| 1. |
- Abelson, Anna-Karin, 1978-
(författare)
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Genetic Risk Factors for Systemic Lupus Erythematosus : From Candidate Genes to Functional Variants
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis has been to identify genetic variants that increase the susceptibility for Systemic Lupus Erythematosus (SLE), an autoimmune disease caused by a complex interplay between various genetic and environmental factors. Five different candidate genes were selected through different strategies, and were analysed for association with SLE in an attempt to distinguish some of the underlying mechanisms of this disease. Two of these genes, PD-L1 and PD-L2, appeared not to contain any major risk factors for SLE in the analysed European and Latin American populations. In two other genes, CD24 and STAT4, there appeared to be population-specific effects. The A57V amino acid substitution in the CD24 gene, previously implicated with multiple sclerosis, was associated in a Spanish cohort, with a weak trend in German samples, and no association in Swedish. The previously reported and highly convincing association of the STAT4 transcription factor gene was confirmed in all our cohorts. Interestingly, the results indicate the presence of at least two independent risk variants: the first, represented by a previously reported SNP, was the strongest in individuals of Northern European ancestry, and the second was more pronounced in individuals from Southern Europe and Latin America. We also report the identification of a novel susceptibility gene. The BANK1 gene, encoding a scaffold protein involved in B-cell activation, contains functional variants affecting important domains, which are associated in all investigated cohorts from Europe and Latin America. These results confirm the existence of replicable associations between genetic variants and SLE, which are common and present in many populations. The results also illustrate a certain degree of heterogeneity, where some risk factors could have variable effect in different populations.
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| 2. |
- Abhyankar, Avinash, et al.
(författare)
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Comparative sequence analysis of the non-protein-coding mitochondrial DNA of inbred rat strains.
- 2009
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:12
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Tidskriftsartikel (refereegranskat)abstract
- The proper function of mammalian mitochondria necessitates a coordinated expression of both nuclear and mitochondrial genes, most likely due to the co-evolution of nuclear and mitochondrial genomes. The non-protein coding regions of mitochondrial DNA (mtDNA) including the D-loop, tRNA and rRNA genes form a major component of this regulated expression unit. Here we present comparative analyses of the non-protein-coding regions from 27 Rattus norvegicus mtDNA sequences. There were two variable positions in 12S rRNA, 20 in 16S rRNA, eight within the tRNA genes and 13 in the D-loop. Only one of the three neutrality tests used demonstrated statistically significant evidence for selection in 16S rRNA and tRNA-Cys. Based on our analyses of conserved sequences, we propose that some of the variable nucleotide positions identified in 16S rRNA and tRNA-Cys, and the D-loop might be important for mitochondrial function and its regulation.
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| 3. |
- Asad, Samina, et al.
(författare)
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HTR1A a Novel Type 1 Diabetes Susceptibility Gene on Chromosome 5p13-q13
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: We have previously performed a genome-wide linkage study in Scandinavian Type 1 diabetes (T1D) families. In the Swedish families, we detected suggestive linkage (LOD less than= 2.2) to the chromosome 5p13-q13 region. The aim of our study was to investigate the linked region in search for possible T1D susceptibility genes. Methodology/Principal Findings: Microsatellites were genotyped in the Scandinavian families to fine-map the previously linked region. Further, SNPs were genotyped in Swedish and Danish families as well as Swedish sporadic cases. In the Swedish families we detected genome-wide significant linkage to the 5-hydroxytryptamine receptor 1A (HTR1A) gene (LOD 3.98, pless than9.8x10(-6)). Markers tagging two separate genes; the ring finger protein 180 (RNF180) and HTR1A showed association to T1D in the Swedish and Danish families (pless than0.002, pless than0.001 respectively). The association was not confirmed in sporadic cases. Conditional analysis indicates that the primary association was to HTR1A. Quantitative PCR show that transcripts of both HTR1A and RNF180 are present in human islets of Langerhans. Moreover, immunohistochemical analysis confirmed the presence of the 5-HTR1A protein in isolated human islets of Langerhans as well as in sections of human pancreas. Conclusions: We have identified and confirmed the association of both HTR1A and RFN180, two genes in high linkage disequilibrium (LD) to T1D in two separate family materials. As both HTR1A and RFN180 were expressed at the mRNA level and HTR1A as protein in human islets of Langerhans, we suggest that HTR1A may affect T1D susceptibility by modulating the initial autoimmune attack or either islet regeneration, insulin release, or both.
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| 4. |
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| 5. |
- Berglundh, Sofia, et al.
(författare)
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C-reactive protein, bone loss, fracture, and mortality in elderly women: a longitudinal study in the OPRA cohort.
- 2015
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 1433-2965 .- 0937-941X. ; 26:2, s. 727-735
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Tidskriftsartikel (refereegranskat)abstract
- This longitudinal study investigates the association between C-reactive protein (CRP), osteoporosis, fractures, and mortality in 1044 elderly women. CRP was not an indicator for low bone mineral density (BMD), bone loss, or fracture in elderly women; however, women with elevated CRP levels over a prolonged period lost more bone over the 10-year follow-up, although fracture risk was not increased.
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| 6. |
- Dahlin, Lars, et al.
(författare)
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Nerve compression induces activating transcription factor 3 in neurons and Schwann cells in diabetic rats.
- 2008
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Ingår i: NeuroReport. - 1473-558X. ; 19:9, s. 987-990
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Tidskriftsartikel (refereegranskat)abstract
- Expression of transcription factor ATF3 in sensory neurons in dorsal root ganglion and in Schwann cells in sciatic nerve of diabetic (BB and Goto-Kakizaki rats; experimental models of types 1 and 2 diabetes, respectively) and healthy rats were examined by immunocytochemistry after nerve compression (silicone tube) for 3, 6 or 14 days. ATF3-stained sensory neurons in dorsal root ganglia and Schwann cells at compression site were more frequent in diabetic BB rats. Decompression of nerves in Goto-Kakizaki rats did not reduce number of ATF3-stained cells. Diabetes (BB; i.e. type 1) confers on the peripheral nerve an increased susceptibility to nerve compression indicated by an increased expression of stained ATF3 neurons and Schwann cells.
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| 7. |
- Ebrahimi, Parvaneh, et al.
(författare)
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Epigenome-wide cross-tissue correlation of human bone and blood DNA methylation–can blood be used as a surrogate for bone?
- 2021
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Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 16:1, s. 92-105
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Tidskriftsartikel (refereegranskat)abstract
- Difficulty in obtaining bone tissue is an obstacle to studying epigenetics to understand gene–environment interactions, and their role in disease pathogenesis. Blood is an obvious alternative and in this proof of principle study, our aim was to systematically investigate whether blood is a viable surrogate for bone. We measured epigenome-wide DNA methylation at 850 K CpG sites in matched trabecular bone and peripheral blood collected from the same patients at the same time-point (n = 12 women; 66–85y), to investigate the between-tissue correspondence. What constituted a CpG site with corresponding methylation in both tissues was stringently defined. Only sites highly correlated (r2 > 0.74; FDR q-value <0.05) and at least 80% similarity in methylation level (Δβ <0.2) between paired samples were retained. In total, 28,549 CpG sites were similarly methylated in bone and blood. Between 33% and 49% of loci associated with bone phenotypes through GWAS were represented among these sites, and major pathways relevant to bone regulation were enriched. The results from this study indicate that blood can mirror the bone methylome and capture sites related to bone regulation. This study shows that in principal, peripheral blood is a feasible surrogate for bone tissue in DNA methylation investigations. As the first step, this will provide a platform for future studies in bone epigenetics, and possibly for larger-scale epidemiological studies.
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| 8. |
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| 9. |
- Garg, Gaurav, et al.
(författare)
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Glucose-dependent insulinotropic polypeptide (GIP) and GIP receptor (GIPR) genes : An association analysis of polymorphisms and bone in young and elderly women
- 2016
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Ingår i: Bone Reports. - : Elsevier BV. - 2352-1872. ; 4, s. 23-27
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The gastro-intestinal hormone glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-induced insulin secretion, with bone anabolic effects through GIP receptor (GIPR) in animal models. We explore its potential in humans by analyzing association between polymorphisms (SNPs) in the GIP and GIPR genes with bone phenotypes in young and elderly women. Methods: Association between GIP (rs2291725) and GIPR (rs10423928) and BMD, bone mineral content (BMC), bone microarchitecture, fracture and body composition was analyzed in the OPRA (75y, n. =. 1044) and PEAK-25 (25y; n. =. 1061) cohorts and serum-GIP in OPRA. Results: The GIP receptor AA-genotype was associated with lower ultrasound values in young women (BUA p=0.011; SI p=0.030), with no association to bone phenotypes in the elderly. In the elderly, the GIP was associated with lower ultrasound (GG vs. AA; SOS padj=0.021) and lower femoral neck BMD and BMC after adjusting for fat mass (padj=0.016 and padj=0.03). In young women, neither GIPR nor GIP associated with other bone phenotypes including spine trabecular bone score. In the elderly, neither SNP associated with fracture. GIP was associated with body composition only in Peak-25; GIPR was not associated with body composition in either cohort. Serum-GIP levels (in elderly) were not associated with bone phenotypes, however lower levels were associated with the GIPR A-allele (β=-6.93; padj=0.03). Conclusions: This first exploratory association study between polymorphisms in GIP and GIPR in relation to bone phenotypes and serum-GIP in women at different ages indicates a possible, albeit complex link between glucose metabolism genes and bone, while recognizing that further studies are warranted.
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| 10. |
- Garg, Gaurav, et al.
(författare)
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Variation in the MC4R Gene Is Associated with Bone Phenotypes in Elderly Swedish Women.
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. Fat mass is a determinant of bone strength and both phenotypes have a strong genetic component. In this study, we examined the association between obesity associated polymorphisms (SNPs) with body composition, BMD, Ultrasound (QUS), fracture and biomarkers (Homocysteine (Hcy), folate, Vitamin D and Vitamin B12) for obesity and osteoporosis. Five common variants: rs17782313 and rs1770633 (melanocortin 4 receptor (MC4R); rs7566605 (insulin induced gene 2 (INSIG2); rs9939609 and rs1121980 (fat mass and obesity associated (FTO) were genotyped in 2 cohorts of Swedish women: PEAK-25 (age 25, n = 1061) and OPRA (age 75, n = 1044). Body mass index (BMI), total body fat and lean mass were strongly positively correlated with QUS and BMD in both cohorts (r(2) = 0.2-0.6). MC4R rs17782313 was associated with QUS in the OPRA cohort and individuals with the minor C-allele had higher values compared to T-allele homozygotes (TT vs. CT vs.
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| 11. |
- Ghandil, P, et al.
(författare)
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Crohn's disease associated CARD15 (NOD2) variants are not involved in the susceptibility to type 1 diabetes
- 2005
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Ingår i: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192. ; 86:3, s. 379-383
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Tidskriftsartikel (refereegranskat)abstract
- Three variants in the caspase recruitment domain 15/nucleotide-binding oligomerization domain 2 (CARD15/NOD2) gene have been shown to be associated with Crohn's disease (CD). There is a strong support for shared genetic determinants between various autoimmune and inflammatory diseases. In particular, linkage of type 1 diabetes (T1D) and other autoimmune and inflammatory diseases has been reported on chromosome 16, encompassing the region containing the CARD15 gene. We therefore considered this gene as a good candidate for the T1D locus mapped to this region, and we tested the three CARD15 variants in the susceptibility to T I D in two independent settings: family based association analysis in Scandinavian multiplex families that we previously showed to be linked to this region, and case/control association study in a large cohort of French diabetic patients. We found no evidence for association of these variants with T1D overall, nor in subgroups of patients with or without the major risk genotypes at HLA-DRB1, at insulin (INS), or positive or negative for autoantibodies specific to other autoimmune diseases. Our results do not support a role for CD-associated CARD15 variants in the susceptibility to T1D, and suggest that another gene is responsible for the shared susceptibility between autoimmune and inflammatory diseases mapping to this region.
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| 12. |
- Granhall, Charlotte, et al.
(författare)
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High-resolution QTL Analysis Reveals Multiple Diabetes Susceptibility Loci Mapped to Intervals less than 800-kb in the Species Conserved Niddm1i of the GK Rat.
- 2006
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Ingår i: Genetics. - : Oxford University Press (OUP). - 0016-6731 .- 1943-2631. ; 174:Sep 1, s. 1565-1572
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Tidskriftsartikel (refereegranskat)abstract
- Niddmli, a 16-Mb locus within the major diabetes QTL in the diabetic GK rat, causes impaired glucose tolerance in the congenic NIDDM11 strain. Niddm1i is homologous to both human and mouse regions linked with type 2 diabetes susceptibility. We employed multiple QTL analyses of congenic F2 progeny selected for one recombination event within Niddm1i combined with characterization of subcongenic strains. Fine mapping located one hyperglycemia locus within 700 kb (Niddmli4, P = 5 X 10(-6)). Two adjacent loci were also detected, and the GK allele at Niddn1i2 (500 kb) showed a glucose-raising effect, whereas it had a glucose-lowering effect at Niddm1i3 (400 kb). Most proximally, Niddm1i1 (800 kb) affecting body weight was identified. Experimental data from subcongenics supported the four loci. Sorcs1, one of the two known diabetes susceptibility genes in the region, resides within Niddm1i3, while TJ712 maps outside all four loci. Multiple-marker QTL analysis incorporating the effect of cosegregating QTL as cofactors together with genetically selected progeny can remarkably enhance resolution of QTL. The data demonstrate that the species-conserved Niddm1i is a composite of at least four QTL affecting type 2 diabetes susceptibility and that two adjacent QTL (Niddm1i2(GK) and Niddm1i3(GK)) act in opposite directions.
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| 13. |
- Granhall, Charlotte, et al.
(författare)
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Separately inherited defects in insulin exocytosis and beta-cell glucose metabolism contribute to type 2 diabetes.
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 55:12, s. 3494-3500
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Tidskriftsartikel (refereegranskat)abstract
- The effects of genetic variation on molecular functions predisposing to type 2 diabetes are still largely unknown. Here, in a specifically designed diabetes model, we couple separate gene loci to mechanisms of P-cell pathology. Niddm1i is a major glucose-controlling 16-Mb region in the diabetic GK rat that causes defective insulin secretion and corresponds to loci in humans and mice associated with type 2 diabetes. Generation of a series of congenic rat strains harboring different parts of GK-derived Niddm1i enabled fine mapping of this locus. Congenic strains carrying the GK genotype distally in Niddm1i displayed reduced insulin secretion in response to both glucose and high potassium, as well as decreased single-cell exocytosis. By contrast, a strain carrying the GK genotype proximally in Niddm1i exhibited both intact insulin release in response to high potassium and intact single-cell exocytosis, but insulin secretion was suppressed when stimulated by glucose. Islets from this strain also failed to respond to glucose by increasing the cellular ATP-to-ADP ratio. Changes in P-cell mass did not contribute to the secretory defects. We conclude that the failure of insulin secretion in type 2 diabetes includes distinct functional defects in glucose metabolism and insulin exocytosis of the P-cell and that their genetic fundaments are encoded by different loci within Niddm1i.
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| 14. |
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| 15. |
- Holm, P, et al.
(författare)
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Interaction and association analysis of a type 1 diabetes susceptibility locus on chromosome 5q11-q13 and the 7q32 chromosomal region in Scandinavian families
- 2004
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 53:6, s. 1584-1591
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Tidskriftsartikel (refereegranskat)abstract
- We have previously reported suggestive linkage to chromosome 5p13-q13 in type 1 diabetic families. ISL1, a transcription factor involved in pancreas development, maps to this region. Sequencing of the ISL1 gene in patients and control subjects identified seven single nucleotide polymorphisms (SNPs) and one microsatellite in noncoding regions. Four haplotypes formed by six of these SNPs and one microsatellite were associated with type 1 diabetes in Swedish families (P < 0.04). To identify possible interactions with the 5q11-q13 region, we applied pathway-restricted linkage analysis by analyzing for effects from regions encoding other transcription factors that are active during pancreas development and maintenance of insulin production. Linkage analysis allowing for interaction between 5q11-q13 and 7q32 resulted in an increase of logarithm of odds from 2.2 to 5.3. This increase was estimated to correspond to a P value <0.0016 using permutation. The transcription factor PAX4 is located at 7q32 and participates downstream of ISL1 in the transcription factor cascade critical to β-cell development. Association with type 1 diabetes was also observed using the transmission disequilibrium test for two haplotypes at the PAX4 locus (P < 0.05). We conclude that pathway-restricted linkage analysis assists in the identification of possible gene-gene interactions and that 5q11-q13 and 7q32 together constitute a significant susceptibility factor for type 1 diabetes.
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| 16. |
- Holm, P, et al.
(författare)
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No evidence for linkage in Swedish multiplex T1DM families to IL12B on chromosome 5q33-34
- 2003
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 1005, s. 352-355
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which the 0 cells in the pancreas are destroyed by the body's own immune system. IL12 plays a role in pathological situations, such as septic shock, tissue damage during inflammation, and organ-specific autoimmune diseases. In NOD mice, administration of IL12 induces T1DM and administration of IL12 antagonists prevents T1DM. Linkage and association of IL12 to T1DM have been reported previously. We are unable to replicate this linkage on chromosome 5q33-34 in 184 Swedish families. Further, we exclude a gene with lambda(s) > 1.4 from this region. Together with previously published findings, these data make IL12 an unlikely major susceptibility gene for T1DM.
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| 17. |
- Janunger, Tomas, 1972-
(författare)
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The genetic contribution to stroke in northern Sweden
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Stroke is a common multi factorial cerebrovascular disorder with a large impact on global health. It is a disorder primarily associated with old age but environmental factors, lifestyle choices and medical history are all important for the risk of developing the disorder. It is also known that heritability is important for predisposition to the disorder. The aim of this work has been to identify genetic variations that increase the risk of being affected by stroke in the population of northern Sweden, a population well apt for genetic studies due to well kept church and medical records together with limited genetic diversity. In the first paper we used linkage analysis in families with early onset of stroke. By this approach we identified a region on chromosome 5q to be linked to an increased risk of developing stroke, a region previously identified as a susceptibility locus for stroke in the Icelandic population. In the second study we used genealogy to identify common ancestry and thereby identify common susceptibility to stroke. The seven families we connected showed significant linkage to the chromosome 9q31-33 region and four of the families shared a common haplotype over 2.1 megabases. In the third manuscript we investigated sequence variation of two candidate genes, TNFSF15 and TLR4. Sequencing of the TLR4 gene revealed previously identified variations in affected individuals from two of the families. Further SNP analysis showed five separate haplotypes among the investigated families and four haplotypes for TNFSF15. However none of these co-segregated with stroke among the investigated families. In the final paper we used a case-control stroke cohort to ascertain association for genetic variation in five genes and genetic regions previously suggested to be linked with stroke. Initial analyses showed association for the 9p21 chromosomal region and a variant in Factor 5 that showed protection against stroke, but after adjustments for common risk factors for stroke, the findings were no longer significant. In conclusion, by studying selected families we have been able to show linkage to two chromosomal regions, 5q and 9q31-33, that indicate genetic predisposition for developing stroke. Further we have shown that family based studies are still an important tool in deciphering the underlying mechanisms for complex disease.
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| 18. |
- Juko-Pecirep, Ivana, 1984-
(författare)
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Analysis of genetic susceptibility to cervical cancer using candidate gene and GWAS approaches
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cervical cancer is the forth most commonly diagnosed cancer among women worldwide. It is caused by persistent infection with an oncogenic type of Human Papillomavirus (HPV). The HPV is a necessary but not sufficient cause of cervical cancer. Environmental factors such as smoking, high parity and long-term use of oral contraceptives increases the risk of cervical cancer. Genetic factors also affect the risk of developing the disease. The aim of this thesis is to search for and evaluate genetic risk factors for cervical cancer using both a candidate gene approach and a genome-wide association study (GWAS).Paper I examined the association of genetic variation in three Fanconi Anemia (FA) genes (FANCA, FANCC and FANCL), involved in DNA repair, with cervical cancer susceptibility in the Swedish population. No association was observed. Paper II evaluated the association of genetic variation in the TMC6 and TMC8 genes with susceptibility to cervical cancer in the Swedish population and an association of two SNPs (rs2290907 and rs16970849) with cervical cancer was observed. In paper III the first GWAS performed in cervical cancer was reported. Three independent loci in the major histocompatibility complex (MHC) region at 6p21.3 were found to affect the susceptibility to cervical cancer. Paper IV examined the sequence variation in the TMC6 and TMC8 region and its association with cervical cancer. A highly polymorphic 21 bp sequence was identified and found to be repeated 5 to 42 times in both cases and controls. Lack of this repeat was associated with increased risk of cervical cancer. An intronic SNP (rs2926778) located in between the TNRC6C and TMC6 genes was also found to be associated with cervical cancer.The thesis provides evidence for the importance of genes in the immune system for cervical cancer susceptibility. The genetic risk factors identified explain only a part of the genetic susceptibility, implying that other risk factors remains to be identified
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| 19. |
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| 20. |
- Koeck, Thomas, et al.
(författare)
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A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes.
- 2011
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 13:1, s. 80-91
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) evolves when insulin secretion fails. Insulin release from the pancreatic β cell is controlled by mitochondrial metabolism, which translates fluctuations in blood glucose into metabolic coupling signals. We identified a common variant (rs950994) in the human transcription factor B1 mitochondrial (TFB1M) gene associated with reduced insulin secretion, elevated postprandial glucose levels, and future risk of T2D. Because islet TFB1M mRNA levels were lower in carriers of the risk allele and correlated with insulin secretion, we examined mice heterozygous for Tfb1m deficiency. These mice displayed lower expression of TFB1M in islets and impaired mitochondrial function and released less insulin in response to glucose in vivo and in vitro. Reducing TFB1M mRNA and protein in clonal β cells by RNA interference impaired complexes of the mitochondrial oxidative phosphorylation system. Consequently, nutrient-stimulated ATP generation was reduced, leading to perturbed insulin secretion. We conclude that a deficiency in TFB1M and impaired mitochondrial function contribute to the pathogenesis of T2D.
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| 21. |
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| 22. |
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| 23. |
- Lagerholm, Sofia, et al.
(författare)
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Genetic loci for bone architecture determined by three-dimensional CT in crosses with the diabetic GK rat.
- 2010
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 47, s. 1039-1047
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Tidskriftsartikel (refereegranskat)abstract
- The F344 rat carries alleles contributing to bone fragility while the GK rat spontaneously develops type-2 diabetes. These characteristics make F344xGK crosses well suited for the identification of genes related to bone size and allow for future investigation on the association with type-2 diabetes. The aim of this study was to identify quantitative trait loci (QTLs) for bone size phenotypes measured by a new application of three-dimensional computed tomography (3DCT) and to investigate the effects of sex- and reciprocal cross. Tibia from male and female GK and F344 rats, representing the parental, F1 and F2 generations, were examined with 3DCT and analyzed for: total and cortical volumetric BMD, straight and curved length, peri- and endosteal area at mid-shaft. F2 progeny (108 male and 98 female) were genotyped with 192 genome-wide microsatellite markers (average distance 10cM). Sex- and reciprocal cross-separated QTL analyses were performed for the identification of QTLs linked to 3DCT phenotypes and true interactions were confirmed by likelihood ratio analysis in all F2 animals. Several genome-wide significant QTLs were found in the sex- and reciprocal cross-separated progeny on chromosomes (chr) 1, 3, 4, 9, 10, 14, and 17. Overlapping QTLs for both males and females in the (GKxF344)F2 progeny were located on chr 1 (39-67cM). This region confirms previously reported pQCT QTLs and overlaps loci for fasting glucose. Sex separated linkage analysis confirmed a male specific QTL on chr 9 (67-82cM) for endosteal area at the fibula site. Analyses separating the F2 population both by sex and reciprocal cross identified cross specific QTLs on chr 14 (males) and chr 3 and 4 (females). Two loci, chr 4 and 6, are unique to 3DCT and separate from pQCT generated loci. The 3DCT method was highly reproducible and provided high precision measurements of bone size in the rat enabling identification of new sex- and cross-specific loci. The QTLs on chr 1 indicate potential genetic association between bone-related phenotypes and traits affecting type-2 diabetes. The results illustrate the complexity of the genetic architecture of bone size phenotypes and demonstrate the importance of complementary methods for bone analysis.
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| 24. |
- Lagerholm, Sofia, et al.
(författare)
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Genetic regulation of bone traits is influenced by sex and reciprocal cross in F(2) progeny from GK and F344 rats.
- 2009
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Ingår i: Journal of bone and mineral research. - : Wiley. - 1523-4681 .- 0884-0431. ; 24:6, s. 1066-74
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Tidskriftsartikel (refereegranskat)abstract
- A genome-wide linkage analysis to identify quantitative trait loci (QTLs) for bone phenotypes was performed in an F(2) intercross of inbred spontaneously type 2 diabetic GK and normoglycemic F344 rats (108 males and 98 females). The aim of the study was to locate genome regions with candidate genes affecting trabecular and cortical bone and to investigate the effects of sex and reciprocal cross. pQCT was used to determine tibial bone phenotypes in the F(2) rats, comprising reciprocal crosses with divergent mitochondrial (mt) DNA. Sex and reciprocal cross-separated QTL analyses were performed followed by assessment of specific interactions. Four genome-wide significant QTLs linked to either cortical vBMD, tibia length, body length, or metaphyseal area were identified in males on chromosomes (chr) 1, 8, and 15. In females, three significant QTLs linked to cortical BMC or metaphyseal total vBMD were identified on chr 1 and 2. Several additional suggestive loci for trabecular and cortical traits were detected in both males and females. Four female-specific QTLs on chr 2, 3, 5, and 10 and four reciprocal cross-specific QTLs on chr 1, 10, and 18 were identified, suggesting that both sex and mt genotype influence the expression of bone phenotypes.
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| 25. |
- Lagerholm, Sofia, et al.
(författare)
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Genetic Regulation of Bone Traits Is Influenced by Sex and Reciprocal Cross in F-2 Progeny From GK and F344 Rats
- 2009
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Ingår i: Journal of Bone and Mineral Research. - 1523-4681. ; 24:6, s. 1066-1074
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Tidskriftsartikel (refereegranskat)abstract
- A genome-wide linkage analysis to identify quantitative trait loci (QTLs) for bone phenotypes was performed in an F-2 intercross of inbred spontaneously type 2 diabetic GK and normoglycemic F344 rats (108 males and 98 females). The aim of the study was to locate genome regions with candidate genes affecting trabecular and cortical bone and to investigate the effects of sex and reciprocal cross. pQCT was used to determine tibia] bone phenotypes in the F2 rats, comprising reciprocal crosses with divergent mitochondrial (mt) DNA. Sex and reciprocal cross-separated QTL analyses were performed followed by assessment of specific interactions. Four genome-wide significant QTLs linked to either cortical vBMD, tibia length, body length, or metaphyseal area were identified in males on chromosomes (chr) 1, 8, and 15. In females, three significant QTLs linked to cortical BMC or metaphyseal total vBMD were identified on chr 1 and 2. Several additional suggestive loci for trabecular and cortical traits were detected in both males and females. Four female-specific QTLs on chr 2, 3, 5, and 10 and four reciprocal cross-specific QTLs on chr 1, 10, and 18 were identified, suggesting that both sex and mt genotype influence the expression of bone phenotypes. J Bone Miner Res 2009;24:1066-1074. Published online on December 29, 2008; doi: 10.1359/JBMR.081252
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| 26. |
- Lagerholm, Sofia, et al.
(författare)
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Identification of Candidate Gene Regions in the Rat by Co-Localization of QTLs for Bone Density, Size, Structure and Strength.
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- Susceptibility to osteoporotic fracture is influenced by genetic factors that can be dissected by whole-genome linkage analysis in experimental animal crosses. The aim of this study was to characterize quantitative trait loci (QTLs) for biomechanical and two-dimensional dual-energy X-ray absorptiometry (DXA) phenotypes in reciprocal F2 crosses between diabetic GK and normo-glycemic F344 rat strains and to identify possible co-localization with previously reported QTLs for bone size and structure. The biomechanical measurements of rat tibia included ultimate force, stiffness and work to failure while DXA was used to characterize tibial area, bone mineral content (BMC) and areal bone mineral density (aBMD). F2 progeny (108 males, 98 females) were genotyped with 192 genome-wide markers followed by sex- and reciprocal cross-separated whole-genome QTL analyses. Significant QTLs were identified on chromosome 8 (tibial area; logarithm of odds (LOD) = 4.7 and BMC; LOD = 4.1) in males and on chromosome 1 (stiffness; LOD = 5.5) in females. No QTLs showed significant sex-specific interactions. In contrast, significant cross-specific interactions were identified on chromosome 2 (aBMD; LOD = 4.7) and chromosome 6 (BMC; LOD = 4.8) for males carrying F344mtDNA, and on chromosome 15 (ultimate force; LOD = 3.9) for males carrying GKmtDNA, confirming the effect of reciprocal cross on osteoporosis-related phenotypes. By combining identified QTLs for biomechanical-, size- and qualitative phenotypes (pQCT and 3D CT) from the same population, overlapping regions were detected on chromosomes 1, 3, 4, 6, 8 and 10. These are strong candidate regions in the search for genetic risk factors for osteoporosis.
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| 27. |
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| 28. |
- Lindgren, Arne, et al.
(författare)
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Prevalence of Stroke and Vascular Risk Factors among First-Degree Relatives of Stroke Patients and Control Subjects.
- 2005
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Ingår i: Cerebrovascular Diseases. - : S. Karger AG. - 1421-9786 .- 1015-9770. ; 20:5, s. 381-387
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Tidskriftsartikel (refereegranskat)abstract
- <i>Background:</i> Genetic and environmental factors may be of importance for stroke risk. We assessed the prevalence of stroke and vascular risk factors among first-degree relatives and spouses of stroke patients and control subjects. <i>Methods:</i> As a part of the Lund Stroke Register study, we asked 925 consecutive patients with first-ever stroke and 286 control subjects to complete a questionnaire about all their first-degree relatives and spouses. The questionnaires addressed whether these relatives had been affected by stroke or TIA, hypertension, heart disease, diabetes mellitus, and if they were smokers. <i>Results:</i> A total of 606 patients and 261 control subjects returned the questionnaire, providing information on 4,972 first-degree relatives and 738 spouses. The prevalence of stroke or TIA was 12.3% among first-degree relatives of patients and 7.5% among first-degree relatives of control subjects (OR 1.74, 95% CI 1.36–2.22). Corresponding results for hypertension were 21.0 and 16.7% (OR 1.33, 95% CI 1.10–1.60). The prevalences of heart disease, diabetes mellitus and smoking did not differ significantly between first-degree relatives of patients and control subjects. Spouses of patients and control subjects had similar prevalences of stroke or TIA and vascular risk factors. <i>Conclusions:</i> The prevalences of stroke or TIA and hypertension are higher among first-degree relatives of stroke patients than among first-degree relatives of control subjects. This, and the lack of differences between spouses of patients and control subjects, indicates that an increased risk of stroke may in part be explained by heritability of hypertension.
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| 29. |
- Ling, Charlotte, et al.
(författare)
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Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion.
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 51, s. 615-622
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Insulin secretion in pancreatic islets is dependent upon mitochondrial function and production of ATP. The transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator-1 alpha (protein PGC-1alpha; gene PPARGC1A) is a master regulator of mitochondrial genes and its expression is decreased and related to impaired oxidative phosphorylation in muscle from patients with type 2 diabetes. Whether it plays a similar role in human pancreatic islets is not known. We therefore investigated if PPARGC1A expression is altered in islets from patients with type 2 diabetes and whether this expression is influenced by genetic (PPARGC1A Gly482Ser polymorphism) and epigenetic (DNA methylation) factors. We also tested if experimental downregulation of PPARGC1A expression in human islets influenced insulin secretion. METHODS: The PPARGC1A Gly482Ser polymorphism was genotyped in human pancreatic islets from 48 non-diabetic and 12 type 2 diabetic multi-organ donors and related to PPARGC1A mRNA expression. DNA methylation of the PPARGC1A promoter was analysed in pancreatic islets from ten type 2 diabetic and nine control donors. Isolated human islets were transfected with PPARGC1A silencing RNA (siRNA). RESULTS: PPARGC1A mRNA expression was reduced by 90% (p < 0.005) and correlated with the reduction in insulin secretion in islets from patients with type 2 diabetes. After downregulation of PPARGC1A expression in human islets by siRNA, insulin secretion was reduced by 41% (p
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| 30. |
- Lövkvist, Håkan, et al.
(författare)
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A large-sample assessment of possible association between ischaemic stroke and rs12188950 in the PDE4D gene
- 2012
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 20:7, s. 783-789
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Tidskriftsartikel (refereegranskat)abstract
- Previous reports have shown ambiguous findings regarding the possible associations between ischaemic stroke (IS) and single nucleotide polymorphisms (SNPs) in the phosphodiesterase 4D (PDE4D) gene region. The SNP rs12188950 (or SNP45) has often been studied in this context. We performed a multi-centre study involving a large sample of 2599 IS patients and 2093 control subjects from the south and west regions of Sweden to replicate previous studies regarding IS risk and rs12188950. Subjects from Lund Stroke Register (LSR), Malmo Diet and Cancer Study (MDC) and Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) were enroled. Subgroups of participants with hypertension and participants <55 years of age, as well as the TOAST subgroups large vessel disease, small vessel disease and cardioembolism, were also assessed. Univariate odds ratios (ORs) and ORs controlling for hypertension, diabetes and current smoking were calculated. We additionally performed a meta-analysis including 10 500 patients and 10 102 control subjects from 17 publications (including the present study). When assessing pooled data from LSR, MDC and SAHLSIS we obtained no association between IS and rs12188950 for all participants (OR=0.93; 95% confidence interval (CI): 0.83-1.05). Significant associations were not found for hypertensive participants or participants with age <55, or when separately evaluating patients from the three different TOAST subgroups. The meta-analysis showed no significant overall estimate (OR=0.96; 95% CI: 0.89-1.04) with significant heterogeneity for random effect (P=0.042). No effect from rs12188950 on IS was found from either our pooled multi-centre data or the performed meta-analysis. We did not find any association between the examined subgroups and rs12188950 either. European Journal of Human Genetics (2012) 20, 783-789; doi: 10.1038/ejhg.2012.4; published online 25 January 2012
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| 31. |
- Lövkvist, Håkan, et al.
(författare)
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Ischaemic stroke in hypertensive patients is associated with variations in the PDE4D genome region.
- 2008
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 16, s. 1117-1125
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Tidskriftsartikel (refereegranskat)abstract
- Previous Icelandic studies reported that single nucleotide polymorphisms (SNPs) in the phosphodiesterase 4D (PDE4D) region and the 5-lipoxygenase activating protein ALOX5AP were associated with ischaemic stroke, whereas other studies reported ambiguous findings. We examined 932 ischaemic stroke patients from a Swedish population-based stroke register, and 396 control subjects. We assessed possible associations between ischaemic stroke and nine preselected SNPs in the chromosome regions of the PDE4D gene, including rs12188950 (SNP45) and rs3887175 (SNP39); the ALOX5AP gene, including rs17222814 (SG13S25) and the promoter region of the MHC class II transactivator, MHC2TA. The T allele of SNP45 showed negative association with ischaemic stroke (odds ratio, OR=0.72; 95% confidence interval (CI): 0.58-0.91; P=0.0055). Among hypertensive subjects, this influence of the T allele of SNP45, and the T allele of SNP39, were more pronounced (with OR=0.52; 95% CI: 0.37-0.73; P=0.0001 and OR=0.57; 95% CI: 0.41-0.79; P=0.0007, respectively). These SNPs also interacted with hypertension with a relative excess risk due to interaction of -1.66 (P=0.0002) for SNP45 and -1.65 (P=0.0005) for SNP39. The P-values remained significant after correction for multiple testing. Among nonhypertensives, the A allele of SG13S25 indicated increased stroke risk (OR=1.82; 95% CI: 1.21-2.74; P=0.0039; not significant after Bonferroni correction). SNP45 was associated with ischaemic stroke even when controlling for hypertension, diabetes, heart disease and smoking. Our meta-analysis of 13 studies (including ours) showed no overall influence of SNP45 on ischaemic stroke. However, the 13 studies may differ because of nonrandom causes, as suggested by the heterogeneity test (P=0.042). This might support previously undetected mechanisms causing fluctuating ischaemic stroke risk.European Journal of Human Genetics advance online publication, 9 April 2008; doi:10.1038/ejhg.2008.62.
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| 32. |
- Lövkvist, Håkan, et al.
(författare)
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Variations in apolipoprotein D and sigma non-opioid intracellular receptor 1 genes with relation to risk, severity and outcome of ischemic stroke
- 2014
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Ingår i: BMC Neurology. - : Springer Science and Business Media LLC. - 1471-2377. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: In experimental studies, the apolipoprotein D (APOD) and the sigma receptor type 1 (SIGMAR1) have been related to processes of brain damage, repair and plasticity. Methods: We examined blood samples from 3081 ischemic stroke (IS) patients and 1595 control subjects regarding 10 single nucleotide polymorphisms (SNPs) in the APOD (chromosomal location 3q29) and SIGMAR1 (chromosomal location 9p13) genes to find possible associations with IS risk, IS severity (NIHSS-score) and recovery after IS (modified Rankin Scale, mRS, at 90 days). Simple/multiple logistic regression and Spearman's rho were utilized for the analyses. Results: Among the SNPs analyzed, rs7659 within the APOD gene showed a possible association with stroke risk (OR = 1.12; 95% CI: 1.01-1.25; P = 0.029) and stroke severity (NIHSS >= 16) (OR = 0.70; 95% CI: 0.54-0.92; P = 0.009) when controlling for age, sex and vascular risk factors for stroke. No SNP showed an association with stroke recovery (mRS). Conclusions: We conclude that the SNP rs7659 within the APOD gene might be related to risk and severity of ischemic stroke in patients.
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| 33. |
- Markljung, Ellen, 1978-
(författare)
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QTL Analysis in the Pig : From the Identification of Quantitative Trait Loci to the Understanding of Molecular Mechanisms
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Domestic pigs have become very different form the wild ancestors they originate from. Selection for muscle growth and meat quality has made the pig a good model for genetic studies of muscle development.The first part of this thesis presents a genome-wide scan for quantitative trait loci (QTL) in a cross between Landrace and Hampshire pigs. Traits such as body composition, fat deposition, body length, meat quality and weight measurements of individual muscles were investigated. In total we identified 15 different QTLs that reached genome-wide significance. The three most significant QTLs were for carcass length on chromosome 17 and two overlapping QTLs on chromosome 1 for body composition and weight of M. biceps femoris, respectively. A strong candidate gene for the body composition QTL is melanocortin 4 receptor (MC4R). We also identified several QTLs for sizes of different muscles, fat deposition and meat quality traits.In a previous study using a cross between the domestic Large White and wild boar, the mutation underlying a major QTL for muscle growth and fat deposition was identified as a single nucleotide substitution (QTN) in intron 3 of the IGF2 gene. The QTN disrupts the binding of a repressor affecting IGF2 mRNA expression. In the second part of this thesis, the identification of the repressor is presented. The repressor, named ZBED6, is a previously unknown mammalian member of the BED-domain protein family. We could show that Zbed6 specifically binds the wild-type but not the mutated sequence surrounding the QTN. Further studies of silenced Zbed6 in the mouse myoblast cell line C2C12 showed that it represses transcription in a luciferase reporter assay and affects Igf2 mRNA transcription and proliferation. ZBED6 shows very high sequence conservation and has a broad tissue distribution of expression suggesting that ZBED6 also has important biological function outside the muscle cell.
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| 34. |
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| 35. |
- McGuigan, Fiona, et al.
(författare)
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Variation in the BMP2 gene: Bone mineral density and ultrasound in young adult and elderly women
- 2007
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 81:4, s. 254-262
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Tidskriftsartikel (refereegranskat)abstract
- Bone morphogenetic protein-2 (BMP2) plays a key role in bone formation and maintenance. Studies of polymorphisms within the gene in relation to bone mineral density (BMD) and fracture have been inconsistent. Our aim was to investigate associations between polymorphisms in the BMP2 gene and bone mass, fracture, and quantitative ultrasound (QUS) measures at different stages of skeletal development. Study subjects were participants of two population-based cohorts of Swedish women: the PEAK-25 cohort of young adult women aged 25 years (n = 993) and the OPRA cohort of elderly women aged 75 years (n = 1,001). We analyzed four single-nucleotide polymorphisms (SNPs) across the BMP2 gene including the Ser37Ala SNP previously identified in relation to BMD, QUS of the calcaneus, and, in the elderly women, fracture. BMP2 gene variations were associated with QUS of bone, independent of BMD, but only in the young women. Even after adjusting for confounding factors, SNP rs235754 in the 3' region of the gene was significantly associated with the ultrasound parameters speed of sound (P = 0.003) and stiffness (P = 0.002). The 5' SNP rs235710 showed trends for QUS parameters (P = 0.02-0.07). No association with BMP2 SNPs was observed in either cohort for either BMD or fracture. While further, more extensive genotyping across the gene is recommended, as we may not have captured all information, our preliminary data suggest that variation in BMP2 may play a previously unidentified role in aspects of bone quality, which may be age- and site-dependent.
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| 36. |
- McGuigan, Fiona, et al.
(författare)
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Variation in the bone morphogenetic protein-2 gene: effects on fat and lean body mass in young and elderly women.
- 2008
-
Ingår i: European Journal of Endocrinology. - 1479-683X. ; 158:5, s. 661-668
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Bone morphogenetic protein-2 (BMP2) plays a critical role in osteoblastogenesis and adipogenesis from osteoprogenitor cells. The balance between osteogenic and adipogenic effects is influenced by BMP2 concentration, transcription factors and age. BMP2 single nucleotide polymorphisms (SNPs) may contribute to osteoporosis risk, but the relationship between adiposity and body composition has not been explored. We investigated the relationship between BMP2 polymorphisms and body composition in young and elderly women. DESIGN: Population-based association study. METHODS: Four BMP2 SNPs studied. Total body fat and lean mass measured by DEXA in two cohorts: 'PEAK-25' women aged 25 (+/-0.00) (n=993) and osteoporosis prospective risk assessment (OPRA) women aged 75 (+/-0.00) years (n=1001). RESULTS: We found no association between BMP2 SNPs and fat or lean mass, however, we observed consistent although non-significant trends. Polymorphisms, rs235767 and Ser37Ala, exerted opposing effects on most parameters of soft tissue and bone mass in both cohorts. This relationship appeared to be age specific with large differences between alleles observed (fat mass; Ser37Ala: 14.3% (PEAK-25), -3.5% (OPRA)). These initial results appear to suggest that alleles exerting a beneficial effect in young women may subsequently contribute to phenotypes associated with osteoporosis risk in elderly women. CONCLUSIONS: While further analyses in other comparative populations are necessary, in this study of almost 2000 women we observed interesting, although non-significant trends, regarding the effects of variation in the BMP2 gene on parameters of body mass. Although the exact nature of the relationship remains uncertain, we suggest that the mechanisms are influenced by age and environmental factors.
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| 37. |
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| 38. |
- Nordquist, Niklas, et al.
(författare)
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Linkage study of embryopathy-Polygenic inheritance of diabetes-induced skeletal malformations in the rat
- 2012
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Ingår i: Reproductive Toxicology. - : Elsevier BV. - 0890-6238 .- 1873-1708. ; 33:3, s. 297-307
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Tidskriftsartikel (refereegranskat)abstract
- We developed an inbred rat model of diabetic embryopathy, in which the offspring displays skeletal malformations (agnathia or micrognathia) when the mother is diabetic, and no malformations when she is not diabetic. Our aim was to find genes controlling the embryonic maldevelopment in a diabetic environment. We contrasted the fetal outcome in inbred Sprague-Dawley L rats (20% skeletal malformations in diabetic pregnancy) with that of inbred Wistar Furth rats (denoted W, no skeletal malformations in diabetic pregnancy). We used offspring from the backcross F-1 x L to probe for the genetic basis for malformation of the mandible in diabetic pregnancy. A set of 186 fetuses (93 affected, 93 unaffected) was subjected to a whole genome scan with 160 micro satellites. Analysis of genotype distribution indicated 7 loci on chromosome 4, 10 (3 loci), 14, 18, and 19 in the teratogenic process (and 14 other loci on 12 chromosomes with less strong association to the malformations), several of which contained genes implicated in other experimental studies of diabetic embryopathy. These candidate genes will be scrutinized in further experimentation. We conclude that the genetic involvement in rodent diabetic embryopathy is polygenic and predisposing for congenital malformations.
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| 39. |
- Nosadini, R, et al.
(författare)
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Altered transcapillary escape of albumin and microalbuminuria reflects two different pathogenetic mechanisms
- 2005
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Ingår i: Diabetes. - 1939-327X. ; 54:1, s. 228-233
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Tidskriftsartikel (refereegranskat)abstract
- We studied the following in normo- and microalbuminuric hypertensive type 2 diabetic patients: 1) transcapillary escape rate of albumin (TERalb) and 2) expression of mRNA slit diaphragm and podocyte proteins in renal biopsies. Normoalbuminuric subjects had renal cancer, and kidney biopsy was performed during surgery. TERalb was evaluated by clearance of I-125- albumin. Real-time PCR of mRNA slit diaphragm was measured in kidney specimens. Albumin excretion rate (AER) was by definition lower in normoalbuminuric subjects than in microalbuminuric subjects with typical diabetic glomerulopathy (group 1), in microalbuminuric subjects with normal or near-normal glomerular structure (group 2), and in microalbuminuric subjects with atypical diabetic nephropathy (group 3). This classification was based on light microscopy analysis of renal tissue. TERalb (%/h) was similar in normoalbuminuric and microalbuminuric group 1, 2, and 3 diabetic patients (medians: 14.1 vs. 14.4 vs. 15.7 vs. 14.9, respectively) (ANOVA, NS). mRNA expression of slit diaphragm proteins CD2AP, FAT, Actn 4, NPHS1, and NPHS2 was higher in normoalbuminuric patients than in microalbuminuric patients (groups 1, 2, and 3) (ANOVA, P < 0.001). All diabetic patients had greater carotid artery intimal thickness than normal control subjects using ultrasound technique (ANOVA, P < 0.01). In conclusion, the present study suggests that microalbuminuria identifies a subgroup of hypertensive type 2 diabetic patients who have altered mRNA expression of slit diaphragm and podocyte proteins, even before glomerular structure shows abnormalities using light microscopy analysis. On the contrary, altered TERalb and increased carotid artery intimal thickness are shown by all hypertensive type 2 diabetic patients, both with normal and altered patterns of AER.
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| 40. |
- Nosadini, R, et al.
(författare)
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Increased renal arterial resistance predicts the course of renal function in type 2 diabetes with microalbuminuria
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 55:1, s. 234-239
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetic patients often die because of end-stage renal failure, but no definitive reliable factor predicting long-term renal outcome has been identified. We tested whether a renal arterial resistance index (R/I) >= 80, using Doppler ultrasound technique, was predictive of worsening renal function. The primary end points of the study were 1) the course of glomerular filtration rate (GFR) and 2) the albumin excretion rate in 157 microalbuminuric, hypertensive, type 2 diabetic patients after a 7.8-year follow-up period (range 7.1-9.2). Kaplan-Meier curves for the primary end point (decrease of GFR 3.0 ml/min per 1.73 in per year) was two to three times more frequently observed in patients with R/I >= 80. Four- to fivefold fewer patients showed a regression to normoalbuminuria during the follow-up period from baseline microalbuminuria in the cohort with R/I >= 80. Overt proteinuria did develop in 24% of patients with R/I >= 80 and in 5% of patients with R/I <80 (P < 0.01). In conclusion, intrarenal arterial resistance appears to play a nontrivial role in deteriorating renal function in type 2 diabetic patients. R/I is a noninvasive diagnostic procedure, which strongly predicts the outcome of renal function in type 2 diabetic patients, even when GFR patterns are still normal.
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| 41. |
- Park, Hee-Bok, 1973-
(författare)
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Genetic Analysis of Quantitative Traits Using Domestic Animals : A Candidate Gene and Genome Scanning Approach
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Domestication has led to genetic changes that affect quantitative traits in farm animals. Both candidate gene analysis using association tests and genome scans based on linkage analysis have been performed to understand the molecular basis underlying quantitative genetic variation in horses, pigs and chickens. To test a possible association of polymorphisms in the PRKAG3 gene, previously found to be associated with excess glycogen content in pig skeletal muscle, with quantitative traits in the horse, the major coding part of the equine PRKAG3 sequence was identified. Bioinformatic characterization of the equine PRKAG3 gene was conducted. A single nucleotide polymorphism (SNP) causing a missense mutation (Pro258Leu) was found. Screening this SNP showed that the Leu258 allele was more frequent in breeds with heavy muscularity. To assess previously reported associations between polymorphisms in the MC4R gene and obesity-related traits further, we conducted linkage analysis between the MC4R locus and fatness-related traits using a Wild BoarxLarge White intercross. No significant association between segregation at the MC4R locus and fatness was detected in this pedigree. A genome scan of quantitative trait loci (QTLs) has been performed in an intercross between chicken lines divergently selected for growth. Divergent parental lines have been established by selecting for high and low 56-day body weight for over 40 generations. The selection has led to approximately a 9-fold difference in 56-day body weight between lines and resulted in correlated responses for a number of traits including appetite, immune response, body composition and metabolic traits. Phenotypic data on growth and other correlated traits were collected from more than 800 F2 individuals. Genome scans using 145 markers on 26 linkage groups have identified QTLs affecting growth and correlated responses to selection for 56-day body weight. No major QTL explaining a large portion of phenotypic variation in growth was revealed in this study.
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| 42. |
- Ribbhammar, U, et al.
(författare)
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High resolution mapping of an arthritis susceptibility locus on rat chromosome 4, and characterization of regulated phenotypes
- 2003
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 48:9, s. S228-S228
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Tidskriftsartikel (refereegranskat)abstract
- The rat Natural Killer cell gene Complex (NKC) encodes molecules that can regulate immunity. It is located within an interval on DA rat chromosome 4 (RNO4) that is linked to immune-mediated inflammatory joint diseases, including oil-induced arthritis (OIA). We aimed to test the hypothesis that NKC regulates arthritis, by performing advanced mapping of arthritis and additional phenotypes induced by an intradermal injection of incomplete Freund's adjuvant-oil. Reciprocal transfer of RNO4 intervals established that alleles from DA confer arthritis susceptibility to inbred LEW.1AV1 and PVG.1AV1 rats, whereas LEW.1AV1 and PVG.1AV1 alleles confer resistance to inbred DA. Subcongenic strains with PVG.1AV1 alleles introduced on DA allowed mapping of disease predisposition to 0.8 cM on the cytogenetic band 4q42, within the quantitative trait locus oil-induced arthritis-2 (Oia2), but outside the NKC. Alleles in Oia2 regulated arthritis in an additive fashion, and determined arthritis incidence, severity and day of onset, in both males and females. Besides macroscopic joint-inflammation, Oia2 also regulated other oil-induced phenotypes, including lymphoplasia and plasma levels of the inflammation marker alpha1-acid glycoprotein. The high-impact Oia2 region harbors gene sequences similar to human C3AR1, Ribosomal protein L7, DNAJA2, C-type lectins, C1s and CD163. These candidate disease genes may be of general interest, given that rat 4q42, and the syntenic mouse 6F2 and human 12p13 regions are linked to several inflammatory diseases, including rheumatoid arthritis.
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| 43. |
- Rintisch, Carola, et al.
(författare)
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Positional cloning of the Igl genes controlling rheumatoid factor production and allergic bronchitis in rats
- 2008
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 105:37, s. 14005-14010
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid factors (RF), autoantibodies that bind the Fc region of IgG, are one of the major diagnostic marker in rheumatoid arthritis (RA) but occur with lower frequency also in other infectious and inflammatory conditions. Through positional cloning of the previously described quantitative trait locus (QTL) Rf1 in congenic and advanced intercrossed rats, we identified the Ig lambda light chain locus as a locus that regulates the production of RF in rats. The congenic rats produce RF-Ig lambda and have significant higher levels of RF-IgG and RF-IgM in serum, while the DA rat has an impaired RF production and does not produces RF-Ig lambda. Thus, we could investigate the role of RF in pristane-induced arthritis (PIA) as well as ovalbumin-induced airway inflammation. We show that there was no difference in the development and severity of PIA between congenic and parental DA rats, suggesting that RIP using lambda light chains have no impact on PIA. However, the RF producing congenic rats developed a more severe airway inflammation as indicated in the significantly increased number of eosinophils in bronchoalveolar lavage fluid as well as total IgE in serum. In addition, RF congenic rats had a significantly enhanced immune response toward OVA due to increased OVA-Igk but not OVA-IgI antibodies, suggesting a possible involvement of RF in the regulation of the humoral immune response.
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| 44. |
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| 45. |
- Rosengren, Anders, et al.
(författare)
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Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes
- 2010
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 327:5962, s. 217-20
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Tidskriftsartikel (refereegranskat)abstract
- Several common genetic variations have been associated with type 2 diabetes, but the exact disease mechanisms are still poorly elucidated. Using congenic strains from the diabetic Goto-Kakizaki rat, we identified a 1.4-megabase genomic locus that was linked to impaired insulin granule docking at the plasma membrane and reduced beta cell exocytosis. In this locus, Adra2a, encoding the alpha2A-adrenergic receptor [alpha(2A)AR], was significantly overexpressed. Alpha(2A)AR mediates adrenergic suppression of insulin secretion. Pharmacological receptor antagonism, silencing of receptor expression, or blockade of downstream effectors rescued insulin secretion in congenic islets. Furthermore, we identified a single-nucleotide polymorphism in the human ADRA2A gene for which risk allele carriers exhibited overexpression of alpha(2A)AR, reduced insulin secretion, and increased type 2 diabetes risk. Human pancreatic islets from risk allele carriers exhibited reduced granule docking and secreted less insulin in response to glucose; both effects were counteracted by pharmacological alpha(2A)AR antagonists.
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| 46. |
- Sahlqvist, Anna-Stina, 1980-
(författare)
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Genetic Characterization of Chicken Models for Autoimmune Disease
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Autoimmune diseases are endemic, but the disease mechanisms are poorly understood. A way to better understand these are to find disease-regulating genes. However, this is difficult as the diseases are complex, with several genes as well as environmental factors influencing the development of disease. A way to facilitate the search for genes responsible for the diseases is to use comparative genomic studies. Animal models are relatively easy to analyze since control of environment and breeding are obtained.The University of California at Davies – line 200 (UCD-200) chickens have a hereditary disease that is similar to systemic sclerosis. Using a backcross between UCD-200 chickens and red junglefowl (RJF) chickens we identified three loci linked to the disease. The loci contained immune-regulatory genes suggested to be involved in systemic sclerosis in humans, as well as a previously unidentified linkage between systemic sclerosis in UCD-200 chickens and IGFBP3.The Dark brown (Db) gene enhances red pheomelanin and restricts expression of eumelanin in chickens. The Db phenotype is regulated by an 8 kb deletion upstream of SOX10. Pigmentation studies are potentially useful when trying to identify pathogenic mechanisms and candidate genes in vitiligoThe Obese strain (OS) of chickens spontaneously develops an autoimmune thyroiditis which closely resembles human Hashimoto’s thyroiditis. By using an intercross between OS chickens and RJF chickens, we found several disease phenotypes that can be used in an ongoing linkage analysis with the goal to find candidate genes for autoimmune disease. An important phenotype to record and add to the linkage analysis is autoantibodies against thyroid peroxidase, since this phenotype is a key feature in Hashimoto’s thyroiditis. Previous attempts to measure these titres in OS chickens have failed, hence an assay was developed for this purpose.
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| 47. |
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| 48. |
- Svenningsson, Anna, et al.
(författare)
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Genome-wide linkage analysis in families with infantile hypertrophic pyloric stenosis indicates novel susceptibility loci
- 2012
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Ingår i: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 57:2, s. 115-121
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Tidskriftsartikel (refereegranskat)abstract
- Infantile hypertrophic pyloric stenosis (IHPS) is a common cause of upper gastrointestinal obstruction during infancy. A multifactorial background of the disease is well established. Multiple susceptibility loci including the neuronal nitric oxide synthase (NOS1) gene have previously been linked to IHPS, but contradictory results of linkage studies in different materials indicate genetic heterogeneity. To identify IHPS susceptibility loci, we conducted a genome-wide linkage analysis in 37 Swedish families. In regions where the Swedish material showed most evidence in favor of linkage, 31 additional British IHPS families were analyzed. Evidence in favor of significant linkage was observed in the Swedish material to two loci on chromosome 2q24 (non-parametric linkage (NPL)=3.77) and 7p21 (NPL=4.55). In addition, evidence of suggestive linkage was found to two loci on chromosome 6p21 (NPL=2.97) and 12q24 (NPL=2.63). Extending the material with British samples did not enhance the level of significance. Regions with linkage harbor interesting candidate genes, such as glucagon-like peptide-2 (GLP-2 encoded by the glucagon gene GCG), NOS1, motilin (MLN) and neuropeptide Y (NPY). The coding exons for GLP-2, and NPY were screened for mutations with negative results. In conclusion, we could confirm suggestive linkage to the region harboring the NOS1 gene and detected additional novel susceptibility loci for IHPS. Journal of Human Genetics (2012) 57, 115-121; doi:10.1038/jhg.2011.137; published online 8 December 2011
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| 49. |
- Swanberg, Maria, et al.
(författare)
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MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction
- 2005
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 37:5, s. 486-494
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Tidskriftsartikel (refereegranskat)abstract
- Antigen presentation to T cells by MHC molecules is essential for adaptive immune responses. To determine the exact position of a gene affecting expression of MHC molecules, we finely mapped a previously defined rat quantitative trait locus regulating MHC class II on microglia in an advanced intercross line. We identified a small interval including the gene MHC class II transactivator (Mhc2ta) and, using a map over six inbred strains combined with gene sequencing and expression analysis, two conserved Mhc2ta haplotypes segregating with MHC class II levels. In humans, a -168A --> G polymorphism in the type III promoter of the MHC class II transactivator (MHC2TA) was associated with increased susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction, as well as lower expression of MHC2TA after stimulation of leukocytes with interferon-gamma. We conclude that polymorphisms in Mhc2ta and MHC2TA result in differential MHC molecule expression and are associated with susceptibility to common complex diseases with inflammatory components.
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| 50. |
- Tenne, Max, et al.
(författare)
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Genetic variation in the PTH pathway and bone phenotypes in elderly women: Evaluation of PTH, PTHLH, PTHR1 and PTHR2 genes.
- 2008
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 42, s. 719-727
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Parathyroid hormone (PTH) is a key regulator of calcium metabolism. Parathyroid hormone-like hormone (PTHrP) contributes to skeletal development through regulation of chondrocyte proliferation and differentiation during early bone growth. Both PTH and PTHrP act through the same receptor (PTHR1). A second receptor, PTHR2, has been identified although its function is comparatively unknown. PTH hyper-secretion induces bone resorption, whereas intermittent injection of PTH increases bone mass. To explore the effects of genetic variation in the PTH pathway, we have analysed variations in PTH, PTHLH, PTHR1 and PTHR2 in relation to bone mass and fracture incidence in elderly women. MATERIALS AND METHODS: This study includes 1044 elderly women, all 75 years old, from the Malmö Osteoporosis Prospective Risk Assessment study (OPRA). Single nucleotide polymorphisms (SNPs) from 4 genes and derived haplotypes in the PTH signaling pathway were analysed in 745-1005 women; 6 SNPs in the PTH gene and 3 SNPs each in the PTHLH, PTHR1 and PTHR2 genes were investigated in relation to BMD (assessed at baseline), fracture (434 prevalent fractures of all types over lifetime, self-reported and 174 incident fractures up to 7 years, X-ray verified) and serum PTH. RESULTS AND CONCLUSION: Individually, SNPs in the 4 loci did not show any significant association with BMD. Neither were PTHLH, PTHR1 and PTHR2 polymorphisms associated with fracture. Three of 5 common haplotypes, accounting for >98% of alleles at the PTH locus, were identified as independent predictors of fracture. Haplotype 9 (19%) was suggestive of an association with fractures of any type sustained during lifetime (p=0.018), with carriers of one or more copies of the haplotype having the lowest incidence (p=0.006). Haplotypes 1 (13%) and 5 (37%) and 9 were suggestive of an association with fractures sustained between 50 and 75 years (p=0.02, p=0.013 and p=0.034). Carriers of haplotypes 1 and 5 were more likely to suffer a fracture (haplotype 1, p=0.045; haplotype 5, p=0.008). We conclude, that while further genotyping across the gene is recommended, in this cohort of elderly Swedish women, polymorphisms in PTH may contribute to the risk of fracture through mechanisms that are independent of BMD.
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