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Jacek Majewski

Publications and source records attributed to Jacek Majewski.

30 records · Page 2Linked to original sources
PubMed2003

Age-related macular degeneration--a genome scan in extended families.

We performed a genomewide scan and genetic linkage analysis, to identify loci associated with age-related macular degeneration (AMD). We collected 70 families, ranging from small nuclear families to extended multigenerational pedigrees and consisting of a total of 344 affected and 217 unaffected members available for genotyping. We performed linkage analyses using parametric and allele-sharing models. We performed the analyses on the complete pedigrees but also subdivided the families into nuclear pedigrees. Finally, to dissect potential genetic factors responsible for differences in disease manifestation, we stratified the sample by two major AMD phenotypes (neovascular AMD and geographic atrophy) and by age of affected family members at the time of our evaluation. We have previously demonstrated linkage between AMD and 1q25-31 in a single large family. In the combined sample, we have detected the following loci with scores exceeding a LOD=2 cutoff under at least one of the models considered: 1q31 (HLOD=2.07 at D1S518), 3p13 (HLOD=2.19 at D3S1304/D3S4545), 4q32 (HLOD=2.66 at D4S2368, for the subset of families with predominantly dry AMD), 9q33 (LODZlr=2.01 at D9S930/D9S934), and 10q26 (HLOD=3.06 at D10S1230). Using correlation analysis, we have found a statistically significant correlation between LOD scores at 3p13 and 10q26, providing evidence for epistatic interactions between the loci and, hence, a complex basis of AMD. Our study has identified new loci that should be considered in future mapping and mutational analyses of AMD and has strengthened the evidence in support of loci suggested by other studies.

Aging↗
PubMed2003

Dependence of mutational asymmetry on gene-expression levels in the human genome.

A great deal of effort has been devoted to measuring the rates of different types of nucleotide substitutions. Mutation rates are known to depend on factors such as methylation status and nearest-neighbor nucleotide effects. However, until recently, in eukaryotes, the rates have not been considered to be strand specific. In a recent analysis of mammalian lineages, Green et al. (2003) uncovered an asymmetry in the frequencies of substitutions on the coding and noncoding strands of genes and showed that this resulted in a nucleotide-content asymmetry within most genes. The authors argue that this bias may be caused by the mammalian transcription-coupled repair in germ cells, but they did not demonstrate an association with germ-cell gene expression. In this work, I analyze nucleotide contents in genes with known expression patterns and levels and provide evidence that the observed asymmetry in mutation rates is, in fact, caused by transcription. The results also imply that germline transcription may occur in a large percentage, 71%-91%, of all human genes.

Databases, Genetic↗
PubMed2003

Amino acid substitutions in the human genome: evolutionary implications of single nucleotide polymorphisms.

Functional differences between amino acids have long been of interest in understanding protein evolution. Several indices exist for comparing residues on the basis of their physicochemical properties and frequencies of occurrence in conserved protein alignments. Here we present a residue dissimilarity index based on coding single nucleotide polymorphisms (SNPs) in the human genome. The index represents an average, organism-wide set of differences between residues and provides important insight into evolutionary restraints on residue substitutions in the human genome. Unlike previous models, it is not restricted to highly conserved protein structures, nor confounded by evolutionary differences between species. Our results confirm earlier observations regarding residue mutabilities but also suggest that in addition to the established key properties, such as size and polarity, charge conservation may be an important and currently underestimated factor in protein evolution. We also estimate that less than 51% of amino acid substitutions occurring in the human genome are evolutionarily neutral.

Amino Acid Substitution↗
PubMed2003

Lack of an association of apolipoprotein E gene polymorphisms with familial age-related macular degeneration.

BACKGROUND: Previously, the epsilon 4 allele of apolipoprotein E (APOE) was reported to have a significant association with a decreased risk of age-related macular degeneration (AMD). In addition, the epsilon 2 allele of APOE was reported to be possibly associated with an increased risk of AMD. OBJECTIVE: To determine if APOE polymorphisms, previously reported to be associated with AMD, affect its expression in medium to large families, as well as in unrelated patients with AMD. METHODS: The APOE genotype was determined by HhaI restriction digests of polymerase chain reaction-amplified products in a collection of 259 affected and 207 unaffected individuals from 56 AMD families. Genotypes were determined similarly in a set of 104 unrelated AMD patients and in 113 unaffected control subjects. Diagnosis of AMD was based on clinical examination and evaluation of fundus photographs. Evidence of an association between alleles of APOE and AMD in families was tested by the following 4 statistical methods: chi2 analysis of simple allele counting, logistic regression analysis adjusting for age, construction of likelihood ratios of haplotype frequencies, and the pedigree disequilibrium test. RESULTS: None of the statistical methods used showed a significant association between the common alleles of APOE and AMD in our collection of families or in the set of unrelated AMD patients. CONCLUSIONS: No evidence was found to support an association between AMD in medium to large families and the epsilon 4 or epsilon 2 alleles of APOE. Neither was any evidence found for an association of APOE polymorphisms with the set of unrelated patients with AMD. However, a trend for a decreased risk of AMD associated with APOE epsilon 4 was observed in the set of unrelated patients with a family history of AMD.

Aged↗
PubMed2003

Familial juvenile hyperuricaemic nephropathy (FJHN): linkage analysis in 15 families, physical and transcriptional characterisation of the FJHN critical region on chromosome 16p11.2 and the analysis of seven candidate genes.

Familial juvenile hyperuricaemic nephropathy (FJHN) is an autosomal dominant renal disease characterised by juvenile onset of hyperuricaemia, gouty arthritis, and progressive renal failure at an early age. Recent studies in four kindreds showed linkage of a gene for FJHN to the same genomic interval on chromosome 16p11.2, where the gene for the phenotypically similar medullary cystic disease type 2 (MCKD2) has been localised. In this study we performed linkage analysis in additional 15 FJHN families. Linkage of FJHN to 16p11.2 was confirmed in six families, which suggests that, in a large proportion of FJHN kindreds, the disease is likely to be caused by a gene or genes located outside of 16p11.2. Haplotype analysis of the new and previously analysed families provided two non-overlapping critical regions on 16p11.2-FJHN1, delimited by markers D16S499-D16S3036 and FJHN2, delimited by markers D16S412-D16S3116. Considering MCKD2 to be a distinct molecular entity, the analysis suggests that as many as three kidney disease genes may be located in close proximity on 16p11.2. From genomic databases we compiled integrated physical and transcription maps of whole critical genomic region in which 45 known genes and 129 predicted loci have been localised. We selected, analysed and found no pathogenic mutations in seven candidate genes. The linkage and haplotype analysis reported here demonstrates the genetic heterogeneity of FJHN. The report of integrated physical and mostly in-silico predicted transcription maps of the FJHN critical region provides a basis for precise experimental annotation of the current transcript map, which is essential for final identification of the FJHN gene(s).

Chromosome Mapping↗
PubMed2003

[Pacemaking in Cracow in years 1966-1980].

Permanent pacemaking, a new and effective bradycardia--treatment method, has appeared in the sixties. In Cracow the first emergency temporary stimulation by means of transvenously inserted intracardiac electrode was performed in 1966. Permanent technique of artificial pacing was introduced soon after. The number of pacemaker implantations grew successfully, obtaining 750 of the end of the seventies when the Institute of Cardiology of Nicolaus Copernicus Medical Academy was established. Assortment of implantable devices also became wider, including such rare constructions like nuclear pacemakers and an inductive coupled pacemaker.

Bradycardia↗
PubMed2002

Cold-induced sweating syndrome is caused by mutations in the CRLF1 gene.

In 1978, Sohar et al. described a strikingly peculiar syndrome in two Israeli sisters. These young women responded to environmental temperatures of 18 degrees C-7 degrees C with profuse sweating on large segments on their back and chest. Both had additional abnormalities, including a high-arched palate, nasal voice, depressed nasal bridge, inability to fully extend their elbows, and kyphoscoliosis. We have observed this disorder in two Norwegian brothers. Genome-wide screening in the two families, followed by saturation marker studies and linkage analysis, identified a 1.4-Mb homozygous candidate region on chromosome 19p12. The maximum multipoint LOD score was 4.22. In both families, DNA sequencing of 25 genes within the candidate region identified potentially deleterious CRLF1 sequence variants that were not found in unaffected control individuals. Our findings confirm that the cold-induced sweating syndrome is an autosomal recessive disorder that is probably caused by impaired function of the CRLF1 gene, and they suggest important developmental functions for human CRLF1.

Adolescent↗
PubMed2002

Distribution and characterization of regulatory elements in the human genome.

The regulation of transcription and subsequent gene splicing are crucial to correct gene expression. Although a number of regulatory sequences involved in both processes are known, it is not clear how general their functions are in the genomic context, nor how the regulatory regions are distributed throughout the genome. Here we study the distribution of known mutagenic elements within human introns and exons to deduce the properties of regions essential for splicing and transcription. We show that intronic splicing regulators are generally found close to the splice sites, but may be found as far as 200 nucleotides away from the splice junctions. Similarly, sequences important for splicing may be located as far as 125 nucleotides away from the junctions, within exons. We characterize several types of simple repetitive sequences and low-complexity regions that are overrepresented close to both intron ends and are likely to play important roles in the splicing process. We show that the first introns within most genes play a particularly important regulatory role that is most likely, however, to be involved in transcription control. We also study the distribution of two known regulatory motifs, the GGG trinucleotide and the CpG dinucleotide, and deduce their respective importance to splicing and transcription regulation.

Base Composition↗
PubMed2002

[The importance of echocardiographic evaluation in patients treated with cardiac pacing].

This study evaluated the usefulness of echocardiographic evaluation in the selection of optimal atrioventricular delay (AVD) in DDD-paced patients. We discussed the influence of various AVD programming on systolic and diastolic left ventricle function. The detrimental effect of diastolic mitral regurgitation (DMR) on stroke volume was emphasized. Clinically useful echocardiographic methods of optimal AVD selection and prevention of DMR was discussed.

Atrioventricular Node↗
PubMed2002

[Efficacy of radiofrequency ablation with anatomical approach in the treatment of atrioventricular nodal re-entrant tachycardia].

UNLABELLED: The aim of the study was to evaluate the efficacy of radiofrequency (RF) ablation with anatomical approach in treatment of atrioventricular nodal reentrant tachycardia (AVNRT). The study group consisted of 45 patients (pts), 34 F, 11 M, mean age 46.3 +/- 11.8 y in whom AVNRT was diagnosed. In all the pts successful RF ablation of slow pathway was performed. Ablation catheter was positioned under fluoroscopy control in the bottom part of Koch's triangle using anatomical approach. Mean number of RF applications during the procedure was 6.9 +/- 7.5. During successful RF application accelerated junctional rhythm or junctional beats were present in 36 pts (80%) and in 6 pts (13.3%) respectively. Slow pathway potentials (SPp) were recorded at successful ablation site in 8 pts (17.8%). Follow-up time after ablation was mean 15.5 +/- 10.7 m. In 2 pts (4.4%) tachycardia recurred after successful procedure. In 1 pt episodic asymptomatic second degree atrioventricular block developed 4 weeks after ablation. CONCLUSIONS: 1) slow pathway RF ablation using anatomical approach is highly effective in the treatment of AVNRT, 2) SPp have a low sensitivity as indicators of successful ablation site.

Catheter Ablation↗