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2. Response to Li and Hopper.

Author

Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Huyghe J.R., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., Hsu L., Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Huyghe J.R., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., and Hsu L.

Published
2021

3. Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

Author

Huyghe J.R., Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., Hsu L., Huyghe J.R., Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., and Hsu L.

Abstract

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might be

Published
2020

4. A polygenic and phenotypic risk prediction for polycystic ovary syndrome evaluated by phenomewide association studies

Author

Joo, Y.Y. (Yoonjung Yoonie), Actkins, K. (Ky'Era), Pacheco, J.A. (Jennifer A.), Basile, A.O. (Anna O.), Carroll, R. (Robert), Crosslin, D.R. (David), Day, F.R. (Felix), Denny, J.C. (Joshua C.), Edwards, D.R.V. (Digna R. Velez), Hakonarson, H. (Hakon), Harley, J.B. (John B.), Hebbring, S.J. (Scott J.), Ho, K. (Kevin), Jarvik, G.P. (Gail), Jones, M.R. (Michelle), Karaderi, T. (Tugce), Mentch, F.D. (Frank D.), Meun, C. (Cindy), Namjou, B. (Bahram), Pendergrass, S.A. (Sarah), Ritchie, M.D. (Marylyn D.), Stanaway, I.B. (Ian B.), Urbanek, M. (Margrit), Walunas, T.L. (Theresa L.), Smith, M. (Maureen), Chisholm, R.L. (Rex L.), Kho, M.M.L. (Marcia), Davis, L. (Lea), Geoffrey Hayes, M. (M.), Joo, Y.Y. (Yoonjung Yoonie), Actkins, K. (Ky'Era), Pacheco, J.A. (Jennifer A.), Basile, A.O. (Anna O.), Carroll, R. (Robert), Crosslin, D.R. (David), Day, F.R. (Felix), Denny, J.C. (Joshua C.), Edwards, D.R.V. (Digna R. Velez), Hakonarson, H. (Hakon), Harley, J.B. (John B.), Hebbring, S.J. (Scott J.), Ho, K. (Kevin), Jarvik, G.P. (Gail), Jones, M.R. (Michelle), Karaderi, T. (Tugce), Mentch, F.D. (Frank D.), Meun, C. (Cindy), Namjou, B. (Bahram), Pendergrass, S.A. (Sarah), Ritchie, M.D. (Marylyn D.), Stanaway, I.B. (Ian B.), Urbanek, M. (Margrit), Walunas, T.L. (Theresa L.), Smith, M. (Maureen), Chisholm, R.L. (Rex L.), Kho, M.M.L. (Marcia), Davis, L. (Lea), and Geoffrey Hayes, M. (M.)

Abstract

Context: As many as 75% of patients with polycystic ovary syndrome (PCOS) are estimated tobe unidentified in clinical practice. Objective: Utilizing polygenic risk prediction, we aim to identify the phenome-widecomorbidity patterns characteristic of PCOS to improve accurate diagnosis and preventivetreatment.Design, Patients, and Methods: Leveraging the electronic health records (EHRs) of 124 852individuals, we developed a PCOS risk prediction algorithm by combining polygenic risk scores(PRS) with PCOS component phenotypes into a polygenic and phenotypic risk score (PPRS). Weevaluated its predictive capability across different ancestries and perform a PRS-based phenomewide association study (PheWAS) to assess the phenomic expression of the heightened risk ofPCOS.Results: The integrated polygenic prediction improved the average performance (pseudo-R2)for PCOS detection by 0.228 (61.5-fold), 0.224 (58.8-fold), 0.211 (57.0-fold) over the null modelacross European, African, and multi-ancestry participants respectively. The subsequent PRSpowered PheWAS identified a high level of shared biology between PCOS and a range ofmetabolic and endocrine outcomes, especially with obesity and diabetes: "morbid obesity","type 2 diabetes", "hypercholesterolemia", "disorders of lipid metabolism", "hypertension",and "sleep apnea" reaching phenome-wide significance.Conclusions: Our study has expanded the methodological utility of PRS in patient stratificationand risk prediction, especially in a multifactorial condition like PCOS, across different geneticorigins. By utilizing the individual genome-phenome data available from the EHR, our approachalso demonstrates that polygenic prediction by PRS can provide valuable opportunities todiscover the pleiotropic phenomic network associated with PCOS pathogenesis.Abbreviations: AA, African ancestry; ANOVA, analysis of variance; BMI, body mass index; EA,European ancestry; EHR, electronic health records; eMERGE, electronic Medical Records andGenomi

Published
2020
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6. Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus

Author

Sawalha, A.H., Kaufman, K.M., Kelly, J.A., Adler, A.J., Aberle, T., Kilpatrick, J., Wakeland, E.K., Li, Q.-Z., Wandstrat, A.E., Karp, D.R., James, J.A., Merrill, J.T., Lipsky, P., and Harley, J.B.

Subjects
Interleukin-21 -- Research, Interleukin-21 -- Physiological aspects, Systemic lupus erythematosus -- Genetic aspects, Systemic lupus erythematosus -- Physiological aspects, Genetic polymorphisms -- Research, Genetic polymorphisms -- Physiological aspects, Health
Published
2008

7. Editorial Acknowledgment

Author

Aarvak, T., Abedi-Valugerdi, M., Abrahamsen, T., Akdis, C., Akuffo, H.O., Alarcon-Riquelme, M., Andersen, P., Arstila, P., Austgulen, R., Baecker-Allan, C., Baggiolini, M., Baker, B.S., Bakke, O., Bakken, V., Barclay, A.N., Bemark, M., Benestad, H.B., Berzins, K., Bjerkvik, R., Bjørge, L., Bland, P., Bolstad, A.I., Born, W., Bowman, S., Brinchmann, J., Britton, S., Brokstad, K.A., Brunet, L.R., Bruserud, Ø., Cardona, P.J., Ceyppens, J.L., Cirino, G., Cohn, M., Cox, R.J., Cunliffe, J., Dahlgren, U., Dellacasagrande, J., Ditzel, H., Dobryszycka, E., Dyrhol-Riise, A.M., Edwards, J.C., Egeland, T., Elsayed, S., Eray, M., Erb, K.J., Esch, T., Eugen-Olsen, J., Everse, L.A., Fagerhol, M., Farstad, I., Feldmann, M., Fernandez, C., Fleck, M., Franksson, R., Freitas, A., Garred, P., Gidlund, M., Gilhus, N.E., Goldbach-Mansky, R., Gordon, J., Gordon, T., Grandien, A., Gregerson, P., Grewal, H., Hakulinen, J., Halstensen, T., Haneberg, B., Hanej, S.H.E., Hansen, T., Harley, J.B., Haukenes, G., Hengartner, H., Henz, B.M., Holen, E., Hurme, M., Husby, G., Husby, S., Hörnqvist-Hultgren, E., Haaheim, L.R., Isenberg, D., Jahnson, F., Jakobsen, H., James, J.A., Jansson, J.O., Jarva, H., Jeansson, S., Johannessen, A.C., Johansen, F.E., Julkunen, I., Kalland, K.H., Kaye, J., Kazatchkine, M., Kihlström, E., Kohler, L., Konttinen, Y., Kotenko, S., Koutzov, S., Krammer, P., Kristoffersen, E., Kunzendorf, U., Lachmann, P., Langman, R., Langner, J., Lanzavecchia, L., Lappalainen, M., Laskay, T., Lea, T., Lefvert, A.K., Lehmann, A.C., Louka, A, Lúdviksson, B.R., Mariette, X., Marion, T., Marker-Herrmann, E., Mattsson, R., McAdam, S., Mellbye, O.J., Mellgren, G., Mellgren, S.I., Mestecky, J., Michaelsen, T., Michalek, S., Miettinen, A., Moestrup, S.K., Moretta, A., Moser, M., Mountz, J., Moutsopoulos, H., Munthe, L.A., Mustafa, T., Myrmel, H., Nannemark, G., Netea, M.G., Nilsen, R., Notarangelo, L.D., Ögmundsdóttir, H., Olsson, I., Olweus, J., Osland, A., Paludan, S.R., Parsons, K.R., Patarroyo, M., Paul, W.E., Perlman, P., Pollock, J.M., Puolakkainen, M., Quale, A., Rajewsky, K., Raman, C., Reichlin, M., Renkonen, R., Rese Shadidi, K., Ricciardi-Castagnoli, P., Rickinson, A.B., Ringdén, O., Risto, R., Rodinov, D., Rosenkrands, I., Rottenberg, M., Russel, M., Rygaard, J., Rødahl, E., Röllinghof, M., Sandberg, M., Schenk, K., Seppälä, I., Shevach, E., Shortman, K., Siegrist, C.A., Sigurdardóttir, S., Silvennoinen, O., Sinigaglia, F., Sistonen, L., Skarstein, K., Skogh, T., Smith, E., Spurkland, A., Stendahl, O., Sugden, B., Suri-Payer, E., Svennerholm, A.M., Szodoray, P., Theofilopoulos, A., Thorley-Lawson, D.A., Timonen, T., Trowsdale, J., Tuomo, T., Ulmer, A.J., Ulvestad, E., Ulvik, R., Vaerman, J.P., van, der Merwe J.P., van Eden, W., Vedeler, C., Vintermyr, O.K., Vyse, J., Wahlgren, M., Wahren-Herlenius, M., Walsh, L.J., Weetman, A.P., Westermark, P., Wiker, H., Yang, J., Yewdell, J.W., Youinou, P., and Zouali, M.

Published
2002

8. A hypothesis for the HLA-B27 immune dysregulation in spondyloarthropathy: contributions from enteric organisms, B27 structure, peptides bound by B27, and convergent evoluton

Author

Scofield, R.H., Warren, W.L., Koelsch, G., and Harley, J.B.

Subjects
Spondyloarthropathies -- Research, Peptides -- Research, Amino acid sequence -- Analysis, Science and technology
Abstract

The histocompatibility (HLA) class I alkele B27 was investigated by the use of the consolidated database of protein sequences to determine whether the primary amino acid sequence of the hypervariable sites of HLA-B27 shares short sequence with the proteins of Gram-negative enteric bacteria. The matching of the enteric proteins to the structural prerequisites for peptide binding to B27 in those areas of the sequence shared with B27 was also studied. A subset of T-cell receptor, B27, and the peptides bound by B27 mediates the B27-linked diseases.

Published
1993

10. The new history of cartography

Author

Harley, J.B.

Subjects
Geography, Ancient -- Portrayals, Cartography -- History, World maps -- Evaluation, Map-projection -- Evaluation, International relations, Political science, Evaluation, History, Portrayals
Abstract

IN the beginning there were maps. There has always been a mapping impulse in individual consciousness. The sensing of space and the development of cognitive structures to understand it can [...]

Published
1991

13. Systemic lupus erythematosus and vitiligo: share common gene(s)!

Author

Nath, S.K., Kelly, J., Namjou, B., Bruner, G., Scofield, R.H., Aston, C.E., and Harley, J.B.

Subjects
Genetic disorders -- Research, Systemic lupus erythematosus -- Genetic aspects, Autoimmune diseases -- Genetic aspects, Biological sciences
Published
2001

21. The TRAF1-C5 region on chromosome 9q33 is associated with multiple autoimmune diseases

Author

Kurreeman, F.A.S., Goulielmos, G.N., Alizadeh, B.Z., Rueda, B., Houwing-Duistermaat, J., Sanchez, E., Bevova, M., Radstake, T.R., Vonk, M.C., Galanakis, E., Ortego, N., Verduyn, W., Zervou, M.I., Roep, B.O., Dema, B., Espino, L., Urcelay, E., Boumpas, D.T., Van Den Berg, L.H., Wijmenga, C., Koeleman, B.P.C., Huizinga, T.W.J., Toes, R.E.M., Martin, J., Jiménez-Alonso, J., Sanchez-Román, J., De-Ramon, E., Camps, M., Aguirre, M.A., García-Portales, R., Harley, J.B., Criswell, L.A., Vyse, T., Kimberly, R., Jacob, C., Moser, K., Langfeldt, C., Alarcón-Riquelme, M.E., and Tsao, B.

Subjects
medicine.medical_specialty, Genotype, Immunology, Genome-wide association study, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Auto-immunity, transplantation and immunotherapy [N4i 4], General Biochemistry, Genetics and Molecular Biology, Autoimmune Diseases, Rheumatology, immune system diseases, Internal medicine, Immunopathology, medicine, Immunology and Allergy, Humans, Lupus Erythematosus, Systemic, Genetic Predisposition to Disease, Allele, skin and connective tissue diseases, Autoimmune disease, Scleroderma, Systemic, systemic-lupus-erythematosus genome-wide association juvenile idiopathic arthritis rheumatoid-arthritis susceptibility risk polymorphism variants locus populations, business.industry, medicine.disease, Connective tissue disease, TNF Receptor-Associated Factor 1, Celiac Disease, Diabetes Mellitus, Type 1, Rheumatoid arthritis, business, Chromosomes, Human, Pair 9, Infection and autoimmunity [NCMLS 1]
Abstract

Item does not contain fulltext OBJECTIVES: The TRAF1-C5 locus has recently been identified as a genetic risk factor for rheumatoid arthritis (RA). Since genetic risk factors tend to overlap with several autoimmune diseases, a study was undertaken to investigate whether this region is associated with type 1 diabetes (TID), celiac disease (CD), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). METHODS: The most consistently associated SNP, rs10818488, was genotyped in a total of 735 patients with T1D, 1049 with CD, 367 with SSc, 746 with SLE and 3494 ethnically- and geographically-matched healthy individuals. The replication sample set consisted of 99 patients with T1D, 272 with SLE and 482 healthy individuals from Crete. RESULTS: A significant association was detected between the rs10818488 A allele and T1D (OR 1.14, p=0.027) and SLE (OR 1.16, p=0.016), which was replicated in 99 patients with T1D, 272 with SLE and 482 controls from Crete (OR 1.64, p=0.002; OR 1.43, p=0.002, respectively). Joint analysis of all patients with T1D (N=961) and all patients with SLE (N=1018) compared with 3976 healthy individuals yielded an allelic common OR of 1.19 (p=0.002) and 1.22 (p=2.6 x 10(-4)), respectively. However, combining our dataset with the T1D sample set from the WTCCC resulted in a non-significant association (OR 1.06, p=0.087). In contrast, previously unpublished results from the SLEGEN study showed a significant association of the same allele (OR 1.19, p=0.0038) with an overall effect of 1.22 (p=1.02 x 10(-6)) in a total of 1577 patients with SLE and 4215 healthy individuals. CONCLUSION: A significant association was found for the TRAF1-C5 locus in SLE, implying that this region lies in a pathway relevant to multiple autoimmune diseases. 01 april 2010

Published
2010

23. Historical geography and the cartographic illusion

Author

Harley, J.B.

Subjects
Cartography -- History, Geography, Historical -- Research, Maps -- Usage, Geography, History
Abstract

The cartographic representation of historical sources, epitomised in H. C. Darby's Domesday Geography and becoming a classic hallmark of British historical geography, remains a largely unexamined aspect of our discourse. This essay links the emphasis on maps to a perception of their objectivity shared by academic cartography. It proposes that we treat such maps as a text rather than as a mirror of reality so that we can understand how their rhetoric has narrowed the practice of historical geography. Such a deconstruction opens the way to reintegrate cartography more fully as part of a humanistic historical geography.

Published
1989

26. Conserved features of Y RNAs: a comparison of experimentally derived secondary structures.

Author

Teunissen, S.W., Kruithof, M.J., Farris, A.D., Harley, J.B., Venrooij, W.J.W. van, Pruijn, G.J.M., Teunissen, S.W., Kruithof, M.J., Farris, A.D., Harley, J.B., Venrooij, W.J.W. van, and Pruijn, G.J.M.

Abstract

Contains fulltext : 184433.pdf (publisher's version ) (Open Access), In this study, phylogenetically conserved structural features of the Ro RNP associated Y RNAs were investigated. The human, iguana, and frog Y3 and Y4 RNA sequences have been determined previously and the respective RNAs were subjected to enzymatic and chemical probing to obtain structural information. For all of the analyzed RNAs, the probing data were used to compose secondary structures, which partly deviate from previously predicted structures. Our results confirm the existence of two stem structures, which are also found at similar positions in hY1 and hY5 RNA. For the remaining parts of hY3 and hY4 RNA the secondary structures differ from those previously proposed based upon computer predictions. What might be more important is that certain parts of the RNAs appear to be flexible, i.e., to adopt several conformations. Another striking feature is that a characteristic pyrimidine-rich region, present in every Y RNA known, is single-stranded in all secondary structures. This may suggest that this region is readily available for base pairing inter-actions with other cellular nucleic acids, which might be important for the as yet unknown function of the RNAs.

Published
2000

28. Conserved features of Y RNAs revealed by automated phylogenetic secondary structure analysis.

Author

Farris, A.D., Koelsch, G., Pruijn, G.J.M., Venrooij, W.J.W. van, Harley, J.B., Farris, A.D., Koelsch, G., Pruijn, G.J.M., Venrooij, W.J.W. van, and Harley, J.B.

Abstract

Item does not contain fulltext, Y RNAs are small 'cytoplasmic' RNAs which are components of the Ro ribonucleoprotein (RNP) complex. The core of this complex, which is found in the cell nuclei of higher eukaryotes as well as the cytoplasm, is composed of a complex between the 60 kDa Ro protein and Y RNAs. Human cells contain four distinct Y RNAs (Y1, Y3, Y4 and Y5), while other eukaryotes contain a variable number of Y RNA homologues. When detected in a particular species, the Ro RNP has been present in every cell type within that particular organism. This characteristic, along with its high conservation among vertebrates, suggests an important function for Ro RNP in cellular metabolism; however, this function has not yet been definitively elucidated. In order to identify conserved features of Y RNA sequences and structures which may be directly involved in Ro RNP function, a phylogenetic comparative analysis of Y RNAs has been performed. Sequences of Y RNA homologues from five vertebrate species have been obtained and, together with previously published Y RNA sequences, used to predict Y RNA secondary structures. A novel RNA secondary structure comparison algorithm, the suboptimal RNA analysis program, has been developed and used in conjunction with available algorithms to find phylogenetically conserved secondary structure models for YI, Y3 and Y4 RNAs. Short, conserved sequences within the Y RNAs have been identified and are invariant among vertebrates, consistent with a direct role for Y RNAs in Ro function. A subset of these are located wholly or partially in looped regions in the Y3 and Y4 RNA predicted model structures, in accord with the possibility that these Y RNAs base pair with other cellular nucleic acids or are sites of interaction between the Ro RNP and other macromolecules.

Published
1999

29. Gene Expression Analysis of European-American Lupus Patients with Thyroid Disease Compared to Matched Controls

Author

Guo, L., primary, Dominguez, N., additional, Dozmorov, I., additional, Tang, Y.H., additional, Namjou, B., additional, Kelly, J., additional, Hutchings, D., additional, Bruner, G., additional, Klein, W., additional, James, J., additional, Kaufman, K., additional, Scofield, H., additional, Guthridge, J.M., additional, and Harley, J.B., additional

Published
2005
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34. Genome Scan of Human Systemic Lupus Erythematosus by Regression Modeling: Evidence of Linkage and Epistasis at 4p16-15.2

Author

Gray-McGuire, C., primary, Moser, K.L., additional, Gaffney, P.M., additional, Kelly, J., additional, Yu, H., additional, Olson, J.M., additional, Jedrey, C.M., additional, Jacobs, K.B., additional, Kimberly, R.P., additional, Neas, B.R., additional, Rich, S.S., additional, Behrens, T.W., additional, and Harley, J.B., additional

Published
2000
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37. A genome screen of systemic lupus erythematosus using affected-relative-pair linkage analysis with covariates demonstrates genetic heterogeneity.

Author

Olson, J.M., Song, Y., Dudek, D.M., Moser, K.L., Kelly, J.A., Bruner, G.R., Downing, K.J., Berry, C.K., James, J.A., and Harley, J.B.

Subjects
SYSTEMIC lupus erythematosus, PHENOTYPES, GENETICS
Abstract

Systemic lupus erythematosus (SLE) appears to be the consequence of complex genetics and of only partly understood environmental contributions. Previous work by ourselves and by others has established genetic effects on 1q, 2q, 4p, 6p, and 16p using SLE as the phenotype. However, individual SLE affecteds are extraordinarily different from one another by clinical and laboratory measures. This variation may have a genetic basis; if so, it is advantageous to incorporate measures of between-family clinical variability as covariates in a genetic linkage analysis of affected relative pairs (ARPs) to allow for locus heterogeneity. This approach was applied to genome scan marker data from 160 pedigrees multiplex for SLE and containing 202 ARPs. Because the number of potential covariates was large, we used both ad hoc methods and formal principal components analysis to construct four composite covariates using the SLE classification criteria plus age of onset, ethnicity, and sex. Linkage analysis without covariates has detected evidence for linkage at 1q22-24, 2q37, 4p16, 12p12-11, and 17p13. Linkage analysis with these covariates uncovered linkage at 13p11, 17q11-25, and 20q12 and greatly improved evidence for linkage at 1q22-24, 2q37, 12p12-11, and 17p13. Follow-up analysis identified the original variables contributing to locus heterogeneity in each of these locations. In conclusion, allowing for locus heterogeneity through the incorporation of covariates in linkage analysis is a useful way to dissect the genetic contributions to SLE and uncover new genetic effects. [ABSTRACT FROM AUTHOR]

Published
2002
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38. The genetics of systemic lupus erythematosus: putting the pieces together.

Author

Kelly, J.A., Moser, K.L., and Harley, J.B.

Subjects
SYSTEMIC lupus erythematosus, AUTOIMMUNE diseases, PHENOTYPES, GENETICS
Abstract

With λ[sub s] estimates of 10 to 20 and other evidence of familial aggregation, as well as a monozygotic twin concordance rate > 20, systemic lupus erythematosus (SLE) would appear to be a very promising phenotype using modern genetic approaches. Indeed, genetic associations are already known at numerous candidate loci including various HLA alleles, complement component genes, Fcγ receptors, and others, and murine genetic studies of lupus models have provided additional candidate genes and potential syntenic linkages to evaluate in man. The completed genetic linkage studies performed on various collections of pedigrees multiplex for SLE have identified 60 susceptibility loci with varying degrees of evidence for linkage in man. Seven of these meet or exceed the threshold for significant linkage (LOD ≥ 3.3 or P ≤ 0.00005) at 1q22-23, 1q41, 2q37, 4p16, 6p21-11, 16q13 and 17p13. In addition, these linkages usually dominate in one ethnicity or another, suggesting that the responsible polymorphisms, once identified, will also vary by ethnicity. Evidence that these linkages can be reproduced range from outright independent confirmation (1q41, 4p16 and 6p21) to additional suggestive evidence in the genomic region of the purported linkage (1q22-23 and 2q37). The results now available suggest that human lupus genetics are robust and that gene identification should be possible using existing genetic approaches and technologies. [ABSTRACT FROM AUTHOR]

Published
2002
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39. The genetics of systemic lupus erythematosus stratified by renal disease: linkage at 10q22.3 (SLEN1), 2q34-35 (SLEN2), and 11p15.6 (SLEN3).

Author

Quintero-Del-Rio, A.I., Kelly, J.A., Kilpatrick, J., James, J.A., and Harley, J.B.

Subjects
KIDNEY diseases, SYSTEMIC lupus erythematosus, GENEALOGY, LINKAGE (Genetics)
Abstract

Renal disease occurs in 40-75% of systemic lupus erythematosus (SLE) patients and significantly contributes to morbidity and mortality. We used two pedigree stratification strategies to explore the impact of the ACR renal criterion for SLE classification upon genetic linkage with SLE. In both we used SLE as the phenotype. First, we evaluated genome scan data from > 300 microsatellite markers in the 75 pedigrees that had at least one SLE affected with the SLE renal criterion. A maximum-likehood parametric model approach produced a maximum screening LOD score of 3.16 at 10q22.3 in the European-American (EA) pedigrees. The African-American (AA) pedigrees obtained a maximum screening LOD score of 2.58 at 11p15.6. A multipoint sib-pair regression analysis produced P = 0.0000008 in EA at 10q22.3 (SLEN1) and P = 0.000001 in AA at 2q34-35 (SLEN2). A second stratification strategy explored the renal criterion in 35 pedigrees with two or more SLE patients with renal disease and produced a LOD score of 3.34 at 11p15.6 in AA (SLEN3). Sib-pair analysis in these 35 pedigrees revealed P = 0.00003 at 4q13.1 in EA, P = 0.00003 at 11p13 and 0.00007 at 3q23 in AA. Thus, multiple genetic linkages are related to the renal criterion in SLE. Of the significant genetic linkages with SLE described herein, those at 10q22.3 in the EA pedigrees (SLEN1) and at 2q34-35 in the AA pedigrees (SLEN2) have not been previously described. [ABSTRACT FROM AUTHOR]

Published
2002
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40. Genome scan stratified by the presence of anti-double- stranded DNA (dsDNA) autoantibody in pedigrees multiplex for systemic lupus erythematosus (SLE) establishes linkages at 19p13.2 (SLED1) and 18q21.1 (SLED2).

Author

Namjou, B., Nath, S.K., Kilpatrick, J., Kelly, J.A., Reid, J., Reichlin, M., James, J.A., and Harley, J.B.

Subjects
SYSTEMIC lupus erythematosus, GENOMES, DNA, GENETICS
Abstract

Anti-double-stranded DNA (anti-dsDNA) is arguably one of the most specific autoantibodies in systemic lupus erythematosus (SLE). This antibody is associated with more severe SLE and with glomerulonephritis. From 196 pedigrees multiplex for SLE, we selected those that had any SLE affected positive for anti-dsDNA by the Crithidia luciliae kinetoplast imunofluorescence assay. This stratification strategy tested the hypothesis that anti-dsDNA would identify a more genetically homogeneous group of pedigrees, in which previously undetected linkage effects could be established. A genome screen data for linkage to SLE was available at 307 microsatellite markers for this selected group of 71 pedigrees: 37 European-American, 29 African-American, and five others. The most significant results were obtained at 19p13.2 (LOD[sub max] = 4.93), named SLED1, in the 37 European-American pedigrees using a dominant model with mixed penetrances (92% for females and 49% for males) at 100% homogeneity (θ = 0). A second linkage effect, SLED2, was established in the 29 African-American pedigrees at 18q21.1 (LOD[sub max] = 3.40) using a recessive model with 100% penetrance (θ = 0.1). Parametric and non-parametric multipoint analyses were performed, which provided further evidence and support of susceptibility genes residing in these regions. In conclusion, two powerful linkages have been detected with SLE based on the presence of anti-dsDNA. These findings show SLE to be a richly complicated disease phenotype that is now ripe for important new discovery through a genetic approach. [ABSTRACT FROM AUTHOR]

Published
2002
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41. Arachidonic acid metabolism in normal and hypereosinophilic syndrome human eosinophils: generation of leukotrienes B4, C4, D4 and 15-lipoxygenase products.

Author

Henderson, W.R., Harley, J.B., and Fauci, A.S.

Subjects
*ARACHIDONIC acid, *EOSINOPHILS, *IONOPHORES, *LEUKOTRIENES, *LIPOXYGENASES, *SYNDROMES
Abstract

The formation of 5- and 15-lipoxygenase products of arachidonic acid metabolism was examined in human peripheral blood eosinophils obtained from five normal individuals and five patients with the hypereosinophilic syndrome (HES). Normal and HES eosinophils after stimulation with the calcium ionophore A23187 produced in comparable amounts leukotriene (LT)C4, LTD4, LTB4 and two of its isomers (5-(S),12-(R)-6-trans-LTB4 and 5-(S), 12-(S)-6-trans-LTB4), 15-hydroxy-eicosatetraenoic acid (HETE), 5,15-di-HETE and 8,15-di-HETE. No single lipoxygenase product predominated in the absence of added arachidonic acid whereas 15-HETE was the major product formed when either normal or HES eosinophils were stimulated with A23187 in the presence of added arachidonic acid (10-4 M). [ABSTRACT FROM AUTHOR]

Published
1984

46. Definitions.

Author

Blakemore, M.J. and Harley, J.B.

Published
1980

49. A genetic marker within the CD44 gene confirms linkage at 11p13 in African-American families with lupus stratified by thrombocytopenia, but genetic association with CD44 is not present.

Author

Kaufman, K.M., Rankin, J., Harley, I.T.W., Kelly, J.A., Harley, J.B., and Scofield, R.H.

Subjects
SYSTEMIC lupus erythematosus, THROMBOCYTOPENIA, LINKAGE (Genetics), GENETICS
Abstract

Systemic lupus erythematosus (SLE) is complicated from both a clinical and genetic standpoint. We have stratified SLE families by the presence of thrombocytopenia, which is associated with increased mortality among SLE patients, and found genetic linkage at chromosome 11p13 in African-American families. In the present study we have evaluated CD44, a gene very close (0.5 cM) to the peak LOD score marker, as a candidate gene. Using a newly identified short DNA repeat within the CD44 gene, we find a LOD score of 2.7, which confirms linkage within this genetic interval. However, using a panel of four single nucleotide markers spanning the CD44 gene, we find no genetic association with SLE. Therefore, these data further suggest an SLE susceptibility gene at 11p13, but also imply that an ancestral mutation in the CD44 gene does not account for the linkage. [ABSTRACT FROM AUTHOR]

Published
2002
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50. An alternative route to mapping history.

Author

Harley, J.B. and Woodward, D.

Subjects
*HISTORY
Abstract

Studies the maps of what is sometimes still called the first great age of European exploration. For many researchers, maps still hold out the prospect of locating the elusive landfalls of a Columbus or a Drake, or of reconstructing the routes of navigators or tracks of the explorers. History of Cartography project; Maps and the Columbian Encounter Exhibition program; Examples of pre-conquest and post-conquest maps. INSET: Maps to the nth degree..

Published
1991

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