Abstract Variation in genes encoding retinoid acid-inducible gene I (RIG-I)-like receptors (RLRs) has been implicated in the pathogenesis of autoimmune disorders. We investigated if polymorphisms in ...the IFIH1 , RIG - I , LGP2 and VISA genes influence the risk for multiple sclerosis (MS) in a German case–control cohort comprising 716 patients and 706 controls. Evaluation of 18 single nucleotide polymorphisms (SNPs) in the four genes did not reveal significant single-SNP associations with MS risk, but two VISA polymorphisms were modestly associated with age of onset. Further, we provide initial evidence for combinatorial effects of polymorphic variants in the RIG - I , LGP2 and IFIH1 genes on MS risk.
Myopathies comprise a heterogeneous group of disorders characterized by variable phenotypes. The increasing use of next-generation sequencing allows identification of the causative genes in a much ...higher percentage of patients with hereditary muscle disorders and also illustrates a considerable degree of overlap with other clinical entities, including connective tissue disorders. Here, we present a 14-year-old German patient who was initially suspected to suffer from myopathy based on his clinical, radiological, and muscle biopsy findings. Exome sequencing revealed a novel homozygous nonsense mutation in the
gene, causative for spondylocheiro dysplastic Ehlers Danlos syndrome (SCD-EDS), suggesting a connective tissue disorder. Including our patient, only 9 affected individuals from 4 families have been described for SCD-EDS so far. The previously reported patients did not show obvious evidence of myopathy, suggesting a broader clinical presentation than originally suspected. We summarize herein the current knowledge on clinical features as well as pathophysiological pathways for this rare connective tissue disease and discuss the high degree of clinical overlap between myopathic and connective tissue disorders.
► The
CNR1 gene seems to be involved in the regulation of the P300 potential. ► (AAT)
n may alter the sensitivity to the acute effects of cannabinoids on P300. ► The number of AAT repeats correlates ...with P300 variables under acute THC.
Numerous studies demonstrated a close relationship between cannabis abuse and schizophrenia with similar impairments in cognitive processing, particularly in P300 generation. Recently, an (AAT)
n triplet repeat polymorphism within the cannabinoid receptor gene
CNR1 has been found to be associated with both schizophrenia and substance dependence, and to modulate the P300 potential. As previously reported, both acute oral Δ
9-tetrahydrocannabinol (Δ
9-THC), the main psychoactive constituent of cannabis, and standardized cannabis extract containing Δ
9-THC and cannabidiol (CBD) revealed a significant reduction of P300 amplitudes in healthy subjects but did not show any differences among each other. The aim of this study was to investigate whether the (AAT)
n polymorphism differentially modulates the effects of Δ
9-THC and cannabis extract on P300 generation in 20 healthy volunteers during an auditory choice reaction task. For the >10/>10 genotype, there was a significant decrease of P300 amplitude as well as a significant prolongation of P300 latency under pure Δ
9-THC but not under cannabis extract. Moreover, we found a significant correlation between the number of AAT repeats and P300 variables for the Δ
9-THC condition. Our data thus indicate that the
CNR1 gene seems to be involved in the regulation of the P300 wave as a marker of selective attention and working memory. Moreover, it appears that variations within
CNR1 may differentially alter the sensitivity to the acute effects of cannabinoids on P300 generation in healthy subjects.
The brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is involved in nerve growth and survival. Especially, a single nucleotide polymorphism (SNP) in the BDNF gene, ...Val66Met, has gained a lot of attention, because of its effect on activity-dependent BDNF secretion and its link to impaired memory processes. We hypothesize that the BDNF Val66Met polymorphism may have modulatory effects on the visual sensory (iconic) memory performance. Two hundred and eleven healthy German students (106 female and 105 male) were included in the data analysis. Since BDNF is also discussed to be involved in the pathogenesis of depression, we additionally tested for possible interactions with depressive mood. The BDNF Val66Met polymorphism significantly influenced iconic-memory performance, with the combined Val/Met–Met/Met genotype group revealing less time stability of information stored in iconic memory than the Val/Val group. Furthermore, this stability was positively correlated with depressive mood exclusively in the Val/Val genotype group. Thus, these results show that the BDNF Val66Met polymorphism has an effect on pre-attentive visual sensory memory processes.
► BDNF modulates sensory memory processes. ► BDNF especially affects the duration of sensory memory. ► Met-alleles are associated with more fragile sensory memory.
Ecological factors differently affect male and female animals and thereby importantly influence their life history and reproductive strategies. Caviomorph rodents are found in a wide range of ...habitats in South America and different social and mating systems have evolved in closely related species. This permits to study the impact of ecological factors on social evolution. In this study, we investigated the social organization and the mating system of the wild cavy (Cavia aperea), the ancestor of the domestic guinea pig, in its natural habitat in Uruguay. Based on our laboratory investigations, we expected a polygynous system with large males controlling access to females. Results from radiotelemetry and direct observations showed that females occupied small stable home ranges which were largely overlapped by that of one large male, resulting in a social organization of small harems. In some cases, small satellite males were associated with harems and intermediate-sized roaming males were occasionally observed on the study site. However, microsatellite analyses revealed that offspring were exclusively sired by large males of the same or neighboring harems, with a moderate degree of multiple paternity (13-27%). Thus, the mating system of C. aperea can be described as polygynous and contrasts with the promiscuous organization described for other species of cavies (Cavia magna, Galea musteloides and Microcavia australis) living under different ecological conditions. Our findings stress the strong impact of environmental factors on social evolution in Caviomorphs as resource distribution determines female space use and, thereby, the ability of males to monopolize females.
The Norwegian Lundehund breed of dog has undergone a severe loss of genetic diversity as a result of inbreeding and epizootics of canine distemper. As a consequence, the breed is extremely ...homogeneous and accurate sex identification is not always possible by standard screening of X-chromosomal loci. To improve our genetic understanding of the breed we genotyped 17 individuals using a genome-wide array of 170 000 single nucleotide polymorphisms (SNPs). Standard analyses based on expected homozygosity of X-chromosomal loci failed in assigning individuals to the correct sex, as determined initially by physical examination and confirmed with the Y-chromosomal marker, amelogenin. This demonstrates that identification of sex using standard SNP assays can be erroneous in highly inbred individuals.
Recently, a genome-wide association study showed that single-nucleotide polymorphisms (SNPs) in the chromosome 4q27 region containing IL2 and IL21 are associated with celiac disease. Given the ...increased prevalence of inflammatory bowel disease (IBD) among celiac disease patients, we investigated the possible involvement of these SNPs in IBD.
Five SNPs strongly associated with celiac disease within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block on chromosome 4q27 and one coding SNP within the IL21 gene were analyzed in a large German IBD cohort. The study population comprised a total of 2,948 Caucasian individuals, including 1,461 IBD patients (ulcerative colitis (UC): n=514, Crohn's disease (CD): n=947) and 1,487 healthy unrelated controls.
Three of the five celiac disease risk markers had a protective effect on UC susceptibility, and this effect remained significant after correcting for multiple testing: rs6840978: P=0.0082, P(corr)=0.049, odds ratio (OR) 0.77, 95% confidence interval (CI) 0.63-0.93; rs6822844: P=0.0028, P(corr)=0.017, OR 0.73, 95% CI 0.59-0.90; rs13119723: P=0.0058, P(corr)=0.035, OR 0.75, 95% CI 0.61-0.92. A haplotype consisting of the six SNPs tested was markedly associated with UC susceptibility (P=0.0025, P(corr)=0.015, OR 0.72, 95% CI 0.58-0.89). Moreover, in UC, epistasis was observed between the IL23R SNP rs1004819 and three SNPs in the KIAA1109/TENR/IL2/IL21 block (rs13151961, rs13119723, and rs6822844).
Similar to other autoimmune diseases such as celiac disease, rheumatoid arthritis, type 1 diabetes, Graves' disease, and psoriatic arthritis, genetic variation in the chromosome 4q27 region predisposes to UC, suggesting a common genetic background for these diseases.
Mitochondrial DNA (mtDNA) polymorphism is a possible factor contributing to the maternal parent-of-origin effect in multiple sclerosis (MS) susceptibility.
In order to investigate the role of mtDNA ...variations in MS, we investigated six European MS case-control cohorts comprising >5,000 individuals. Three well matched cohorts were genotyped with seven common, potentially functional mtDNA single nucleotide polymorphisms (SNPs). A SNP, nt13708 G/A, was significantly associated with MS susceptibility in all three cohorts. The nt13708A allele was associated with an increased risk of MS (OR = 1.71, 95% CI 1.28-2.26, P = 0.0002). Subsequent sequencing of the mtDNA of 50 individuals revealed that the nt13708 itself, rather than SNPs linked to it, was responsible for the association. However, the association of nt13708 G/A with MS was not significant in MS cohorts which were not well case-control matched, indicating that the significance of association was affected by the population structure of controls.
Taken together, our finding identified the nt13708A variant as a susceptibility allele to MS, which could contribute to defining the role of the mitochondrial genome in MS pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We analyzed ATG16L1, a recently identified Crohn's disease (CD) susceptibility gene, in a large cohort with inflammatory bowel disease (IBD) including potential interactions with other IBD genes as ...well as factors regulating its gene expression.
Genomic DNA from 2,890 Caucasians including 768 patients with CD, 507 patients with ulcerative colitis (UC), and 1,615 healthy controls was analyzed for 9 different ATG16L1 single nucleotide polymorphisms (SNPs). Genotyping included CARD15/NOD2 variants p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008 and polymorphisms in SLC22A4/OCTN1 (1672 C-->T) and SLC22A5/OCTN2 (-207 G-->C) as well as 10 CD-associated IL23R variants. The transcriptional regulation of ATG16L1 was studied in intestinal epithelial cells following stimulation with Toll-like receptor (TLR) ligands and proinflammatory cytokines and in a murine ileitis model and CD biopsies.
All nine ATG16L1 gene variants analyzed displayed highly significant associations with CD demonstrating a CD-protective effect for the minor allele. The strongest associations were found for rs2241879 and the coding SNP rs2241880 (T300A); P= 3.6 x 10(-6) and 3.7 x 10(-6), respectively (OR 0.74, 95% CI 0.65-0.84 for both variants). The genotype-phenotype analysis revealed no significant associations. In UC, only rs6431660 was weakly disease-associated. There was no evidence for epistasis between the ATG16L1 gene and other susceptibility genes (IL23R, CARD15, SLC22A4/5). ATG16L1 mRNA expression was not upregulated in CD and murine ileitis, and was less than threefold increased in cells stimulated with proinflammatory cytokines and TLR ligands.
ATG16L1 is a CD susceptibility gene without epistatic interaction with other CD susceptibility genes and is not upregulated in intestinal inflammation.
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