Biomedical subjects

Marco Zucchelli

Publications and source records attributed to Marco Zucchelli.

7 recordsLinked to original sources

PubMed2007

The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus.

BACKGROUND: Several members of the GIMAP gene family have been suggested as being involved in different aspects of the immune system in different species. Recently, a mutation in the GIMAP5 gene was shown to cause lymphopenia in a rat model of autoimmune insulin-dependent diabetes. Thus it was hypothesised that genetic variation in GIMAP5 may be involved in susceptibility to other autoimmune disorders where lymphopenia is a key feature, such as systemic lupus erythematosus (SLE). MATERIAL AND METHODS: To investigate this, seven single nucleotide polymorphisms in GIMAP5 were analysed in five independent sets of family-based SLE collections, containing more than 2000 samples. RESULT: A significant increase in SLE risk associated with the most common GIMAP5 haplotype was found (OR 1.26, 95% CI 1.02 to 1.54, p = 0.0033). In families with probands diagnosed with trombocytopenia, the risk was increased (OR 2.11, 95% CI 1.09 to 4.09, p = 0.0153). The risk haplotype bears a polymorphic polyadenylation signal which alters the 3' part of GIMAP5 mRNA by producing an inefficient polyadenylation signal. This results in higher proportion of non-terminated mRNA for homozygous individuals (p<0.005), a mechanism shown to be causal in thalassaemias. To further assess the functional effect of the polymorphic polyadenylation signal in the risk haplotype, monocytes were treated with several cytokines affecting apoptosis. All the apoptotic cytokines induced GIMAP5 expression in two monocyte cell lines (1.5-6 times, p<0.0001 for all tests). CONCLUSION: Taken together, the data suggest the role of GIMAP5 in the pathogenesis of SLE.

Cytokines↗

PubMed2007

Potential role for the common cystic fibrosis DeltaF508 mutation in Crohn's disease.

BACKGROUND: Inflammatory bowel disease (IBD) is an epithelial barrier disease that is thought to result from a dysregulated interaction with bacteria in the intestine of genetically predisposed individuals. The cystic fibrosis transmembrane conductance regulator (CFTR), which is mutated in the autosomal recessive disease cystic fibrosis, modulates gut permeability, mucus production, and epithelial interactions with bacteria. The cystic fibrosis DeltaF508 mutation is commonly found in the general population and has been shown to result in a reduced number of CFTR molecules at the surface of epithelial cells. Given the important biological functions of CFTR in the intestine, we tested whether this mutation is of relevance to IBD. METHODS: Using DNA heteroduplex analysis, we investigated the distribution of DeltaF508 heterozygosity in 2568 subjects from three independent cohorts of Italian, Swedish, and Scottish IBD patients and controls. RESULTS: In all three cohorts an association between DeltaF508 and Crohn's disease (CD) was observed. Specifically, DeltaF508 heterozygosity was markedly underrepresented in CD patients from Italy and Sweden (P = 0.021 and 0.027 versus controls, respectively), while stratification for disease location revealed an absence of DeltaF508 carriers among Scottish CD patients with right-sided colitis (P = 0.023 versus all other locations). CONCLUSIONS: DeltaF508 heterozygosity might exert a protective effect in CD.

Adolescent↗

PubMed2005

Strong genetic evidence of DCDC2 as a susceptibility gene for dyslexia.

We searched for linkage disequilibrium (LD) in 137 triads with dyslexia, using markers that span the most-replicated dyslexia susceptibility region on 6p21-p22, and found association between the disease and markers within the VMP/DCDC2/KAAG1 locus. Detailed refinement of the LD region, involving sequencing and genotyping of additional markers, showed significant association within DCDC2 in single-marker and haplotype analyses. The association appeared to be strongest in severely affected patients. In a second step, the study was extended to include an independent sample of 239 triads with dyslexia, in which the association--in particular, with the severe phenotype of dyslexia--was confirmed. Our expression data showed that DCDC2, which contains a doublecortin homology domain that is possibly involved in cortical neuron migration, is expressed in the fetal and adult CNS, which--together with the hypothesized protein function--is in accordance with findings in dyslexic patients with abnormal neuronal migration and maturation.

Base Sequence↗

PubMed2005

Gene mapping with pooled samples on three genotyping platforms.

We have evaluated three genotyping techniques to detect allelic association between single nucleotide polymorphisms (SNPs) and disease loci by using pooled DNA samples. The use of DNA pools instead of individual samples saves considerably time, DNA quantity, and reagent costs. The methods that were compared were PCR-restriction fragment length polymorphism (PCR-RFLP), Single nucleotide primer extension, and chip-based mass spectrometry. As a model disease we studied an autosomal recessive disorder, congenital chloride diarrhea (CLD), caused by mutations in the human gene SLC26A3 on chromosome 7q31. Patient, carrier, and control pools were genotyped with eight SNP markers located within 10 cM around the target gene. Measured allele frequencies were consistent between the three platforms and we detected disease association with a cluster of several SNPs, the most significant being the marker located closest to the target gene (p=1.56 x 10(-16)). The largest source of error in pooled genotyping was shown to be the volumetric error in preparing the pools. The PCR-RFLP method was further evaluated by applying the pooling strategy to an ongoing multicenter-study. Measured allele frequencies of six polymorphisms agreed well with those measured individually and confirmed that multiple platforms are suitable for pooled genotyping.

Chromosome Mapping↗

PubMed2005

Haplotype construction of the FRDA gene and evaluation of its role in type II diabetes.

A GAA-repeat in the X25 gene is causing Friedreich's ataxia (FRDA), a common neurodegenerative disease and >20% of FRDA patients develop type II diabetes (T2D). Linkage has previously been detected between T2D and chromosome 9p13-q21, the region that harbours the X25 gene, but association studies of this gene in T2D have been contradicting. Here, we examined whether genetic variation in the X25 gene is associated with risk for T2D. The GAA-repeat and 18 single nucleotide polymorphisms (SNPs) covering the X25 gene were genotyped in 220 trios in which the affected offspring had abnormal glucose tolerance. Any nominally significant findings were examined in an independent sample consisting of 523 individuals with T2D and 326 healthy controls. Previously reported results were analysed together with our data using a meta-analysis approach. There was no association between the GAA-repeat and T2D susceptibility in our study, which was supported by the meta-analysis including all previous publications. One SNP (rs2498429), 8.2 kb downstream of X25, was nominally associated with T2D in the trios (P=0.02) and showed a trend of association in the same direction in the case-controls (P=0.08; combined permuted P=0.01). Further analysis showed that the nine-marker haplotype containing the rare allele of rs2498429 was nominally associated with T2D in the trios (P<0.01) as well as in the case-controls (P=0.03). In conclusions, this study excludes a role of genetic variation within the X25 gene, but instead suggests that genetic variation downstream the X25 gene, may increase risk for T2D.

Adult↗

PubMed2004

Characterization of a common susceptibility locus for asthma-related traits.

Susceptibility to asthma depends on variation at an unknown number of genetic loci. To identify susceptibility genes on chromosome 7p, we adopted a hierarchical genotyping design, leading to the identification of a 133-kilobase risk-conferring segment containing two genes. One of these coded for an orphan G protein-coupled receptor named GPRA (G protein-coupled receptor for asthma susceptibility), which showed distinct distribution of protein isoforms between bronchial biopsies from healthy and asthmatic individuals. In three cohorts from Finland and Canada, single nucleotide polymorphism-tagged haplotypes associated with high serum immunoglobulin E or asthma. The murine ortholog of GPRA was up-regulated in a mouse model of ovalbumin-induced inflammation. Together, these data implicate GPRA in the pathogenesis of atopy and asthma.

Algorithms↗

PubMed2004

Fine mapping of the 2p11 dyslexia locus and exclusion of TACR1 as a candidate gene.

Developmental dyslexia, or reading disability, is a multigenic complex disease for which at least five loci, i.e. DYX1-3 and DYX5-6, have been clearly identified from the human genome. To date, DYX1C1 is the only dyslexia candidate gene cloned. We have previously reported linkage to 2p11 and 7q32 in 11 Finnish pedigrees. Here, we report the fine mapping of the approximately 40-cM linked region from chromosome 2 as we increased marker density to one per 1.8 cM. Linkage was supported with the highest NPL score of 3.0 (P=0.001) for marker D2S2216. Association analysis using the six pedigrees showing linkage pointed to marker D2S286/rs3220265 (P value <0.001) in the near vicinity of D2S2216. We went on to further characterise this approximately 15-cM candidate region (D2S2110-D2S2181) by adding six SNPs covering approximately 670 kb centred at D2S286/rs3220265. A haplotype pattern could no longer be observed in this region, which was therefore excluded from the candidate area. This also excluded the TACR1 (tachykinin receptor 1) gene, located at marker D2S286. The dyslexia candidate region on 2p11 is, therefore, now limited to the chromosomal area D2S2116-D2S2181, which is approximately 12 Mbp of human sequence and is at a distinct location from the previously reported DYX3 locus, raising the possibility of two distinct loci on chromosome 2p.

Blotting, Northern↗