaline (epinephrine) in human platelets. Marked potentiation of inositol phospholipid metabolism. 总被引:2,自引:0,他引:2
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We have studied synergism between adrenaline (epinephrine) and low concentrations of thrombin in gel-filtered human platelets prelabelled with [32P]Pi. Suspensions of platelets, which did not contain added fibrinogen, were incubated at 37 degrees C to measure changes in the levels of 32P-labelled phosphatidylinositol 4,5-bisphosphate (PIP2), phosphatidylinositol 4-phosphate (PIP) and phosphatidate (PA), aggregation and dense-granule secretion after stimulation. Adrenaline alone (3.5-4.0 microM) did not cause a change in any parameter (phosphoinositide metabolism, aggregation and dense-granule secretion), but markedly enhanced the thrombin-induced responses over a narrow range of thrombin concentrations (0.03-0.08 units/ml). The thrombin-induced hydrolysis of inositol phospholipids by phospholipase C, which was measured as the formation of [32P]PA, was potentiated by adrenaline, as was the increase in the levels of [32P]PIP2 and [32P]PIP. The presence of adrenaline caused a shift to the left for the thrombin-induced changes in the phosphoinositide metabolism, without affecting the maximal levels of 32P-labelled compounds obtained. A similar shift by adrenaline in the dose-response relationship was previously demonstrated for thrombin-induced aggregation and dense-granule secretion. Also, the narrow range of concentrations of thrombin over which adrenaline potentiates thrombin-induced platelet responses is the same for changes in phosphoinositide metabolism and physiological responses (aggregation and dense-granule secretion). Our observations clearly indicate that adrenaline directly or indirectly influences thrombin-induced changes in phosphoinositide metabolism. 相似文献
5.
Plateau distributions of DNA fragment lengths produced by extended light exposure of extranuclear photosensitizers in human cells.
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We have exploited properties of photosensitizers to study an aspect of the packing of chromatin in the cell nucleus. The fluorescent photosensitizers mesotetra(3-hydroxyphenyl) porphyrin and Photofrin II were both localized in the nuclear membrane and other membrane structures, but could not be found inside the nuclei. Light exposure of cells at 1 degrees C in the presence of the sensitizers induced DNA double-strand breaks. The length distributions of DNA fragments were determined by pulsed field gel electrophoresis. Because DNA damage is produced mainly via singlet oxygen diffusing less than 0.1 microns from the sensitizer, DNA double-strand breaks were supposedly produced within this distance of the nuclear membrane. Consistent with this, with prolonged illumination and with increasing concentrations of sensitizer the distribution of DNA fragment lengths reached a plateau level. In contrast, with the hydrophilic, intranuclear sensitizer meso-tetra(4-sulphonatophenyl)porphyrin, no such plateau level was found. The plateau distributions of DNA fragment lengths of different cell types had the same general shape with average fragment lengths ranging from 174 to 194 kilobasepairs. Particular genes, c-myc, fos and p53, were found on broad distributions of photocleaved fragment lengths. The results indicate that on each side of the genes the locus of the chromatin fibre situated close to the nuclear membrane, varied randomly. 相似文献
6.
Suzanne Marcus Ann-Marie Steen Björn Andersson Bo Lambert Ulf Kristoffersson Uta Francke 《Human genetics》1992,89(4):395-400
Summary A nonsense mutation at the CpG-site in the codon for Arg(169) in the gene for hypoxanthine phosphoribosyltransferase (hprt) was identified by genomic polymerase chain reaction (PCR) and DNA sequencing in cultured fibroblasts from two brothers with Lesch Nyhan's syndrome. The recurrence of mutation at this CpG-site in several unrelated Lesch-Nyhan families suggests that deamination of 5-methylcytosine is a possible mechanism for mutagenesis. The level of hprt-mRNA in the fibroblasts of the patients was similar to that in healthy controls, whereas hprt-enzyme activity was not detectable. The mutation in this family was also identified in five female relatives and prenatally in a male fetus. Unexpectedly, results from hair follicle analyses and fibroblast selection studies in 8-azaguanine and 6-thioguanine medium showed a non-carrier phenotype in three of the female heterozygotes, whereas X-inactivation mosaicism was demonstrated in one heterozygote. A possible explanation for the apparent non-random X-inactivation in this family is the co-existence of the hprt mutation with an undefined X-linked lethal mutation. This observation is of practical relevance for carrier detection in other Lesch-Nyhan families. 相似文献
7.
Linkage analysis was performed in a family with nonspecific X-linked mental retardation (MRX). Affected individuals had no clinical characteristics other than mental retardation. Linkage was detected to the marker loci DXS477, DXS465, DXS52, DXS15 and F8C with maximum lod scores of 1.70, 1.32, 2.52, 1.70, and 1.09, respectively ( = 0.0). The results strongly indicate that the gene for mental retardation in the family studied maps close to DXS52. 相似文献
8.
High-affinity binding of3H-folate in Triton X-100 solubilized membranes of human liver displayed characteristics, e.g. apparent positive cooperativity, which are typical of specific folate binding. Ultrogel® AcA 44 chromatography of solubilized membranes saturated with3H-folate revealed a major peak of 100 kDa and a minor peak of 25 kDa. The 100 kDa peak could represent a hydrophobic membrane associated molecular form of the protein. This notion was supported by the fact that the two peaks had identical molecular weights as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis with immunoblotting. 相似文献
9.
Johan B. Steen Øivind Tøien Peder Fiske 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》1991,161(2):155-158
1. | Physiological adaptation to hypothermia were studied in newly hatched great snipe chicks (Gallinago media) by measuring oxygen uptake (VO2), heart rate (HR), respiratory frequency (RF), and body temperature (Tb) at different ambient temperatures (Ta). |
2. | Tb of 1-day-old chicks at Ta of 35°C stabilized at about 40°C. At Ta between 20 and 30°C the chicks maintained a Tb about 8°C above Ta. Hatchlings maintained a higher gradient when active than when resting. Below 20°C they were unable to maintain a stable Tb. |
3. | In resting hatchlings VO2 was similar at Ta between 35 and 20°C (Tb 40–30°C), VO2 range 1.7–2.5 ml·g-1·h-1. Below 20°C, VO2 declined with time. |
4. | The HR of 1-day-old chicks fell linearly with Tb during cooling. The Q10 of the HR was 1.7 at Tb 38°C and increased to 3.0 at 29°C. The RF showed a slight tendency to decrease with decreasing Tb. |
5. | It is concluded that the ability to maintain normal dexterity at low Tb is an important aspect of snipe survival strategy. Maintaining a temperature gradient rather than a constant high Tb presumably saves energy. It is suggested that the mechanisms whereby VO2 is maintained at a low Tb may involve isoenzymes and adaptations of the nervous system. However, such adaptations would not seem to affect the pacemaker mechanism as evidenced by the high Q10 of the HR. |
10.
Niels Gregersen Brage S. Andresen Peter Bross Vibeke Winter Niels Rüdiger Stefan Engst Ernst Christensen Daniel Kelly Arnold W. Strauss Steen Kølvraa Lars Bolund Sandro Ghisla 《Human genetics》1991,86(6):545-551
Summary A series of experiments has established the molecular defect in the medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) gene in a family with MCAD deficiency. Demonstration of intra-mitochondrial mature MCAD indistinguishable in size (42.5-kDa) from control MCAD, and of mRNA with the correct size of 2.4 kb, indicated a point-mutation in the coding region of the MCAD gene to be disease-causing. Consequently, cloning and DNA sequencing of polymerase chain reaction (PCR) amplified complementary DNA (cDNA) from messenger RNA of fibroblasts from the patient and family members were performed. All clones sequenced from the patient exhibited a single base substitution from adenine (A) to guanine (G) at position 985 in the MCAD cDNA as the only consistent base-variation compared with control cDNA. In contrast, the parents contained cDNA with the normal and the mutated sequence, revealing their obligate carrier status. Allelic homozygosity in the patient and heterozygosity for the mutation in the parents were established by a modified PCR reaction, introducing a cleavage site for the restriction endonuclease NcoI into amplified genomic DNA containing G985. The same assay consistently revealed A985 in genomic DNA from 26 control individuals. The A to G mutation was introduced into an E. coli expression vector producing mutant MCAD, which was demonstrated to be inactive, probably because of the inability to form active tetrameric MCAD. All the experiments are consistent with the contention that the G985 mutation, resulting in a lysine to glutamate shift at position 329 in the MCAD polypeptide chain, is the genetic cause of MCAD deficiency in this family. We found the same mutation in homozygous form in 11 out of 12 other patients with verified MCAD deficiency. 相似文献