The age dynamics of stable chromosome aberration (SCA) frequency was analysed by fluorescent in situ hybridization (FISH) in human blood lymphocytes derived from donors, irradiated by low doses of ionizing radiation (Chernobyl clean-up workers, nuclear weapon testers, etc.) and patients with hereditary premature aging--Werner's syndrome and Hutchinson-Gilford's syndrome. It was found that the level of SCA was age-dependent and increased in irradiated persons. So, the SCA level may be really an index of a so-called "radiation senescence", and may show a real biological age of irradiated persons. The patients with Werner's syndrome demonstrate increased SCA level in blood lymphocytes, corresponding to the premature aging of the organisms. But in the case of another form of premature aging--Hutchinson--Gilford's syndrome-- no rise of SCA level was found. Some possible reasons of such results are discussed.
Allergic rhinitis is a common disease of complex inheritance and is characterised by mucosal inflammation caused by allergen exposure. The genetics of closely related phenotypes such as asthma, atopy and to some extend atopic dermatitis has attracted attention in recent years. Genetic reports of allergic rhinitis on the contrary have as yet been most sparse. To identify candidate regions holding genes for allergic rhinitis we performed a total genome-scan on affected sib-pair families. From 100 Danish sib-pair families selected for allergy, families containing sib-pairs matching a phenotype definition of both clinical allergic rhinitis and confirmed specific allergy were chosen. Thirty-three affected sib-pair families qualified for the scan that was undertaken using 446 microsatellite markers. Non-parametric linkage results were obtained from MAPMAKER/SIBS computer program. The study revealed one major candidate region on chromosome 4q24-q27 (LOD=2.83) and eight minor candidate regions 2q12-q33, 3q13, 4p15-q12, 5q13-q15, 6p24-p23, 12p13, 22q13, and Xp21 (LOD=1.04-1.63) likely to contain susceptibility genes for allergic rhinitis. Our findings did not support a previous report of linkage of allergic rhinitis to chromosome 12q14-q24 but they added positive evidence to the asthma and atopy candidate regions 2q33 and 6p23. Further identification of the specific genes involved in allergic rhinitis will give opportunities for improved diagnosis and treatment.
The role of genetic factors in the etiology of the autistic spectrum of disorders has clearly been demonstrated. Ten chromosomal regions, on chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q and 22q have potentially been linked to autism.1-8 We have analyzed these chromosomal regions in a total of 17 multiplex families with autism originating from the isolated Finnish population by pairwise linkage analysis and sib-pair analysis. Mild evidence for putative contribution was found only with the 1p chromosomal region in the susceptibility to autism. Our data suggest that additional gene loci exist for autism which will be detectable in and even restricted to the isolated Finnish population.
Psoriasis is known to be a heterogeneous disease with so far three reported major psoriasis susceptibility loci on chromosome 4q, 6p and 17q. In this study we investigated three reported gene locations by nonparametric and parametric linkage analysis in a large family set consisting of 104 families (153 sib pairs) from Sweden. We could confirm linkage to chromosome 6p. A maximum heterogeneous lod score of 2.78 was reached at locus D6S276 (alpha = 0.60). Allelic association studies within the HLA region indicated linkage disequilibrium at locus TNFbeta with a significant p value of 0.0009. Furthermore, we obtained weak evidence of linkage to the locus on chromosome 17q while no evidence of linkage could be found to the chromosome 4q region.
To identify whether a genetic variation (rs1800857; IVS1-5T>C) in the neuropeptide cholecystokinin-A receptor (CCKAR) gene is a risk factor in the pathogenesis of schizophrenia.
The variation was analysed in a case-control design comprising 508 patients with schizophrenia and 1619 control subjects. A possible functional impact of this variant on CCKAR protein synthesis through alterations in splicing was analysed in an exon-trapping assay.
In males only, the risk variant, IVS1-5C, was associated with a significantly increased risk of schizophrenia. Carrying one risk allele was associated with an increased risk of 1.74 (Odds Ratio, OR) and homozygosity (CC) was associated with an OR of 3.19. The variation had no impact on protein synthesis of CCKAR.
This is the first report associating the CCKAR gene variant with schizophrenia specifically in men. Our study strengthens the conclusion that a CCKAR dysfunction could be involved in the aetiology of schizophrenia.
The use of array comparative genomic hybridization (array CGH) as a diagnostic tool in molecular genetics has facilitated the identification of many new microdeletion/microduplication syndromes (MMSs). Furthermore, this method has allowed for the identification of copy number variations (CNVs) whose pathogenic role has yet to be uncovered. Here, we report on our application of array CGH for the identification of pathogenic CNVs in 79 Russian children with intellectual disability (ID). Twenty-six pathogenic or likely pathogenic changes in copy number were detected in 22 patients (28%): 8 CNVs corresponded to known MMSs, and 17 were not associated with previously described syndromes. In this report, we describe our findings and comment on genes potentially associated with ID that are located within the CNV regions.
BACKGROUND: Atrial fibrillation (AF) and atrial flutter (AFL) are common cardiac conduction disorders affecting many people. Recent studies on sporadic cases of AF/AFL showed a significant association of the single nucleotide polymorphism rs2200733T with the disease, suggesting a genetic factor in the development of the disease. OBJECTIVES: To determine the association of rs2200733 with AF/AFL derived from an Italian population sample. SUBJECTS: 78 patients with AF/AFL and 348 controls took part in the study. DESIGN: Genetic case-control study. RESULTS: The results indicate that there is a positive, significant association between the rs2200733 T allele and patients with AF/AFL of Italian origin (allelic p
Genome wide association studies have shown an association between rs2200733 at 4q25 and atrial fibrillation (AF). In this case-control study we investigate the association of rs2200733 and lone AF in young patients.
We included 196 young patients with lone AF and the first episode before the age of 40 years. We analyzed the single nucleotide polymorphism (SNP) rs2200733 for the lone AF patients and compared them to a control group of 176 age matched healthy individuals.
No significant differences, in neither genotype distribution, nor minor allele frequencies were found between the lone AF patients and the healthy controls.
Our results suggest that the rs220733 is not a risk factor for AF in patients with no other cardiovascular disease and with early onset of the arrhythmia.
The first genome-wide association study performed in a UK coeliac disease (CD) case-control cohort revealed association with a linkage disequilibrium block containing the KIAA1109/Tenr/IL2/IL21 genes. Also recently, an association with a non-synonymous polymorphism in FcgammaRIIa (CD32a) was reported in CD with an unusually strong P-value. We aimed to replicate the reported associations with the single nucleotide polymorphisms rs13119723 A>G and rs6822844 G>T in the KIAA1109/Tenr/IL2/IL21 region and rs1801274 G>A in the FcgammaRIIa gene in a family sample consisting of 325 Swedish/Norwegian families using the robust transmission disequilibrium test. The family sample used in this study included 100 families with two or more children affected by CD and 225 families with one affected child. We could confirm significant association between the polymorphisms rs13119723 A>G and rs6822844 G>T located in the KIAA1109/Tenr/IL2/IL21 region and CD (P-value 0.001 and 0.002, respectively). However, we found no association with the FcgammaRIIa rs1801274 G>A polymorphism (P-value=0.3). In conclusion, our results support the KIAA1109/Tenr/IL2/IL21 region as a true CD susceptibility region.
We report the results of a study of chromosome translocations in 126 Russian subjects who participated in the cleanup activities at Chernobyl and another 53 subjects, from other places in Russia, who were not exposed at Chernobyl. In agreement with our earlier study, we find increased translocation frequencies among the exposed compared to Russian controls. We describe statistical methods for estimating the dose of ionizing radiation determined by scoring chromosome translocations found in circulating lymphocytes sampled several years after exposure. Two statistical models were fitted to the data. One model assumed that translocation frequencies followed an overdispersed Poisson distribution. The second model assumed that translocation frequencies followed a negative binomial distribution. In addition, the effects of radiation exposure were modeled as additive or as multiplicative to the effects of age and smoking history. We found that the negative binomial model fit the data better than the overdispersed Poisson model. We could not distinguish between the additive and the multiplicative model with our data. Individual dose estimates ranged from 0 (for 43 subjects) to 0.56 Gy (mean 0.14 Gy) under the multiplicative model and from 0 to 0.95 Gy (mean 0.15 Gy) under the additive model. Dose estimates were similar under the two models when the number of translocations was less than 4 per 100 cells. The additive model tended to estimate larger doses when the number of translocations was greater than 4 per 100 cells. We also describe a method for estimating upper 95% tolerance bounds for numbers of translocations in unexposed individuals. We found that inclusion of data on age and smoking history was important for dose estimation. Ignoring these factors could result in gross overestimation of exposures, particularly in older subjects who smoke.