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2. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Author

Steinthorsdottir, V. (Valgerdur), McGinnis, R. (Ralph), Williams, N. O. (Nicholas O.), Stefansdottir, L. (Lilja), Thorleifsson, G. (Gudmar), Shooter, S. (Scott), Fadista, J. (Joao), Sigurdsson, J. K. (Jon K.), Auro, K. M. (Kirsi M.), Berezina, G. (Galina), Borges, M.-C. (Maria-Carolina), Bumpstead, S. (Suzannah), Bybjerg-Grauholm, J. (Jonas), Colgiu, I. (Irina), Dolby, V. A. (Vivien A.), Dudbridge, F. (Frank), Engel, S. M. (Stephanie M.), Franklin, C. S. (Christopher S.), Frigge, M. L. (Michael L.), Frisbaek, Y. (Yr), Geirsson, R. T. (Reynir T.), Geller, F. (Frank), Gretarsdottir, S. (Solveig), Gudbjartsson, D. F. (Daniel F.), Harmon, Q. (Quaker), Hougaard, D. M. (David Michael), Hegay, T. (Tatyana), Helgadottir, A. (Anna), Hjartardottir, S. (Sigrun), Jaeaeskelaeinen, T. (Tiina), Johannsdottir, H. (Hrefna), Jonsdottir, I. (Ingileif), Juliusdottir, T. (Thorhildur), Kalsheker, N. (Noor), Kasimov, A. (Abdumadjit), Kemp, J. P. (John P.), Kivinen, K. (Katja), Klungsoyr, K. (Kari), Lee, W. K. (Wai K.), Melbye, M. (Mads), Miedzybrodska, Z. (Zosia), Moffett, A. (Ashley), Najmutdinova, D. (Dilbar), Nishanova, F. (Firuza), Olafsdottir, T. (Thorunn), Perola, M. (Markus), Pipkin, F. B. (Fiona Broughton), Poston, L. (Lucilla), Prescott, G. (Gordon), Saevarsdottir, S. (Saedis), Salimbayeva, D. (Damilya), Scaife, P. J. (Paula Juliet), Skotte, L. (Line), Staines-Urias, E. (Eleonora), Stefansson, O. A. (Olafur A.), Sorensen, K. M. (Karina Meden), Thomsen, L. C. (Liv Cecilie Vestrheim), Tragante, V. (Vinicius), Trogstad, L. (Lill), Simpson, N. A. (Nigel A. B.), Laivuori, H. (Hannele), Morgan, L. (Linda), Aripova, T. (Tamara), Casas, J. P. (Juan P.), Dominiczak, A. F. (Anna F.), Walker, J. J. (James J.), Thorsteinsdottir, U. (Unnur), Iversen, A.-C. (Ann-Charlotte), Feenstra, B. (Bjarke), Lawlor, D. A. (Deborah A.), Boyd, H. A. (Heather Allison), Magnus, P. (Per), Zakhidova, N. (Nodira), Svyatova, G. (Gulnara), Stefansson, K. (Kari), Heinonen, S. (Seppo), Kajantie, E. (Eero), Kere, J. (Juha), Pouta, A. (Anneli), Macphail, S. (Sheila), Kilby, M. (Mark), Habiba, M. (Marwan), Williamson, C. (Catherine), O'Shaughnessy, K. (Kevin), O'Brien, S. (Shaughn), Cameron, A. (Alan), Redman, C. W. (Christopher W. G.), Farrall, M. (Martin), and Caulfield, M. (Mark)

Subjects
embryonic structures, reproductive and urinary physiology, female genital diseases and pregnancy complications
Abstract

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia. Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.

Published
2020

20. Variants in the fetal genome near FLT1 are associated with risk of preeclampsia

Author

McGinnis, R, Steinthorsdottir, V, Williams, NO, Thorleifsson, G, Shooter, S, Hjartardottir, S, Bumpstead, S, Stefansdottir, L, Hildyard, L, Sigurdsson, JK, Kemp, JP, Silva, GB, Thomsen, LCV, Jääskeläinen, T, Kajantie, E, Chappell, S, Kalsheker, N, Moffett, A, Hiby, S, Lee, WK, Padmanabhan, S, Simpson, NAB, Dolby, VA, Staines-Urias, E, Engel, SM, Haugan, A, Trogstad, L, Svyatova, G, Zakhidova, N, Najmutdinova, D, FINNPEC Consortium, GOPEC Consortium, Dominiczak, AF, Gjessing, HK, Casas, JP, Dudbridge, F, Walker, JJ, Pipkin, FB, Thorsteinsdottir, U, Geirsson, RT, Lawlor, DA, Iversen, AC, Magnus, P, Laivuori, H, Stefansson, K, Morgan, L, COLLABORATORS, Heinonen, S, Kere, J, Kivinen, K, Pouta, A, Macphail, S, Kilby, M, Habiba, M, Williamson, C, O'Shaughnessy, K, O'Brien, S, Cameron, A, Poston, L, Miedzybrodzka, Z, Redman, CWG, Farrall, M, and Caulfield, M

Subjects
embryonic structures, female genital diseases and pregnancy complications, reproductive and urinary physiology
Abstract

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10(-11)) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.

Published
2017

21. Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12

Author

Jackson, VE, Ntalla, I, Sayers, I, Morris, R, Whincup, P, Casas, J-P, Amuzu, A, Choi, M, Dale, C, Kumari, M, Engmann, J, Kalsheker, N, Chappell, S, Guetta-Baranes, T, McKeever, TM, Palmer, CNA, Tavendale, R, Holloway, JW, Sayer, AA, Dennison, EM, Cooper, C, Bafadhel, M, Barker, B, Brightling, C, Bolton, CE, John, ME, Parker, SG, Moffat, MF, Wardlaw, AJ, Connolly, MJ, Porteous, DJ, Smith, BH, Padmanabhan, S, Hocking, L, Stirrups, KE, Deloukas, P, Strachan, DP, Hall, IP, Tobin, MD, Wain, LV, Jackson, VE, Ntalla, I, Sayers, I, Morris, R, Whincup, P, Casas, J-P, Amuzu, A, Choi, M, Dale, C, Kumari, M, Engmann, J, Kalsheker, N, Chappell, S, Guetta-Baranes, T, McKeever, TM, Palmer, CNA, Tavendale, R, Holloway, JW, Sayer, AA, Dennison, EM, Cooper, C, Bafadhel, M, Barker, B, Brightling, C, Bolton, CE, John, ME, Parker, SG, Moffat, MF, Wardlaw, AJ, Connolly, MJ, Porteous, DJ, Smith, BH, Padmanabhan, S, Hocking, L, Stirrups, KE, Deloukas, P, Strachan, DP, Hall, IP, Tobin, MD, and Wain, LV

Abstract

BACKGROUND: Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants. OBJECTIVE: To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation. METHODS: 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10(-5)) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays. RESULTS: Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10(-6), preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10(-6)). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10(-6)). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10(-7)). CONCLUSIONS: This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.

Published
2016

23. Association of MMP-2 polymorphisms with severe and very severe COPD: a case control study of MMPs-1, 9 and 12 in a European population

Author

Haq,I., Chappell, S., Johnson, SR., Lotya,J., Daly, L., Morgan, K., Guetta-Baranes, T., Roca Torrent, Josep, Rabinovich, R., Millar, AB., Donnelly, SC., Keatings, V., MacNee, W., Stolk, J., Hiemstra, PS., Miniati, M., Monti, S., O'Connor, CM., Kalsheker, N., and Universitat de Barcelona

Subjects
Genètica mèdica, Medical genetics, Molecular genetics, Chronic obstructive pulmonary diseases, Malalties pulmonars obstructives cròniques, Genètica molecular
Abstract

BACKGROUND: Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease--antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies. METHODS: To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history. RESULTS: Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV. CONCLUSIONS: Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity.

Published
2010

26. A Comprehensive Evaluation of Potential Lung Function Associated Genes in the SpiroMeta General Population Sample

Author

Semple, MG, Obeidat, M, Wain, LV, Shrine, N, Kalsheker, N, Artigas, MS, Repapi, E, Burton, PR, Johnson, T, Ramasamy, A, Zhao, JH, Zhai, G, Huffman, JE, Vitart, V, Albrecht, E, Igl, W, Hartikainen, A-L, Pouta, A, Cadby, G, Hui, J, Palmer, LJ, Hadley, D, McArdle, WL, Rudnicka, AR, Barroso, I, Loos, RJF, Wareham, NJ, Mangino, M, Soranzo, N, Spector, TD, Glaeser, S, Homuth, G, Voelzke, H, Deloukas, P, Granell, R, Henderson, J, Grkovic, I, Jankovic, S, Zgaga, L, Polasek, O, Rudan, I, Wright, AF, Campbell, H, Wild, SH, Wilson, JF, Heinrich, J, Imboden, M, Probst-Hensch, NM, Gyllensten, U, Johansson, A, Zaboli, G, Mustelin, L, Rantanen, T, Surakka, I, Kaprio, J, Jarvelin, M-R, Hayward, C, Evans, DM, Koch, B, Musk, AW, Elliott, P, Strachan, DP, Tobin, MD, Sayers, I, Hall, IP, Semple, MG, Obeidat, M, Wain, LV, Shrine, N, Kalsheker, N, Artigas, MS, Repapi, E, Burton, PR, Johnson, T, Ramasamy, A, Zhao, JH, Zhai, G, Huffman, JE, Vitart, V, Albrecht, E, Igl, W, Hartikainen, A-L, Pouta, A, Cadby, G, Hui, J, Palmer, LJ, Hadley, D, McArdle, WL, Rudnicka, AR, Barroso, I, Loos, RJF, Wareham, NJ, Mangino, M, Soranzo, N, Spector, TD, Glaeser, S, Homuth, G, Voelzke, H, Deloukas, P, Granell, R, Henderson, J, Grkovic, I, Jankovic, S, Zgaga, L, Polasek, O, Rudan, I, Wright, AF, Campbell, H, Wild, SH, Wilson, JF, Heinrich, J, Imboden, M, Probst-Hensch, NM, Gyllensten, U, Johansson, A, Zaboli, G, Mustelin, L, Rantanen, T, Surakka, I, Kaprio, J, Jarvelin, M-R, Hayward, C, Evans, DM, Koch, B, Musk, AW, Elliott, P, Strachan, DP, Tobin, MD, Sayers, I, and Hall, IP

Abstract

RATIONALE: Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium). OBJECTIVES: To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample. METHODS: We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/-10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations. RESULTS: The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV(1) or FEV(1)/FVC traits using a carefully defined significance threshold of 1.3×10(-5). The most significant loci associated with FEV(1) include SNPs tagging MACROD2 (P = 6.81×10(-5)), CNTN5 (P = 4.37×10(-4)), and TRPV4 (P = 1.58×10(-3)). Among ever-smokers, SERPINA1 showed the most significant association with FEV(1) (P = 8.41×10(-5)), followed by PDE4D (P = 1.22×10(-4)). The strongest association with FEV(1)/FVC ratio was observed with ABCC1 (P = 4.38×10(-4)), and ESR1 (P = 5.42×10(-4)) among ever-smokers. CONCLUSIONS: Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV(1) among smokers in the general population.

Published
2011

30. Genetic Variants of Matrix Metalloproteinases 1, 9 and 12 in Chronic Obstructive Pulmonary Disease.

Author

Haq, I, primary, Chappell, S, additional, Johnson, SR, additional, Daly, L, additional, Morgan, K, additional, Baranes, TG, additional, Roca, J, additional, Rabinovich, R, additional, Lotya, J, additional, Millar, AB, additional, Donnelly, SC, additional, Keatings, V, additional, MacNee, W, additional, Stolk, J, additional, Hiemstra, PS, additional, Miniati, M, additional, Monti, S, additional, O'Connor, CM, additional, and Kalsheker, N, additional

Published
2009
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32. Genetic variants of microsomal epoxide hydrolase and glutamate-cysteine ligase in COPD

Author

Chappell, S., primary, Daly, L., additional, Morgan, K., additional, Guetta-Baranes, T., additional, Roca, J., additional, Rabinovich, R., additional, Lotya, J., additional, Millar, A. B., additional, Donnelly, S. C., additional, Keatings, V., additional, MacNee, W., additional, Stolk, J., additional, Hiemstra, P. S., additional, Miniati, M., additional, Monti, S., additional, O'Connor, C. M., additional, and Kalsheker, N., additional

Published
2008
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33. Variation in the tumour necrosis factor gene is not associated with susceptibility to COPD

Author

Chappell, S., primary, Daly, L., additional, Morgan, K., additional, Baranes, T. G., additional, Roca, J., additional, Rabinovich, R., additional, Millar, A., additional, Donnelly, S. C., additional, Keatings, V., additional, MacNee, W., additional, Stolk, J., additional, Hiemstra, P. S., additional, Miniati, M., additional, Monti, S., additional, O'Connor, C. M., additional, and Kalsheker, N., additional

Published
2007
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39. A patient with the rare alpha-1-antitrypsin variant Zbristol in compound heterozygosity with the Z mutation.

Author

Bates, KJ, Puxley, M, Hill, M, Kalsheker, N, Barlow, A, Clark, BE, and Sherwood, RA

Subjects
ALPHA 1-antitrypsin, BILIARY tract, HETEROZYGOSITY, TRYPSIN inhibitors, ELECTROPHORESIS
Abstract

Alpha-1-antitrypsin (AAT) is a protease inhibitor (PI), deficiency of which is associated with emphysema and liver disease. The most common deficiency alleles are the S (p.Glu288Val) and Z (p.Glu366Lys) alleles. The Z allele predisposes the AAT protein to polymerization with accumulation in hepatocytes leading to liver disease in PIZ individuals. Most AAT variants have a characteristic pattern of isoforms by isoelectric focusing (IEF). A novel AAT variant called PIZbristol (p.Thr109Met) with an unusual pattern on IEF was described in 1997. We report a patient with the PIZZbristol phenotype that has not been previously described. A 43-year-old man was referred by his GP to a respiratory clinic for breathlessness. His AAT concentration was 0.50 g/L (reference range 1.0–2.0 g/L). An unusual pattern on IEF was seen and sequencing revealed the presence of the rare variant Zbristol in combination with the Z mutation. This is the second reported case of Zbristol and the first in combination with the Z mutation. The patient maintained plasma AAT concentrations around 0.50–0.70 g/L which suggested that the Zbristol protein contributed to the low plasma concentration of AAT. The clinical symptoms associated with PIZ are usually attributed to the plasma deficiency, but his only respiratory complaint was that of breathlessness. This suggests that the PIZZbristol phenotype may confer an effect on respiratory function but is not involved in liver disease. [ABSTRACT FROM AUTHOR]

Published
2013
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