| 1. |
- Kiemeney, Lambertus A, et al.
(författare)
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A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.
- 2010
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 415-9
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Tidskriftsartikel (refereegranskat)abstract
- Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
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| 2. |
- Pétursdóttir, Vigdís, 1962
(författare)
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Giant cell arteritis. Epidemiological, morphological and molecular genetic studies
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Giant cell arteritis (GCA) is a chronic inflammatory disorder of unknown etiology, affecting large and medium-sized arteries, predominantly in postmenopausal women. Its pathogenesis is probably multifactorial. Several studies suggest that GCA is an antigen-driven disease. Symptoms such as fever and high sedimentation rate may indicate an infectious origin but so far GCA has not been shown to be a truly infectious vasculitis. Previous morphological studies suggest that calcification of the internal elastic membrane (IEM) might be a prerequisite for the disorder. Morphologically, the disease appears to start as a focal foreign-body giant cell reaction directed at the calcified IEM.The purpose of the present series of investigations was to analyse the annual and seasonal incidence of biopsy-verified GCA in Göteborg, to study giant cell aortitis morphologically and also to correlate the degree of inflammation with changes in cross-sectional dimensions in the temporal arteries. Further aims were to investigate the distribution and structure of estrogen receptor a (ER) in temporal artery tissue from GCA patients and controls.A total of 4971 temporal artery biopsies were investigated in Göteborg between 1976 and 1995. Of these 665 (13.4%) displayed signs of GCA which implies an average annual incidence rate of 22.2/ 100,000 inhabitants over 50 years of age. There was a statistically significant increase of 10.9% in the annual incidence during the period. Cyclic yearly fluctuations were not found. In contrast, the seasonal fluctuations were found to be statistically significant with peaks in autumn and late winter, which might indicate that exogenous factors are of importance for the pathogenesis. Staining for a-smooth muscle actin showed widespread areas totally devoid of immunoreactivity in the aortic media. Such areas were acellular and displayed granular calcifications. Focal granulomatous reaction with foreign-body giant cells was found at their ends. The present findings are analogous to the changes in temporal arteries in GCA and support that media atrophy and calcifications are prerequisites for the disorder and the target of the initial granulomatous reaction.Morphometrical analyses of different segments in the same artery revealed a significant positive correlation between the degree of inflammation and the media circumference as well as intima and media cross-sectional areas. While the media cross-sectional area was approximately 15% greater in the most inflamed segment compared with the least inflamed one, the intima area increased by 100%. Even in single cross sections, the intima area showed a positive correlation to the degree of inflammation. The results indicate that the inflammatory cells produce factors leading to local intimal thickening in GCA.The estrogen metabolism might influence the pathogenesis of GCA in several ways. Firstly, reduced estrogen influence might theoretically have negative effects on the vessel wall, thus causing media atrophy. Secondly, there is ample evidence that estrogen affects the immune system via ER in lymphocytes and macrophages. Immunocytochemical analysis displayed a positive cytoplasmic reaction in smooth muscle cells of the media in temporal arteries from patients with GCA and in non-GCA controls. Immunoreactivity was furthermore noticed in activated mononuclear inflammatory cells and giant cells in the GCA arteries. Western blot technique confirmed that the immunoreactive protein corresponds to the expected molecular weight of the ER. Nested RT-PCR and nucleotide sequence analysis of the ER-mRNAs revealed multiple transcript variants, the majority of which may be explained by alternative splicing. Somatic mutations were rare. No significant difference in the number of transcript variants was identified between GCA patients and controls. The combined Western blot and molecular genetic observations indicate that the observed cytoplasmic ER immunoreactivity in GCA and controls is related to an accumulation mainly of wild type ERa.
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| 3. |
- Rafnar, Thorunn, et al.
(författare)
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European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene.
- 2011
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 20:21, s. 4268-81
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Tidskriftsartikel (refereegranskat)abstract
- Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.
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