| 31. |
- Penno, Hendrik, 1962-, et al.
(författare)
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Polymorphic variations in the gene for osteoprotegerin are associated with bone mineral density and predict fractures in elderly men: Data from Mr OS Sweden. :
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Osteoporosis is a polygenetic disorder where several genes are known to be involved. In this report we investigated the association between polymorphic variations in the gene for osteoprotegerin (OPG) and bone mineral density (BMD) and fragility fractures in elderly men. Methods: The study was performed in Mr OS Sweden, a cohort consisting of 3014 randomly selected men between 69 and 81 years of age, where at baseline BMD was measured at hip and spine by dual energy X ray absorbtiometry (DXA) and blood samples extracted. DNA was then isolated and the OPG gene was characterised. Prospective fractures, all verified by X-rays, were recorded for 5 years following baseline. Common variants in the 3’ and 5’UTR of the OPG gene was typed using Sequenom technology. Results: There was a significant association between common genetic variants in the gene for OPG and BMD at both hip (top SNP rs10955908, p<0.0008) and spine (top SNP rs10955908, p<0.0008) . The differences in BMD related to presence of various OPG alleles were between 0.5-3.5%. There was also an association with fragility fractures with odds ratio for rs6993813 reaching statistical significance (p=0.03) For five other SNPs were tested were the association with fractures did not reach statistical significance (p=0.12 - 0.19). Conclusion: Polymorphic variations in the gene for OPG are associated with BMD and fragility fractures in elderly men. The data support the view that variation in the OPG gene is a determinant for BMD and fragility fracture risk also in men.
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| 32. |
- Penno, Hendrik, 1962-, et al.
(författare)
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Polymorphic variations in the gene for osteoprotegerin do not predict prostate cancer incidence: Data from MrOS Sweden.
- 2011
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background Prostate cancer cells have been shown to produce and secrete osteoprotegerin (OPG), that inhibits tumor cell death by binding to TNF-related anti apoptotic ligand (TRAIL), and also is a key regulator of bone turnover . Bone metastases play a central role in prostate cancer spreading. However, the mechanisms underlying the interaction between bone cells and prostate cancer cells are not known. The aim of this study was therefore to investigate whether polymorphic variations in the gene for OPG affect prostate cancer incidence, or extra prostatic disease and metastasis. Methods The study was performed in the MrOS-Sweden cohort consisting of 3,014 men aged 69-81 years. DNA was collected at the start of the study and the gene for OPG was investigated concerning SNPs previously shown to regulate bone mineral density (BMD), and therefore of biological importance. Data on prostate cancer prevalence at baseline, and incidence during a 3-year follow-up were collected from the Swedish Cancer Register. The association of six OPG polymorphisms with prostate cancer was evaluated. Results The association between six OPG polymorphisms and prostate cancer was evaluated. In these analyses there were no significant genotype differences between prostate cancer patients and controls. A tendency for an association between OPG genotypes and more severe disease (p=0.08-0.09) was found however regarding OPG genotypes. Conclusion Polymorphic variations in the gene for OPG are not associated with prostate cancer incidence. Our data on staging of prostate cancer at the diagnose according to the TNM system in regard to the variations in the OPG gene gave some tendencies to possible involvement but further studies are required to investigate the potential role of the OPG/RANK/RANKL system in the metastatic skeletal prostate cancer spreading, and growth, in bone.
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| 33. |
- Raitio, Mirja, et al.
(författare)
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Y-chromosomal SNPs in Finno-Ugric-speaking populations analyzed by minisequencing on microarrays
- 2001
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 11:3, s. 471-482
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Tidskriftsartikel (refereegranskat)abstract
- An increasing number of single nucleotide polymorphisms (SNPs) on the Y chromosome are being identified. To utilize the full potential of the SNP markers in population genetic studies, new genotyping methods with high throughput are required. We describe a microarray system based on the minisequencing single nucleotide primer extension principle for multiplex genotyping of Y-chromosomal SNP markers. The system was applied for screening a panel of 25 Y-chromosomal SNPs in a unique collection of samples representing five Finno--Ugric populations. The specific minisequencing reaction provides 5-fold to infinite discrimination between the Y-chromosomal genotypes, and the microarray format of the system allows parallel and simultaneous analysis of large numbers of SNPs and samples. In addition to the SNP markers, five Y-chromosomal microsatellite loci were typed. Altogether 10,000 genotypes were generated to assess the genetic diversity in these population samples. Six of the 25 SNP markers (M9, Tat, SRY10831, M17, M12, 92R7) were polymorphic in the analyzed populations, yielding six distinct SNP haplotypes. The microsatellite data were used to study the genetic structure of two major SNP haplotypes in the Finns and the Saami in more detail. We found that the most common haplotypes are shared between the Finns and the Saami, and that the SNP haplotypes show regional differences within the Finns and the Saami, which supports the hypothesis of two separate settlement waves to Finland.
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| 34. |
- Sigurdsson, Snaevar, et al.
(författare)
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A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5
- 2008
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 17:18, s. 2868-2876
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is the prototype autoimmune disease where genes regulated by type I interferon (IFN) are over-expressed and contribute to the disease pathogenesis. Because signal transducer and activator of transcription 4 (STAT4) plays a key role in the type I IFN receptor signaling, we performed a candidate gene study of a comprehensive set of single nucleotide polymorphism (SNPs) in STAT4 in Swedish patients with SLE. We found that 10 out of 53 analyzed SNPs in STAT4 were associated with SLE, with the strongest signal of association (P = 7.1 x 10(-8)) for two perfectly linked SNPs rs10181656 and rs7582694. The risk alleles of these 10 SNPs form a common risk haplotype for SLE (P = 1.7 x 10(-5)). According to conditional logistic regression analysis the SNP rs10181656 or rs7582694 accounts for all of the observed association signal. By quantitative analysis of the allelic expression of STAT4 we found that the risk allele of STAT4 was over-expressed in primary human cells of mesenchymal origin, but not in B-cells, and that the risk allele of STAT4 was over-expressed (P = 8.4 x 10(-5)) in cells carrying the risk haplotype for SLE compared with cells with a non-risk haplotype. The risk allele of the SNP rs7582694 in STAT4 correlated to production of anti-dsDNA (double-stranded DNA) antibodies and displayed a multiplicatively increased, 1.82-fold risk of SLE with two independent risk alleles of the IRF5 (interferon regulatory factor 5) gene.
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| 35. |
- Sud, Amit, et al.
(författare)
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Genome-wide association study implicates immune dysfunction in the development of Hodgkin lymphoma
- 2018
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 132:19, s. 2040-2052
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Tidskriftsartikel (refereegranskat)abstract
- To further our understanding of inherited susceptibility to Hodgkin lymphoma (HL), we performed a meta-analysis of seven genome-wide association studies totalling 5,325 HL cases and 22,423 controls. We identify five new HL risk loci at 6p21.31 (rs649775, P = 2.11 × 10-10), 6q23.3 (rs1002658, P = 2.97 × 10-8), 11q23.1 (rs7111520, P = 1.44 × 10-11), 16p11.2 (rs6565176, P = 4.00 × 10-8) and 20q13.12 (rs2425752, P = 2.01 × 10-8). Integration of gene expression, histone modification and in situ promoter capture Hi-C data at the five new and 13 known risk loci implicates dysfunction of the germinal centre reaction, disrupted T-cell differentiation and function, and constitutive NF-κB activation as mechanisms of predisposition. These data provide further insights into the genetic susceptibility and biology of HL.
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| 36. |
- Verlaan, Dominique J., et al.
(författare)
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Targeted screening of cis-regulatory variation in human haplotypes
- 2009
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 19:1, s. 118-127
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Tidskriftsartikel (refereegranskat)abstract
- Regulatory cis-acting variants account for a large proportion of gene expression variability in populations. Cis-acting differences can be specifically measured by comparing relative levels of allelic transcripts within a sample. Allelic expression (AE) mapping for cis-regulatory variant discovery has been hindered by the requirements of having informative or heterozygous single nucleotide polymorphisms (SNPs) within genes in order to assign the allelic origin of each transcript. In this study we have developed an approach to systematically screen for heritable cis-variants in common human haplotypes across >1,000 genes. In order to achieve the highest level of information per haplotype studied, we carried out allelic expression measurements by using both intronic and exonic SNPs in primary transcripts. We used a novel RNA pooling strategy in immortalized lymphoblastoid cell lines (LCLs) and primary human osteoblast cell lines (HObs) to allow for high-throughput AE. Screening hits from RNA pools were further validated by performing allelic expression mapping in individual samples. Our results indicate that >10% of expressed genes in human LCLs show genotype-linked AE. In addition, we have validated cis-acting variants in over 20 genes linked with common disease susceptibility in recent genome-wide studies. More generally, our results indicate that RNA pooling coupled with AE read-out by second generation sequencing or by other methods provides a high-throughput tool for cataloging the impact of common noncoding variants in the human genome.
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| 37. |
- Wahlberg, Per, et al.
(författare)
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DNA methylome analysis of acute lymphoblastic leukemia cells reveals stochastic de novo DNA methylation in CpG islands
- 2016
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Ingår i: Epigenomics. - : Future Medicine Ltd. - 1750-1911 .- 1750-192X. ; 8:10, s. 1367-1387
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To identify regions of aberrant DNA methylation in acute lymphoblastic leukemia (ALL) cells of different subtypes on a genome-wide scale. Materials & methods: Whole-genome bisulfite sequencing (WGBS) was used to determine the DNA methylation levels in cells from four pediatric ALL patients of different subtypes. The findings were confirmed by 450k DNA methylation arrays in a large patient set. Results: Compared with mature B or T cells WGBS detected on average 82,000 differentially methylated regions per patient. Differentially methylated regions are enriched to CpG poor regions, active enhancers and transcriptional start sites. We also identified approximately 8000 CpG islands with variable intermediate DNA methylation that seems to occur as a result of stochastic de novo methylation. Conclusion: WGBS provides an unbiased view and novel insights into the DNA methylome of ALL cells.
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| 38. |
- Zheng, Hou-Feng, et al.
(författare)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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