17 research outputs found
Systemic complement activation in age-related macular degeneration.
No full textDysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility
Genome-Wide Linkage Scan of Nonsyndromic Orofacial Clefting in 91 Families of Central European Origin
No full textOrofacial clefts are among the most common of all congenital disorders. Nonsyndromic cases of cleft lip with or without cleft palate (NSCL/P) and cleft palate only (NSCPO) are considered to have a multifactorial etiology which involves both genetic and environmental factors. We present the results of a genome-wide linkage scan in 91 families of central European descent with nonsyndromic orofacial clefts (NSC). The sample included 74 NSCL/P families, 15 NSCPO families, and 2 mixed families (a total of 217 affected and 230 unaffected individuals were genotyped). We genotyped 542 microsatellite markers (average intermarker distance = 6.9 cM). Multipoint nonparametric linkage analysis was performed using Allegro 2.0f. In addition to the factors investigated in previous genome-wide linkage analyses, we searched for sex-specific susceptibility loci, loci demonstrating parental imprinting and loci that are shared by NSCL/P and NSCPO. Several genomic regions likely to contain susceptibility loci for NSC were identified at the level of nominal significance. Some of these overlap with regions identified in previous studies. Suggestive evidence of linkage was obtained for the loci 4q21-q26 and 1p31-p21, with the chromosome 1 locus showing a male-specific genetic effect. Our study has identified promising chromosomal regions for the identification of NSC-associated genes, and demonstrates the importance of performing detailed statistical analyses which take into account complex genetic mechanisms such as sex-specific effects and genomic imprinting. Further research in large patient samples is necessary to identify factors common to NSCL/P and NSCPO. (C) 2009 Wiley-Liss, Inc.Deutsche Forschungsgemeinschaft [FOR 423
Measurements of DNA methylation at seven loci in various tissues of CD1 mice
No full textIn humans, considerable variation in methylation at single loci and repetitive elements in various cells and tissues is observed. Recently, several inter- and intra-tissue correlations for DNA methylation have been reported. To investigate the extent and reproducibility of such correlations, we investigated inter- and intra-tissue methylation correlations among seven different loci in 9 different tissues in a population of 100 healthy seven-week-old CD1 outbred mice. We used a highly quantitative approach to measure methylation levels to high accuracy at two single loci in the alpha-actin and myosine light chain promoters, at three differentially methylated regions of the Peg3, Snrpn and Lit1 genes associated with imprinted loci, and at two repetitive elements in the Line-1 and IAP-LTR genes in the various tissues. In this population of mice, methylation at several loci was sex-associated and intra-tissue correlations among the studied loci were observed for brain and spleen. Inter-tissue correlations were rarely observed. To investigate method-dependent experimental variability, we re-analyzed the same spleen and tongue samples using SIRPH and pyrosequencing methods and reconfirmed intra-tissue correlations for spleen and sex-associated correlations for DNA methylation for tongue. When we repeated DNA methylation measurements for a second mouse population raised under similar conditions three months later, we did not detect sex-associated or intra-tissues correlations. Additional studies that examine large numbers of loci may be required to further understand the factors that influence stability of DNA methylation.PublishedN/
Spatial assessment of Argentinean genetic admixture with geographical information systems
No full textIn recent years there has been much attention to Argentinean population stratification. We were interested in assessing population stratification from a geographical perspective and summarizing it in form of maps. We mapped the genetic admixture of the extant male population in central and northern Argentina on the basis of forensic Y-chromosomal haplotypes. We addressed the question which group of genetically similar individuals is predominant in this area. Haplotypes containing seven Y-chromosomal short tandem repeat polymorphisms (Y-STRs), also known as microsatellites - DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393 - were constructed for 145 individuals, recruited in 10 provinces. 97 distinct haplotypes were clustered into four clusters according to molecular distances. A genetic geostatistical analysis was conducted with the open-source geographical information system GRASS GIS. For each haplotype cluster, the according frequency was spatially interpolated over the total study area. Juxtaposing the interpolation surfaces, we screened point-wisely the maximal frequency as well as the label of the respective cluster. The screening results were combined in one summary map. We repeated this procedure for the second maximal frequencies. The resulting maps subdivide the study area into continuous regions comprising one predominant group of similar haplotypes. The first summary map divides the study area into three regions and the second summary map divides the area into four regions. The results of our analysis indicate that two groups of similar European haplotypes alternatively dominate the largest extension of the Argentinean territory. A third group, including South-American haplotypes, dominates the indigenous northwestern Argentinean area. The last group, including worldwide dispersed haplotypes, preponderates in frequency in second place in central Argentina. Our findings confirm a widespread European paternal ancestry, a substantial Amerindian contribution in the northwest, as well as a considerable proportion of diverse paternal lineages. In this work, we further discuss these findings in reference to ethno-historical, genetic, and demographic information
Measurements of DNA methylation at seven loci in various tissues of CD1 mice.
No full textIn humans, considerable variation in methylation at single loci and repetitive elements in various cells and tissues is observed. Recently, several inter- and intra-tissue correlations for DNA methylation have been reported. To investigate the extent and reproducibility of such correlations, we investigated inter- and intra-tissue methylation correlations among seven different loci in 9 different tissues in a population of 100 healthy seven-week-old CD1 outbred mice. We used a highly quantitative approach to measure methylation levels to high accuracy at two single loci in the alpha-actin and myosine light chain promoters, at three differentially methylated regions of the Peg3, Snrpn and Lit1 genes associated with imprinted loci, and at two repetitive elements in the Line-1 and IAP-LTR genes in the various tissues. In this population of mice, methylation at several loci was sex-associated and intra-tissue correlations among the studied loci were observed for brain and spleen. Inter-tissue correlations were rarely observed. To investigate method-dependent experimental variability, we re-analyzed the same spleen and tongue samples using SIRPH and pyrosequencing methods and reconfirmed intra-tissue correlations for spleen and sex-associated correlations for DNA methylation for tongue. When we repeated DNA methylation measurements for a second mouse population raised under similar conditions three months later, we did not detect sex-associated or intra-tissues correlations. Additional studies that examine large numbers of loci may be required to further understand the factors that influence stability of DNA methylation
Long term tumour control of benign intracranial meningiomas after radiosurgery in a series of 4565 patients.
No full textBACKGROUND:: Radiosurgery is the main alternative to microsurgical resection for benign meningiomas. OBJECTIVE:: To assess the long-term efficacy and safety of radiosurgery for meningiomas with respect to tumour growth and prevention of associated neurological deterioration. Medium to long-term outcomes have been widely reported, but no large multicentre series with long-term follow-up have been published. METHODS:: From 15 participating centers we performed a retrospective observational analysis of 4565 consecutive patients harbouring 5300 benign meningiomas. All were treated with Gamma-Knife radiosurgery at least five years prior to assessment for this study. Clinical and imaging data were retrieved from each center and uniformly entered into a database by one author (AS). RESULTS:: Median tumour-volume was 4.8cc and median dose to tumour margin was 14Gy. All tumours with imaging follow-up less than 24 months were excluded. Detailed results from 3768 meningiomas (71\%) were analyzed. Median imaging follow-up was 63 months. The volume of treated tumours decreased in 2187 (58\%), remained unchanged in 1300 (34.5\%), and increased in 281 lesions (7.5\%), giving a control rate of 92.5\%. Only 84 (2.2\%) enlarging tumours required further treatment. Five and ten years progression-free-survival (PFS) rates were 95.2\% and 88.6\%, respectively. Tumour-control was higher for imaging defined tumours vs. Grade-I meningiomas (p<0.0001), for females vs. males (p<0.0001), for sporadic vs. multiple meningiomas (p<0.0001) and for skull-base vs. convexity tumours (p<0.0001). Permanent morbidity rate was 6.6\% at last follow-up. CONCLUSION:: Radiosurgery is a safe and effective method for treating benign meningiomas even in the medium to long-term
Heat maps of methylation values and variances.
No full text<p>A) Heat map and clustering of average methylation values (based on SIRPH results for the CpG-1 and first population of mice). Using the average linkage and Euclidean distance clustering method the average of all methylation values at a given loci/tissue in males (M) and females (F) (separate) are clustered. B) Heat map of variance of methylation values. The variance at each loci and tissue combination in both male and female mice subpopulations is shown. The levels of variances are noticeably similar in both sexes.</p
Methylation of L1Hs promoters is lower on the inactive X, has a tendency of being higher on autosomes in smaller genomes and shows inter-individual variability at some loci
No full textLINE-1 repeats account for ∼17% of the human genome. Little is known about their individual methylation patterns, because their repetitive, almost identical sequences make them difficult to be individually targeted. Here, we used bisulfite conversion to study methylation at individual LINE-1 repeats. The loci studied included 39 X-linked loci and 5 autosomal loci. On the X chromosome in women, we found statistically significant less methylation at almost all L1Hs compared with men. Methylation at L1P and L1M did not correlate with the inactivation status of the host DNA, while the majority of L1Hs that were possible to be studied lie in inactivated regions. To investigate whether the male–female differences at L1Hs on the X are linked to the inactivation process itself rather than to a mere influence of gender, we analyzed six of the L1Hs loci on the X chromosome in Turners and Klinefelters which have female and male phenotype, respectively, but with reversed number of X chromosomes. We could confirm that all samples with two X chromosomes are hypomethylated at the L1Hs loci. Therefore, the inactive X is hypomethylated at L1Hs; the latter could play an exclusive role in the X chromosome inactivation process. At autosomal L1Hs, methylation levels showed a correlation tendency between methylation level and genome size, with higher methylation observed at most loci in individuals with one X chromosome and the lowest in XXY individuals. In summary, loci-specific LINE-1 methylation levels show considerable plasticity and depend on genomic position and constitution.PublishedN/
Box plots of methylation values.
No full text<p>Box plots represent both male and female individual methylation data at each loci/tissues. Red boxes represent females and blue boxes represent males. Significant t-test (corrected for multiple testing by Bonferoni method) differences between sexes are indicated by a green bracket and a star (for detailed p values see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044585#pone.0044585.s006" target="_blank">Table S2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044585#pone.0044585.s007" target="_blank">S3</a>).</p
