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1. Transancestral mapping and genetic load in systemic lupus erythematosus.

Author

Langefeld, Carl D, Ainsworth, Hannah C, Cunninghame Graham, Deborah S, Kelly, Jennifer A, Comeau, Mary E, Marion, Miranda C, Howard, Timothy D, Ramos, Paula S, Croker, Jennifer A, Morris, David L, Sandling, Johanna K, Almlöf, Jonas Carlsson, Acevedo-Vásquez, Eduardo M, Alarcón, Graciela S, Babini, Alejandra M, Baca, Vicente, Bengtsson, Anders A, Berbotto, Guillermo A, Bijl, Marc, Brown, Elizabeth E, Brunner, Hermine I, Cardiel, Mario H, Catoggio, Luis, Cervera, Ricard, Cucho-Venegas, Jorge M, Dahlqvist, Solbritt Rantapää, D'Alfonso, Sandra, Da Silva, Berta Martins, de la Rúa Figueroa, Iñigo, Doria, Andrea, Edberg, Jeffrey C, Endreffy, Emőke, Esquivel-Valerio, Jorge A, Fortin, Paul R, Freedman, Barry I, Frostegård, Johan, García, Mercedes A, de la Torre, Ignacio García, Gilkeson, Gary S, Gladman, Dafna D, Gunnarsson, Iva, Guthridge, Joel M, Huggins, Jennifer L, James, Judith A, Kallenberg, Cees GM, Kamen, Diane L, Karp, David R, Kaufman, Kenneth M, Kottyan, Leah C, Kovács, László, Laustrup, Helle, Lauwerys, Bernard R, Li, Quan-Zhen, Maradiaga-Ceceña, Marco A, Martín, Javier, McCune, Joseph M, McWilliams, David R, Merrill, Joan T, Miranda, Pedro, Moctezuma, José F, Nath, Swapan K, Niewold, Timothy B, Orozco, Lorena, Ortego-Centeno, Norberto, Petri, Michelle, Pineau, Christian A, Pons-Estel, Bernardo A, Pope, Janet, Raj, Prithvi, Ramsey-Goldman, Rosalind, Reveille, John D, Russell, Laurie P, Sabio, José M, Aguilar-Salinas, Carlos A, Scherbarth, Hugo R, Scorza, Raffaella, Seldin, Michael F, Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D, Toloza, Sergio MA, Truedsson, Lennart, Tusié-Luna, Teresa, Vasconcelos, Carlos, Vilá, Luis M, Wallace, Daniel J, Weisman, Michael H, Wither, Joan E, Bhangale, Tushar, Oksenberg, Jorge R, Rioux, John D, Gregersen, Peter K, Syvänen, Ann-Christine, Rönnblom, Lars, Criswell, Lindsey A, Jacob, Chaim O, Sivils, Kathy L, Tsao, Betty P, Schanberg, Laura E, and Behrens, Timothy W

Subjects
Humans, Lupus Erythematosus, Systemic, HLA Antigens, Logistic Models, Case-Control Studies, Mutagenesis, Insertional, Age of Onset, Sequence Deletion, Genetic Load, Multifactorial Inheritance, Polymorphism, Single Nucleotide, African Continental Ancestry Group, American Native Continental Ancestry Group, European Continental Ancestry Group, Hispanic Americans, Lupus Erythematosus, Systemic, Mutagenesis, Insertional, Polymorphism, Single Nucleotide
Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P

Published
2017

2. Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States

Author

Wang, Li-San, Naj, Adam C, Graham, Robert R, Crane, Paul K, Kunkle, Brian W, Cruchaga, Carlos, Murcia, Josue D. Gonzalez, Cannon-Albright, Lisa, Baldwin, Clinton T, Zetterberg, Henrik, Blennow, Kaj, Kukull, Walter A, Faber, Kelley M, Schupf, Nicole, Norton, Maria C, Tschanz, JoAnn T, Munger, Ronald G, Corcoran, Christopher D, Rogaeva, Ekaterina, Lin, Chiao-Feng, Dombroski, Beth A, Cantwell, Laura B, Partch, Amanda, Valladares, Otto, Hakonarson, Hakon, St George-Hyslop, Peter, Green, Robert C, Goate, Alison M, Foroud, Tatiana M, Carney, Regina M, Larson, Eric B, Behrens, Timothy W, Kauwe, John S. K, Haines, Jonathan L, Farrer, Lindsay A, Pericak-Vance, Margaret A, Mayeux, Richard, Schellenberg, Gerard D, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Barber, Robert, Barmada, M. Michael, Barnes, Lisa L, Beach, Thomas G, Becker, James T, Beecham, Gary W, Beekly, Duane, Bennett, David A, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Buxbaum, Joseph D, Cairns, Nigel J, Cao, Chuanhai, Carlson, Chris S, Carroll, Steven L, Chui, Helena C, Clark, David G, Cribbs, David H, Crocco, Elizabeth A, DeCarli, Charles, DeKosky, Steven T, Demirci, F. Yesim, Dick, Malcolm, Dickson, Dennis W, Duara, Ranjan, Ertekin-Taner, Nilufer, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Frosch, Matthew P, Galasko, Douglas R, Ganguli, Mary, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Glass, Jonathan D, Graff-Radford, Neill R, Growdon, John H, Hamilton, Ronald L, Hamilton-Nelson, Kara L, Harrell, Lindy E, Head, Elizabeth, Honig, Lawrence S, Hulette, Christine M, Hyman, Bradley T, Jarvik, Gail P, Jicha, Gregory A, Jin, Lee-Way, Jun, Gyungah, Kamboh, M. Ilyas, Karydas, Anna, and Kaye, Jeffrey A

Published
2015

3. Two Functional Lupus-Associated BLK Promoter Variants Control Cell-Type- and Developmental-Stage-Specific Transcription

Author

Guthridge, Joel M, Lu, Rufei, Sun, Harry, Sun, Celi, Wiley, Graham B, Dominguez, Nicolas, Macwana, Susan R, Lessard, Christopher J, Kim-Howard, Xana, Cobb, Beth L, Kaufman, Kenneth M, Kelly, Jennifer A, Langefeld, Carl D, Adler, Adam J, Harley, Isaac TW, Merrill, Joan T, Gilkeson, Gary S, Kamen, Diane L, Niewold, Timothy B, Brown, Elizabeth E, Edberg, Jeffery C, Petri, Michelle A, Ramsey-Goldman, Rosalind, Reveille, John D, Vilá, Luis M, Kimberly, Robert P, Freedman, Barry I, Stevens, Anne M, Boackle, Susan A, Criswell, Lindsey A, Vyse, Tim J, Behrens, Timothy W, Jacob, Chaim O, Alarcón-Riquelme, Marta E, Sivils, Kathy L, Choi, Jiyoung, Bin Joo, Young, Bang, So-Young, Lee, Hye-Soon, Bae, Sang-Cheol, Shen, Nan, Qian, Xiaoxia, Tsao, Betty P, Scofield, R Hal, Harley, John B, Webb, Carol F, Wakeland, Edward K, James, Judith A, Nath, Swapan K, Graham, Robert R, and Gaffney, Patrick M

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Lupus, Autoimmune Disease, Clinical Research, Stem Cell Research, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Alleles, Chromosomes, Human, Pair 8, Electrophoretic Mobility Shift Assay, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Lupus Erythematosus, Systemic, Male, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Transcription, Genetic, src-Family Kinases, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.

Published
2014

4. Previously reported placebo-response-associated variants do not predict patient outcomes in inflammatory disease Phase III trial placebo arms

Author

Haug-Baltzell, Asher, Bhangale, Tushar R., Chang, Diana, Dressen, Amy, Yaspan, Brian L., Ortmann, Ward, Brauer, Matthew J., Hunkapiller, Julie, Reeder, Jens, Mukhyala, Kiran, Cuenco, Karen T., Tom, Jennifer A., Cowgill, Amy, Vogel, Jan, Forrest, William F., Behrens, Timothy W., Graham, Robert R., and Wuster, Arthur

Published
2019
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5. Unraveling Multiple MHC Gene Associations with Systemic Lupus Erythematosus: Model Choice Indicates a Role for HLA Alleles and Non-HLA Genes in Europeans

Author

Morris, David L, Taylor, Kimberly E, Fernando, Michelle MA, Nititham, Joanne, Alarcón-Riquelme, Marta E, Barcellos, Lisa F, Behrens, Timothy W, Cotsapas, Chris, Gaffney, Patrick M, Graham, Robert R, Pons-Estel, Bernardo A, Gregersen, Peter K, Harley, John B, Hauser, Stephen L, Hom, Geoffrey, Network, International MHC and Autoimmunity Genetics, Langefeld, Carl D, Noble, Janelle A, Rioux, John D, Seldin, Michael F, Consortium, Systemic Lupus Erythematosus Genetics, Criswell, Lindsey A, and Vyse, Timothy J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Immunology, Clinical Research, Autoimmune Disease, Lupus, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Alleles, Gene Expression Profiling, Genetic Predisposition to Disease, Genotype, HLA Antigens, HLA-B Antigens, HLA-C Antigens, HLA-DQ alpha-Chains, HLA-DRB1 Chains, Haplotypes, Humans, Lupus Erythematosus, Systemic, Major Histocompatibility Complex, Polymorphism, Single Nucleotide, White People, International MHC and Autoimmunity Genetics Network, Systemic Lupus Erythematosus Genetics Consortium, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

We have performed a meta-analysis of the major-histocompatibility-complex (MHC) region in systemic lupus erythematosus (SLE) to determine the association with both SNPs and classical human-leukocyte-antigen (HLA) alleles. More specifically, we combined results from six studies and well-known out-of-study control data sets, providing us with 3,701 independent SLE cases and 12,110 independent controls of European ancestry. This study used genotypes for 7,199 SNPs within the MHC region and for classical HLA alleles (typed and imputed). Our results from conditional analysis and model choice with the use of the Bayesian information criterion show that the best model for SLE association includes both classical loci (HLA-DRB1(∗)03:01, HLA-DRB1(∗)08:01, and HLA-DQA1(∗)01:02) and two SNPs, rs8192591 (in class III and upstream of NOTCH4) and rs2246618 (MICB in class I). Our approach was to perform a stepwise search from multiple baseline models deduced from a priori evidence on HLA-DRB1 lupus-associated alleles, a stepwise regression on SNPs alone, and a stepwise regression on HLA alleles. With this approach, we were able to identify a model that was an overwhelmingly better fit to the data than one identified by simple stepwise regression either on SNPs alone (Bayes factor [BF] > 50) or on classical HLA alleles alone (BF > 1,000).

Published
2012

6. European genetic ancestry is associated with a decreased risk of lupus nephritis

Author

Richman, Ilana B, Taylor, Kimberly E, Chung, Sharon A, Trupin, Laura, Petri, Michelle, Yelin, Edward, Graham, Robert R, Lee, Annette, Behrens, Timothy W, Gregersen, Peter K, Seldin, Michael F, and Criswell, Lindsey A

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Autoimmune Disease, Kidney Disease, Lupus, Clinical Research, Inflammatory and immune system, Adult, Alleles, Asian People, Black People, Cross-Sectional Studies, Female, Genetic Predisposition to Disease, Genotype, HLA Antigens, Humans, Lupus Nephritis, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk, White People, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveAfrican Americans, East Asians, and Hispanics with systemic lupus erythematosus (SLE) are more likely to develop renal disease than are SLE patients of European descent. This study was undertaken to investigate whether European genetic ancestry protects against the development of lupus nephritis, with the aim of exploring the genetic and socioeconomic factors that might explain this effect.MethodsThis was a cross-sectional study of SLE patients from a multiethnic case collection. Participants were genotyped for 126 single-nucleotide polymorphisms (SNPs) informative for ancestry. A subset of participants was also genotyped for 80 SNPs in 14 candidate genes for renal disease in SLE. Logistic regression was used to test the association between European ancestry and renal disease. Analyses were adjusted for continental ancestries, socioeconomic status (SES), and candidate genes.ResultsParticipants (n = 1,906) had, on average, 62.4% European, 15.8% African, 11.5% East Asian, 6.5% Amerindian, and 3.8% South Asian ancestry. Among the participants, 656 (34%) had renal disease. A 10% increase in the proportion of European ancestry estimated in each participant was associated with a 15% reduction in the odds of having renal disease, after adjustment for disease duration and sex (odds ratio 0.85, 95% confidence interval 0.82-0.87; P = 1.9 × 10(-30) ). Adjustment for other genetic ancestries, measures of SES, or SNPs in the genes most associated with renal disease (IRF5 [rs4728142], BLK [rs2736340], STAT4 [rs3024912], and HLA-DRB1*0301 and DRB1*1501) did not substantively alter this relationship.ConclusionEuropean ancestry is protective against the development of renal disease in SLE, an effect that is independent of other genetic ancestries, candidate risk alleles, and socioeconomic factors.

Published
2012

7. A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE

Author

Sandling, Johanna K, Garnier, Sophie, Sigurdsson, Snaevar, Wang, Chuan, Nordmark, Gunnel, Gunnarsson, Iva, Svenungsson, Elisabet, Padyukov, Leonid, Sturfelt, Gunnar, Jönsen, Andreas, Bengtsson, Anders A, Truedsson, Lennart, Eriksson, Catharina, Rantapää-Dahlqvist, Solbritt, Mälarstig, Anders, Strawbridge, Rona J, Hamsten, Anders, Criswell, Lindsey A, Graham, Robert R, Behrens, Timothy W, Eloranta, Maija-Leena, Alm, Gunnar, Rönnblom, Lars, and Syvänen, Ann-Christine

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Autoimmune Disease, Lupus, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Humans, I-kappa B Kinase, Interferon Type I, Interleukin-8, Linkage Disequilibrium, Lupus Erythematosus, Systemic, STAT1 Transcription Factor, Signal Transduction, Sweden, White People, systemic lupus erythematosus, type I interferon system, candidate gene study, single nucleotide polymorphism, IKBKE, IL8, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease in which the type I interferon pathway has a crucial role. We have previously shown that three genes in this pathway, IRF5, TYK2 and STAT4, are strongly associated with risk for SLE. Here, we investigated 78 genes involved in the type I interferon pathway to identify additional SLE susceptibility loci. First, we genotyped 896 single-nucleotide polymorphisms in these 78 genes and 14 other candidate genes in 482 Swedish SLE patients and 536 controls. Genes with P

Published
2011

8. Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production.

Author

Chung, Sharon A, Taylor, Kimberly E, Graham, Robert R, Nititham, Joanne, Lee, Annette T, Ortmann, Ward A, Jacob, Chaim O, Alarcón-Riquelme, Marta E, Tsao, Betty P, Harley, John B, Gaffney, Patrick M, Moser, Kathy L, SLEGEN, Petri, Michelle, Demirci, F Yesim, Kamboh, M Ilyas, Manzi, Susan, Gregersen, Peter K, Langefeld, Carl D, Behrens, Timothy W, and Criswell, Lindsey A

Subjects
SLEGEN, Humans, Lupus Erythematosus, Systemic, Genetic Predisposition to Disease, DNA, Autoantibodies, Case-Control Studies, Major Histocompatibility Complex, Polymorphism, Single Nucleotide, STAT4 Transcription Factor, Interferon Regulatory Factors, Genetic Variation, Genome-Wide Association Study, CD11b Antigen, Lupus Erythematosus, Systemic, Polymorphism, Single Nucleotide, Antigens, CD11b, Genetics, Developmental Biology
Abstract

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04), with p(heterogeneity)

Published
2011

9. High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions.

Author

Barcellos, Lisa F, May, Suzanne L, Ramsay, Patricia P, Quach, Hong L, Lane, Julie A, Nititham, Joanne, Noble, Janelle A, Taylor, Kimberly E, Quach, Diana L, Chung, Sharon A, Kelly, Jennifer A, Moser, Kathy L, Behrens, Timothy W, Seldin, Michael F, Thomson, Glenys, Harley, John B, Gaffney, Patrick M, and Criswell, Lindsey A

Subjects
Humans, Lupus Erythematosus, Systemic, Genetic Predisposition to Disease, HLA-DR Antigens, Major Histocompatibility Complex, Polymorphism, Single Nucleotide, Adult, Middle Aged, European Continental Ancestry Group, Female, Male, Young Adult, HLA-DRB1 Chains, Lupus Erythematosus, Systemic, Polymorphism, Single Nucleotide, Genetics, Developmental Biology
Abstract

A substantial genetic contribution to systemic lupus erythematosus (SLE) risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6p21. Previous studies in SLE have lacked statistical power and genetic resolution to fully define MHC influences. We characterized 1,610 Caucasian SLE cases and 1,470 parents for 1,974 MHC SNPs, the highly polymorphic HLA-DRB1 locus, and a panel of ancestry informative markers. Single-marker analyses revealed strong signals for SNPs within several MHC regions, as well as with HLA-DRB1 (global p = 9.99 x 10(-16)). The most strongly associated DRB1 alleles were: *0301 (odds ratio, OR = 2.21, p = 2.53 x 10(-12)), *1401 (OR = 0.50, p = 0.0002), and *1501 (OR = 1.39, p = 0.0032). The MHC region SNP demonstrating the strongest evidence of association with SLE was rs3117103, with OR = 2.44 and p = 2.80 x 10(-13). Conditional haplotype and stepwise logistic regression analyses identified strong evidence for association between SLE and the extended class I, class I, class III, class II, and the extended class II MHC regions. Sequential removal of SLE-associated DRB1 haplotypes revealed independent effects due to variation within OR2H2 (extended class I, rs362521, p = 0.006), CREBL1 (class III, rs8283, p = 0.01), and DQB2 (class II, rs7769979, p = 0.003, and rs10947345, p = 0.0004). Further, conditional haplotype analyses demonstrated that variation within MICB (class I, rs3828903, p = 0.006) also contributes to SLE risk independent of HLA-DRB1*0301. Our results for the first time delineate with high resolution several MHC regions with independent contributions to SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation.

Published
2009

12. Genome-wide association study identifies kallikrein 5 in type 2 inflammation-low asthma

Author

Jackman, Janet K., primary, Stockwell, Amy, additional, Choy, David F., additional, Xie, Markus M., additional, Lu, Peipei, additional, Jia, Guiquan, additional, Li, Hong, additional, Abbas, Alexander R., additional, Bronson, Paola G., additional, Lin, Wei-Yu, additional, Chiu, Cecilia P.C., additional, Maun, Henry R., additional, Roose-Girma, Merone, additional, Tam, Lucinda, additional, Zhang, Juan, additional, Modrusan, Zora, additional, Graham, Robert R., additional, Behrens, Timothy W., additional, White, Steven R., additional, Naureckas, Ted, additional, Ober, Carole, additional, Ferreira, Manuel, additional, Sedlacek, Radislav, additional, Wu, Jiansheng, additional, Lee, Wyne P., additional, Lazarus, Robert A., additional, Koerber, James T., additional, Arron, Joseph R., additional, Yaspan, Brian L., additional, and Yi, Tangsheng, additional

Published
2022
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14. A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death

Author

Wetzel-Smith, Monica K., Hunkapiller, Julie, Bhangale, Tushar R., Srinivasan, Karpagam, Maloney, Janice A., Atwal, Jasvinder K., Sa, Susan M., Yaylaoglu, Murat B., Foreman, Oded, Ortmann, Ward, Rathore, Nisha, Hansen, David V., Tessier- Lavigne, Marc, Consortium, Alzheimers Disease Genetics, Mayeux, Richard, Pericak-Vance, Margaret, Haines, Jonathan, Farrer, Lindsay A., Schellenberg, Gerard D., Goate, Alison, Behrens, Timothy W., Cruchaga, Carlos, Watts, Ryan J., and Graham, Robert R.

Subjects
United States. National Institute on Aging, Biological sciences, Health
Abstract

We have identified a rare coding mutation, T835M (rs137875858), in the UNC5C netrin receptor gene that segregated with disease in an autosomal dominant pattern in two families enriched for late-onset Alzheimer's disease and that was associated with disease across four large case-control cohorts (odds ratio = 2.15, [P.sub.meta] = 0.0095). T835M alters a conserved residue in the hinge region of UNC5C, and in vitro studies demonstrate that this mutation leads to increased cell death in human HEK293T cells and in rodent neurons. Furthermore, neurons expressing T835M UNC5C are more susceptible to cell death from multiple neurotoxic stimuli, including β-amyloid (Aβ), glutamate and staurosporine. On the basis of these data and the enriched hippocampal expression of UNC5C in the adult nervous system, we propose that one possible mechanism in which T835M UNC5C contributes to the risk of Alzheimer's disease is by increasing susceptibility to neuronal cell death, particularly in vulnerable regions of the Alzheimer's disease brain., Although progress has been made in defining the genetic basis of Alzheimer's disease (AD), much of the heritability of AD remains to be discovered (1-12). We elected to study a [...]

Published
2014

15. Three Functional Variants of IFN Regulatory Factor 5 (IRF5) Define Risk and Protective Haplotypes for Human Lupus

Author

Graham, Robert R., Kyogoku, Chieko, Sigurdsson, Snaevar, Vlasova, Irina A., Davies, Leela R. L., Baechler, Emily C., Plenge, Robert M., Koeuth, Thearith, Ortmann, Ward A., Hom, Geoffrey, Bauer, Jason W., Gillett, Clarence, Burtt, Noel, Graham, Deborah S. Cunninghame, Onofrio, Robert, Petri, Michelle, Gunnarsson, Iva, Svenungsson, Elisabet, Rönnblom, Lars, Nordmark, Gunnel, Gregersen, Peter K., Moser, Kathy, Gaffney, Patrick M., Criswell, Lindsey A., Vyse, Timothy J., Syvänen, Ann-Christine, Bohjanen, Paul R., Daly, Mark J., Behrens, Timothy W., and Altshuler, David

Published
2007
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19. ADAR and hnRNPC deficiency synergize in activating endogenous dsRNA-induced type I IFN responses

Author

Herzner, Anna-Maria, primary, Khan, Zia, additional, Van Nostrand, Eric L., additional, Chan, Sara, additional, Cuellar, Trinna, additional, Chen, Ronald, additional, Pechuan-Jorge, Ximo, additional, Komuves, Laszlo, additional, Solon, Margaret, additional, Modrusan, Zora, additional, Haley, Benjamin, additional, Yeo, Gene W., additional, Behrens, Timothy W., additional, and Albert, Matthew L., additional

Published
2021
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20. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline

Author

Jonsson, Thorlakur, Atwal, Jasvinder K., Steinberg, Stacy, Snaedal, Jon, Jonsson, Palmi V., Bjornsson, Sigurbjorn, Stefansson, Hreinn, Sulem, Patrick, Gudbjartsson, Daniel, Maloney, Janice, Hoyte, Kwame, Gustafson, Amy, Liu, Yichin, Lu, Yanmei, Bhangale, Tushar, Graham, Robert R., Huttenlocher, Johanna, Bjornsdottir, Gyda, Andreassen, Ole A., Jonsson, Erik G., Palotie, Aarno, Behrens, Timothy W., Magnusson, Olafur T., Kong, Augustine, Thorsteinsdottir, Unnur, Watts, Ryan J., and Stefansson, Kari

Subjects
Gene mutations -- Research, Alzheimer's disease -- Genetic aspects -- Physiological aspects -- Development and progression, Cognition disorders -- Physiological aspects -- Genetic aspects -- Development and progression, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to [...]

Published
2012

21. Selective IgA Deficiency in Autoimmune Diseases

Author

Wang, Ning, Shen, Nan, Vyse, Timothy J., Anand, Vidya, Gunnarson, Iva, Sturfelt, Gunnar, Rantapää-Dahlqvist, Solbritt, Elvin, Kerstin, Truedsson, Lennart, Andersson, Bengt A., Dahle, Charlotte, Örtqvist, Eva, Gregersen, Peter K., Behrens, Timothy W., and Hammarström, Lennart

Published
2011
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22. Genetics of rheumatoid arthritis contributes to biology and drug discovery

Author

Okada, Yukinori, Wu, Di, Trynka, Gosia, Raj, Towfique, Terao, Chikashi, Ikari, Katsunori, Kochi, Yuta, Ohmura, Koichiro, Suzuki, Akari, Yoshida, Shinji, Graham, Robert R., Manoharan, Arun, Ortmann, Ward, Bhangale, Tushar, Denny, Joshua C., Carroll, Robert J., Eyler, Anne E., Greenberg, Jeffrey D., Kremer, Joel M., Pappas, Dimitrios A., Jiang, Lei, Yin, Jian, Ye, Lingying, Su, Ding-Feng, Yang, Jian, Xie, Gang, Keystone, Ed, Westra, Harm-Jan, Esko, Tõnu, Metspalu, Andres, Zhou, Xuezhong, Gupta, Namrata, Mirel, Daniel, Stahl, Eli A., Diogo, Dorothée, Cui, Jing, Liao, Katherine, Guo, Michael H., Myouzen, Keiko, Kawaguchi, Takahisa, Coenen, Marieke J. H., van Riel, Piet L. C. M., van de Laar, Mart A. F. J., Guchelaar, Henk-Jan, Huizinga, Tom W. J., Dieudé, Philippe, Mariette, Xavier, Bridges, Louis S., Jr, Zhernakova, Alexandra, Toes, Rene E. M., Tak, Paul P., Miceli-Richard, Corinne, Bang, So-Young, Lee, Hye-Soon, Martin, Javier, Gonzalez-Gay, Miguel A., Rodriguez-Rodriguez, Luis, Rantapää-Dahlqvist, Solbritt, Ärlestig, Lisbeth, Choi, Hyon K., Kamatani, Yoichiro, Galan, Pilar, Lathrop, Mark, Eyre, Steve, Bowes, John, Barton, Anne, de Vries, Niek, Moreland, Larry W., Criswell, Lindsey A., Karlson, Elizabeth W., Taniguchi, Atsuo, Yamada, Ryo, Kubo, Michiaki, Liu, Jun S., Bae, Sang-Cheol, Worthington, Jane, Padyukov, Leonid, Klareskog, Lars, Gregersen, Peter K., Raychaudhuri, Soumya, Stranger, Barbara E., De Jager, Philip L., Franke, Lude, Visscher, Peter M., Brown, Matthew A., Yamanaka, Hisashi, Mimori, Tsuneyo, Takahashi, Atsushi, Xu, Huji, Behrens, Timothy W., Siminovitch, Katherine A., Momohara, Shigeki, Matsuda, Fumihiko, Yamamoto, Kazuhiko, and Plenge, Robert M.

Published
2014
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24. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX

Author

Hom, Geoffrey, Graham, Robert R., Modrek, Barmak, Taylor, Kimberly E., Ortmann, Ward, Garnier, Sophie, Lee, Annette T., Chung, Sharon A., Ferreira, Ricardo C., Pant, P.V. Krishna, Ballinger, Dennis G., Kosoy, Roman, Demirci, F. Yesim, Kamboh, Ilyas, Kao, Amy H., Chao Tian, Gunnarsson, Iva, Bengtsson, Anders A., Rantapaa-Dahlqvist, Solbritt, Petri, Michelle, Manzi, Susan, Seldin, Michael F., Ronnblom, Lars, Syvanen, Ann-Christine, Criswell, Lindsey A., Gregersen, Peter K., and Behrens, Timothy W.

Subjects
Gene expression -- Research, Single nucleotide polymorphisms -- Research, Systemic lupus erythematosus -- Development and progression, Systemic lupus erythematosus -- Genetic aspects
Abstract

A study to ascertain if the development of systemic lupus erythematosus (SLE) is influenced by the presence of certain genes is conducted. Results confirm that the hereditary genes play a role in the development as also reduced expression of BLK and increase depression of C8orf13 and variants in the ITGAM-ITGAX region.

Published
2008

26. STAT4 and the risk of rheumatoid arthritis and systematic lupus erythematosus

Author

Remmers, Elaine F., Plenge, Robert M., Lee, Annette T., Graham, Robert R., Hom, Geoffrey, Behrens, Timothy W., de Bakker, Paul I.W., Le, Julie M., Hye-Soon Lee, Batliwalla, Franak, Wentian Li, Masters, Seth L., Booty, Matthew G., Carulli, John P., Padyuko, Leonid, Alfredsson, Lars, Klareskog, Lars, Wei V. Chen, Amos, Christopher I., Criswell, Lindsey A., Seldin, Michael F., Kastner, Daniel L., and Gregersen, Peter K.

Subjects
Rheumatoid arthritis -- Risk factors, Rheumatoid arthritis -- Diagnosis, Lupus erythematosus -- Risk factors, Lupus erythematosus -- Diagnosis
Abstract

The single-necleotide polymorphism was tested within the previously linked chromosome region for association with rheumatoid arthritis. Results showed that the halotype STAT4 was associated with increased risk of both rheumatoid arthritis and systematic lupus erythematosus.

Published
2007

27. Role for Msh5 in the regulation of Ig class switch recombination

Author

Sekine, Hideharu, Ferreira, Ricardo C., Pan-Hammarstrom, Qiang, Graham, Robert R., Ziemba, Beth, de Vries, Sandra S., Liu, Jiabin, Hippen, Keli, Koeuth, Thearith, Ortmann, Ward, Iwahori, Akiko, Elliott, Margaret K., Offer, Steven, Skon, Cara, Du, Likun, Novitzke, Jill, Lee, Annette T., Zhao, Nianxi, Tompkins, Joshua D., Altshuler, David, Gregersen, Peter K., Cunningham-Rundles, Charlotte, Harris, Reuben S., Her, Chengtao, Nelson, David L., Hammarstrom, Lennart, Gilkeson, Gary S., and Behrens, Timothy W.

Subjects
Genetic regulation -- Research, Genetic recombination -- Research, DNA repair -- Research, Immunoglobulin A -- Research, Science and technology
Abstract

Ig class switch recombination (CSR) and somatic hypermutation serve to diversify antibody responses and are orchestrated by the activity of activation-induced cytidine deaminase and many proteins involved in DNA repair and genome surveillance. Msh5, a gene encoded in the central MHC class III region, and its obligate heterodimerization partner Msh4 have a critical role in regulating meiotic homologous recombination and have not been implicated in CSR. Here, we show that MRL/Ipr mice carrying a congenic [H-2.sup.b/b] MHC interval exhibit several abnormalities regarding CSR, including a profound deficiency of IgG3 in most mice and long micro-homologies at Ig switch (S) joints. We found that Msh5 is expressed at low levels on the [H-2.sup.b] haplotype and, importantly, a similar long S joint microhomology phenotype was observed in both Msh5 and Msh4-null mice. We also present evidence that genetic variation in MSH5 is associated with IgA deficiency and common variable immune deficiency (CVID) in humans. One of the human MSH5 alleles identified contains two nonsynonymous polymorphisms, and the variant protein encoded by this allele shows impaired binding to MSH4. Similar to the mice, Ig S joints from CVID and IgA deficiency patients carrying disease-associated MSH5 alleles show increased donor/acceptor microhomology, involving pentameric DNA repeat sequences and lower mutation rates than controls. Our findings suggest that Msh4/5 heterodimers contribute to CSR and support a model whereby Msh4/5 promotes the resolution of DNA breaks with low or no terminal microhomology by a classical nonhomologous end-joining mechanism while possibly suppressing an alternative microhomology-mediated pathway. immunoglobulin subclass deficiency | mismatch repair | Msh4

Published
2007

30. Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus

Author

Bauer, Jason W., Baechler, Emily C., Petri, Michelle, Batliwalla, Franak M., Crawford, Dianna, Ortmann, Ward A., Espe, Karl J., Li, Wentian, Patel, Dhavalkumar D., Gregersen, Peter K., and Behrens, Timothy W.

Subjects
Systemic lupus erythematosus -- Diagnosis, Chemokines -- Observations
Abstract

ABSTRACT Background Systemic lupus erythematosus (SLE) is a serious systemic autoimmune disorder that affects multiple organ systems and is characterized by unpredictable flares of disease. Recent evidence indicates a role [...]

Published
2006

31. Fine-mapping chromosome 20 in 230 systemic lupus erythematosus sib pair and multiplex families: Evidence for genetic epistasis with chromosome 16q12

Author

Gaffney, Patrick M., Rodine, Peter R., Langefeld, Carl D., Moser, Kathy L., Graham, Robert R., Behrens, Timothy W., Ortmann, Ward A., and Williams, Adrienne H.

Subjects
Genotype -- Research, Systemic lupus erythematosus -- Risk factors, Chromosome mapping -- Research, Human chromosomes -- Health aspects, Human chromosomes -- Research, Biological sciences
Abstract

An analysis of genotypes for statistical linkage and/or association with systemic lupus erythematosus(SLE), by use of a combination of nonparametric linkage methods, family-based tests of association, and haplotype sharing statistics in a set of 230SLE pedigrees. The result provides additional support for linkage and association to 20p12 and 20q13.1 in SLE and further refines the intervals of interest.

Published
2006

33. Analysis of families in the Multiple Autoimmune Disease Genetics Consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes

Author

Criswell, Lindsey A., Pfeiffer, Kirsten A., Lum, Raymond F., Gonzales, Bonnie, Novitzke, Jill, Kern, Marlena, Moser, Kathy L., Begovich, Ann B., Carlton, Victoria E.H., Li, Wentian, Lee, Annette T., Ortmann, Ward, Behrens, Timothy W., and Gregersen, Peter K.

Subjects
Autoimmune diseases -- Genetic aspects, Phenotype, Genotype, Biological sciences
Published
2005

34. Genetic Association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE

Author

Kyogoku, Chieko, Langefeld, Carl D., Ortmann, Ward A., Lee, Annette, Selby, Scott, Carlton, Victoria E.H., Chang, Monica, Ramos, Paula, Baechler, Emily C., Batliwalla, Franak M., Novitzke, Jill, Williams, Adrienne H., Gillett, Clarence, Rodine, Peter, Graham, Robert R., Ardlie, Kristin G., Gaffney, Patrick M., Moser, Kathy L., Petri, Michelle, Begovich, Ann B., Gregersen, Peter K., and Behrens, Timothy W.

Subjects
Systemic lupus erythematosus -- Influence, Systemic lupus erythematosus -- Reports, Systemic lupus erythematosus -- Research, Biological sciences
Published
2004

35. Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis

Author

Jawaheer, Damini, Li, Wentian, Graham, Robert R., Chen, Wei, Damle, Aarti, Xiao, Xiangli, Monteiro, Joanita, Khalili, Houman, Lee, Annette, Lundsten, Robert, Begovich, Ann, Bugawan, Teodorica, Erlich, Henry, Elder, James T., Criswell, Lindsey A., Seldin, Michael F., Amos, Christopher I., Behrens, Timothy W., and Gregersen, Peter K.

Subjects
Rheumatoid arthritis -- Genetic aspects, HLA histocompatibility antigens -- Physiological aspects, Genetic disorders -- Research, Human genetics -- Research, Biological sciences
Published
2002

36. Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus

Author

Graham, Robert R., Ortmann, Ward A., Langefeld, Carl D., Jawaheer, Damini, Selby, Scott A., Rodine, Peter R., Baechler, Emily C., Rohlf, Kristine E., Shark, Katherine B., Espe, Karl J., Green, Linda E., Nair, Rajan P., Stuart, Philip E., Elder, James T., King, Richard A., Moser, Kathy L., Gaffney, Patrick M., Bugawan, Teodorica L., Erlich, Henry A., Rich, Stephen S., Gregersen, Peter K., and Behrens, Timothy W.

Subjects
HLA histocompatibility antigens -- Physiological aspects, Human genetics -- Research, Immune system -- Genetic aspects, Systemic lupus erythematosus -- Genetic aspects, Genetic disorders -- Research, Biological sciences
Published
2002

39. Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration

Author

Yu, Yi, Bhangale, Tushar R., Fagerness, Jesen, Ripke, Stephan, Thorleifsson, Gudmar, Tan, Perciliz L., Souied, Eric H., Richardson, Andrea J., Merriam, Joanna E., Buitendijk, Gabriëlle H.S., Reynolds, Robyn, Raychaudhuri, Soumya, Chin, Kimberly A., Sobrin, Lucia, Evangelou, Evangelos, Lee, Phil H., Lee, Aaron Y., Leveziel, Nicolas, Zack, Donald J., Campochiaro, Betsy, Campochiaro, Peter, Smith, R. Theodore, Barile, Gaetano R., Guymer, Robyn H., Hogg, Ruth, Chakravarthy, Usha, Robman, Luba D., Gustafsson, Omar, Sigurdsson, Haraldur, Ortmann, Ward, Behrens, Timothy W., Stefansson, Kari, Uitterlinden, André G., van Duijn, Cornelia M., Vingerling, Johannes R., Klaver, Caroline C.W., Allikmets, Rando, Brantley, Milam A., Jr, Baird, Paul N., Katsanis, Nicholas, Thorsteinsdottir, Unnur, Ioannidis, John P.A., Daly, Mark J., Graham, Robert R., and Seddon, Johanna M.

Published
2011
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42. Functionally defective germline variants of sialic acid acetylesterase in autoimmunity

Author

Surolia, Ira, Pirnie, Stephan P., Chellappa, Vasant, Taylor, Kendra N., Cariappa, Annaiah, Moya, Jesse, Liu, Haoyuan, Bell, Daphne W., Driscoll, David R., Diederichs, Sven, Haider, Khaleda, Netravali, Ilka, Le, Sheila, Elia, Roberto, Dow, Ethan, Lee, Annette, Freudenberg, Jan, De Jager, Philip L., Chretien, Yves, Varki, Ajit, MacDonald, Marcy E., Gillis, Tammy, Behrens, Timothy W., Bloch, Donald, Collier, Deborah, Korzenik, Joshua, Podolsky, Daniel K., Hafler, David, Murali, Mandakolathur, Sands, Bruce, Stone, John H., Gregersen, Peter K., and Pillai, Shiv

Published
2010
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43. Rheumatoid arthritis risk allele PTPRC is also associated with response to anti–tumor necrosis factor α therapy

Author

Cui, Jing, Saevarsdottir, Saedis, Thomson, Brian, Padyukov, Leonid, van der Helm-Van Mil, Annette H. M., Nititham, Joanne, Hughes, Laura B., de Vries, Niek, Raychaudhuri, Soumya, Alfredsson, Lars, Askling, Johan, Wedrén, Sara, Ding, Bo, Guiducci, Candace, Wolbink, Gert Jan, Crusius, J. Bart A., van der Horst-Bruinsma, Irene E., Herenius, Marieke, Weinblatt, Michael E., Shadick, Nancy A., Worthington, Jane, Batliwalla, Franak, Kern, Marlena, Morgan, Ann W., Wilson, Anthony G., Isaacs, John D., Hyrich, Kimme, Seldin, Michael F., Moreland, Larry W., Behrens, Timothy W., Allaart, Cornelia F., Criswell, Lindsey A., Huizinga, Tom W. J., Tak, Paul P., Bridges, S. Louis, Jr., Toes, Rene E. M., Barton, Anne, Klareskog, Lars, Gregersen, Peter K., Karlson, Elizabeth W., and Plenge, Robert M.

Published
2010
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46. European Population Substructure Is Associated With Mucocutaneous Manifestations and Autoantibody Production in Systemic Lupus Erythematosus

Author

Chung, Sharon A., Tian, Chao, Taylor, Kimberly E., Lee, Annette T., Ortmann, Ward A., Hom, Geoffrey, Graham, Robert R., Nititham, Joanne, Kelly, Jennifer A., Morrisey, Jean, Wu, Hui, Yin, Hong, Alarcón-Riquelme, Marta E., Tsao, Betty P., Harley, John B., Gaffney, Patrick M., Moser, Kathy L., Manzi, Susan, Petri, Michelle, Gregersen, Peter K., Langefeld, Carl D., Behrens, Timothy W., Seldin, Michael F., and Criswell, Lindsey A.

Published
2009
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49. A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families

Author

Geffney, Patrick M., Kearns, Grainne M., Shark, Katherine B., Ortmann, Ward A., Selby, Scott A., Malmgren, Michelle L., Rohlf, Kristine E., Ockenden, Theresa C., Messner, Ronald P., King, Richard A., Rich, Stephen S., and Behrens, Timothy W.

Subjects
Genetic markers -- Usage, Genomes -- Research, Human genetics -- Research, Lupus erythematosus -- Genetic aspects, Science and technology
Abstract

Systemic lupus erythematosus (SLE) is an autoimmune multisystem inflammatory disease characterized by the production of pathogenic autoantibodies. Previous genetic studies have suggested associations with HLA Class II alleles, complement gene deficiencies, and Fc receptor polymorphisms; however, it is likely that other genes contribute to SLE susceptibility and pathogenesis. Here, we report the results of a genome-wide microsatellite marker screen in 105 SLE sib-pair families. By using multipoint nonparametric methods, the strongest evidence for linkage was found near the HLA locus (6p11-p21) [D6S257, logarithm of odds (lod) = 3.90, P = 0.000011] and at three additional regions: 16q13 (D16S415, lod = 3.64, P = 0.000022), 14q21-23 (D14S276, lod = 2.81, P = 0.00016), and 20p12 (D20S186, lod = 2.62, P = 0.00025). Another nine regions (1p36, 1p13, 1q42, 2p15, 2q21-33, 3cent-q11, 4q28, 11p15, and 15q26) were identified with lod scores [greater than or equal to]1.00. These data support the hypothesis that multiple genes, including one in the HLA region, influence susceptibility to human SLE.

Published
1998

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