| 1. |
- Bergman, Annika, et al.
(författare)
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No germline mutations in supposed tumour suppressor genes SAFB1 and SAFB2 in familial breast cancer with linkage to 19p.
- 2008
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Ingår i: BMC Medical Genetics. - : BioMed Central. - 1471-2350. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The scaffold attachment factor B1 and B2 genes, SAFB1/SAFB2 (both located on chromosome 19p13.3) have recently been suggested as tumour suppressor genes involved in breast cancer development. The assumption was based on functional properties of the two genes and loss of heterozygosity of intragenic markers in breast tumours further strengthened the postulated hypothesis. In addition, linkage studies in Swedish breast cancer families also indicate the presence of a susceptibility gene for breast cancer at the 19p locus. Somatic mutations in SAFB1/SAFB2 have been detected in breast tumours, but to our knowledge no studies on germline mutations have been reported. In this study we investigated the possible involvement of SAFB1/SAFB2 on familiar breast cancer by inherited mutations in either of the two genes.RESULTS: Mutation analysis in families showing linkage to the SAFB1/2 locus was performed by DNA sequencing. The complete coding sequence of the two genes SAFB1 and SAFB2 was analyzed in germline DNA from 31 affected women. No missense or frameshift mutations were detected. One polymorphism was found in SAFB1 and eight polymorphisms were detected in SAFB2. MLPA-anlysis showed that both alleles of the two genes were preserved which excludes gene inactivation by large deletions.CONCLUSION: SAFB1 and SAFB2 are not likely to be causative of the hereditary breast cancer syndrome in west Swedish breast cancer families.
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| 2. |
- von Otter, Malin, 1978, et al.
(författare)
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Association of Nrf2-encoding NFE2L2 haplotypes with Parkinson's disease.
- 2010
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Ingår i: BMC medical genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Oxidative stress is heavily implicated in the pathogenic process of Parkinson's disease. Varying capacity to detoxify radical oxygen species through induction of phase II antioxidant enzymes in substantia nigra may influence disease risk. Here, we hypothesize that variation in NFE2L2 and KEAP1, the genes encoding the two major regulators of the phase II response, may affect the risk of Parkinson's disease. METHODS: The study included a Swedish discovery case-control material (165 cases and 190 controls) and a Polish replication case-control material (192 cases and 192 controls). Eight tag single nucleotide polymorphisms representing the variation in NFE2L2 and three representing the variation in KEAP1 were chosen using HapMap data and were genotyped using TaqMan Allelic Discrimination. RESULTS: We identified a protective NFE2L2 haplotype in both of our European case-control materials. Each haplotype allele was associated with five years later age at onset of the disease (p = 0.001) in the Swedish material, and decreased risk of PD (p = 2 x 10(-6)), with an odds ratio of 0.4 (95% CI 0.3-0.6) for heterozygous and 0.2 (95% CI 0.1-0.4) for homozygous carriers, in the Polish material. The identified haplotype includes a functional promoter haplotype previously associated with high transcriptional activity. Genetic variation in KEAP1 did not show any associations. CONCLUSION: These data suggest that variation in NFE2L2 modifies the Parkinson's disease process and provide another link between oxidative stress and neurodegeneration.
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| 3. |
- Montén, Caroline, et al.
(författare)
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Genes involved in muscle contractility and nutrient signaling pathways within celiac disease risk loci show differential mRNA expression
- 2015
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Risk gene variants for celiac disease, identified in genome-wide linkage and association studies, might influence molecular pathways important for disease development. The aim was to examine expression levels of potential risk genes close to these variants in the small intestine and peripheral blood and also to test if the non-coding variants affect nearby gene expression levels in children with celiac disease. Methods: Intestinal biopsy and peripheral blood RNA was isolated from 167 children with celiac disease, 61 with potential celiac disease and 174 disease controls. Transcript levels for 88 target genes, selected from celiac disease risk loci, were analyzed in biopsies of a smaller sample subset by qPCR. Differentially expressed genes (3 from the pilot and 8 previously identified) were further validated in the larger sample collection (n = 402) of both tissues and correlated to nearby celiac disease risk variants. Results: All genes were significantly down-or up-regulated in the intestinal mucosa of celiac disease children, NTS being most down-regulated (Fold change 3.6, p < 0.001). In contrast, PPP1R12B isoform C was up-regulated in the celiac disease mucosa (Fold change 1.9, p < 0.001). Allele specific expression of GLS (rs6741418, p = 0.009), INSR (rs7254060, p = 0.003) and NCALD (rs652008, p = 0.005) was also detected in the biopsies. Two genes (APPL2 and NCALD) were differentially expressed in peripheral blood but no allele specific expression was observed in this tissue. Conclusion: The differential expression of NTS and PPP1R12B indicate a potential role for smooth muscle contractility and cell proliferation in celiac disease, whereas other genes like GLS, NCALD and INSR suggests involvement of nutrient signaling and energy homeostasis in celiac disease pathogenesis. A disturbance in any of these pathways might contribute to development of childhood celiac disease.
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| 4. |
- von Otter, Malin, 1978, et al.
(författare)
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Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson's disease: a multicenter study
- 2014
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 15:1, s. artikel nr 131-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The transcription factor Nrf2, encoded by the NFE2L2 gene, is an important regulator of the cellular protection against oxidative stress. Parkinson s disease is a neurodegenerative disease highly associated with oxidative stress. In a previously published study, we reported associations of NFE2L2 haplotypes with risk and age at onset of idiopathic Parkinson s disease in a Swedish discovery material and a Polish replication material. Here, we have extended the replication study and performed meta-analyses including the Polish material and four new independent European patient-control materials. Furthermore, all SNPs included in the haplotype windows were investigated individually for associations with Parkinson s disease in meta-analyses including all six materials.Methods: Totally 1038 patients and 1600 control subjects were studied. Based on previous NFE2L2 haplotype associations with Parkinson s disease, five NFE2L2 tag SNPs were genotyped by allelic discrimination and three functional NFE2L2 promoter SNPs were genotyped by sequencing. The impact of individual SNPs and haplotypes on risk and age at onset of Parkinson s disease were investigated in each material individually and in meta-analyses of the obtained results.Results: Meta-analyses of NFE2L2 haplotypes showed association of haplotype GAGCAAAA, including the fully functional promoter haplotype AGC, with decreased risk (OR = 0.8 per allele, p = 0.012) and delayed onset (+ 1.1 years per allele, p = 0.048) of Parkinson s disease. These results support the previously observed protective effect of this haplotype in the first study. Further, meta-analyses of the SNPs included in the haplotypes revealed four NFE2L2 SNPs associated with age at onset of Parkinson s disease (rs7557529 G > A, -1.0 years per allele, p = 0.042; rs35652124 A > G, -1.1 years per allele, p = 0.045; rs2886161 A > G, -1.2 years per allele, p = 0.021; rs1806649 G > A, + 1.2 years per allele, p = 0.029). One of these (rs35652124) is a functional SNP located in the NFE2L2 promoter. No individual SNP was associated with risk of Parkinson s disease.Conclusion: Our results support the hypothesis that variation in the NFE2L2 gene, encoding a central protein in the cellular protection against oxidative stress, may contribute to the pathogenesis of Parkinson s disease. Functional studies are now needed to explore these results further.
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