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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. The IRF5–TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share

Author

Kottyan, Leah C, Zoller, Erin E, Bene, Jessica, Lu, Xiaoming, Kelly, Jennifer A, Rupert, Andrew M, Lessard, Christopher J, Vaughn, Samuel E, Marion, Miranda, Weirauch, Matthew T, Namjou, Bahram, Adler, Adam, Rasmussen, Astrid, Glenn, Stuart, Montgomery, Courtney G, Hirschfield, Gideon M, Xie, Gang, Coltescu, Catalina, Amos, Chris, Li, He, Ice, John A, Nath, Swapan K, Mariette, Xavier, Bowman, Simon, Rischmueller, Maureen, Lester, Sue, Brun, Johan G, Gøransson, Lasse G, Harboe, Erna, Omdal, Roald, Cunninghame-Graham, Deborah S, Vyse, Tim, Miceli-Richard, Corinne, Brennan, Michael T, Lessard, James A, Wahren-Herlenius, Marie, Kvarnström, Marika, Illei, Gabor G, Witte, Torsten, Jonsson, Roland, Eriksson, Per, Nordmark, Gunnel, Ng, Wan-Fai, Anaya, Juan-Manuel, Rhodus, Nelson L, Segal, Barbara M, Merrill, Joan T, James, Judith A, Guthridge, Joel M, Scofield, R Hal, Alarcon-Riquelme, Marta, Bae, Sang-Cheol, Boackle, Susan A, Criswell, Lindsey A, Gilkeson, Gary, Kamen, Diane L, Jacob, Chaim O, Kimberly, Robert, Brown, Elizabeth, Edberg, Jeffrey, Alarcón, Graciela S, Reveille, John D, Vilá, Luis M, Petri, Michelle, Ramsey-Goldman, Rosalind, Freedman, Barry I, Niewold, Timothy, Stevens, Anne M, Tsao, Betty P, Ying, Jun, Mayes, Maureen D, Gorlova, Olga Y, Wakeland, Ward, Radstake, Timothy, Martin, Ezequiel, Martin, Javier, Siminovitch, Katherine, Sivils, Kathy L Moser, Gaffney, Patrick M, Langefeld, Carl D, Harley, John B, and Kaufman, Kenneth M

Subjects
Biological Sciences, Genetics, Autoimmune Disease, Biotechnology, Lupus, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Autoimmune Diseases, Bayes Theorem, Case-Control Studies, Cohort Studies, DNA-Binding Proteins, Haplotypes, Humans, Interferon Regulatory Factors, Lupus Erythematosus, Systemic, Male, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, beta Karyopherins, UK Primary Sjögren's Syndrome Registry, Medical and Health Sciences, Genetics & Heredity
Abstract

Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.

Published
2015

3. Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome

Author

Harris, Valerie M., Sharma, Rohan, Cavett, Joshua, Kurien, Biji T., Liu, Ke, Koelsch, Kristi A., Rasmussen, Astrid, Radfar, Lida, Lewis, David, Stone, Donald U., Kaufman, C. Erick, Li, Shibo, Segal, Barbara, Wallace, Daniel J., Weisman, Michael H., Venuturupalli, Swamy, Kelly, Jennifer A., Alarcon-Riquelme, Marta E., Pons-Estel, Bernardo, Jonsson, Roland, Lu, Xianglan, Gottenberg, Jacques-Eric, Anaya, Juan-Manuel, Cunninghame-Graham, Deborah S., Huang, Andrew J.W., Brennan, Michael T., Hughes, Pamela, Alevizos, Ilias, Miceli-Richard, Corinne, Keystone, Edward C., Bykerk, Vivian P., Hirschfield, Gideon, Xie, Gang, Ng, Wan-Fai, Nordmark, Gunnel, Bucher, Sara Magnusson, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L., Rischmueller, Maureen, Rohrer, Michael, Wahren-Herlenius, Marie, Witte, Torsten, Mariette, Xavier, Lessard, Christopher J., Harley, John B., Sivils, Kathy L., and Scofield, R. Hal

Published
2016
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4. Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus

Author

Odhams, Christopher A., Roberts, Amy L., Vester, Susan K., Duarte, Carolina S. T., Beales, Charlie T., Clarke, Alexander J., Lindinger, Sonja, Daffern, Samuel J., Zito, Antonino, Chen, Lingyan, Jones, Leonardo L., Boteva, Lora, Morris, David L., Small, Kerrin S., Fernando, Michelle M. A., Cunninghame Graham, Deborah S., and Vyse, Timothy J.

Published
2019
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5. COVID-19 and systemic lupus erythematosus genetics: A balance between autoimmune disease risk and protection against infection

Author

Wang, Yuxuan, primary, Guga, Suri, additional, Wu, Kejia, additional, Khaw, Zoe, additional, Tzoumkas, Konstantinos, additional, Tombleson, Phil, additional, Comeau, Mary E., additional, Langefeld, Carl D., additional, Cunninghame Graham, Deborah S., additional, Morris, David L., additional, and Vyse, Timothy J., additional

Published
2022
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7. Brief Report: Rare X Chromosome Abnormalities in Systemic Lupus Erythematosus and Sjögrenʼs Syndrome

Author

Sharma, Rohan, Harris, Valerie M., Cavett, Joshua, Kurien, Biji T., Liu, Ke, Koelsch, Kristi A., Fayaaz, Anum, Chaudhari, Kaustubh S., Radfar, Lida, Lewis, David, Stone, Donald U., Kaufman, C. Erick, Li, Shibo, Segal, Barbara, Wallace, Daniel J., Weisman, Michael H., Venuturupalli, Swamy, Kelly, Jennifer A., Pons‐Estel, Bernardo, Jonsson, Roland, Lu, Xianglan, Gottenberg, Jacques‐Eric, Anaya, Juan‐Manuel, Cunninghame‐Graham, Deborah S., Huang, Andrew J. W., Brennan, Michael T., Hughes, Pamela, Alevizos, Ilias, Miceli‐Richard, Corinne, Keystone, Edward C., Bykerk, Vivian P., Hirschfield, Gideon, Nordmark, Gunnel, Bucher, Sara Magnusson, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L., Rischmueller, Maureen, Rohrer, Michael, Wahren‐Herlenius, Marie, Witte, Torsten, Alarcón‐Riquelme, Marta, Mariette, Xavier, Lessard, Christopher J., Harley, John B., Ng, Wan‐Fai, Rasmussen, Astrid, Sivils, Kathy L., and Scofield, R. Hal

Published
2017
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9. X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögrenʼs Syndrome

Author

Liu, Ke, Kurien, Biji T., Zimmerman, Sarah L., Kaufman, Kenneth M., Taft, Diana H., Kottyan, Leah C., Lazaro, Sara, Weaver, Carrie A., Ice, John A., Adler, Adam J., Chodosh, James, Radfar, Lida, Rasmussen, Astrid, Stone, Donald U., Lewis, David M., Li, Shibo, Koelsch, Kristi A., Igoe, Ann, Talsania, Mitali, Kumar, Jay, Maier-Moore, Jacen S., Harris, Valerie M., Gopalakrishnan, Rajaram, Jonsson, Roland, Lessard, James A., Lu, Xianglan, Gottenberg, Jacques-Eric, Anaya, Juan-Manuel, Cunninghame-Graham, Deborah S., Huang, Andrew J. W., Brennan, Michael T., Hughes, Pamela, Illei, Gabor G., Miceli-Richard, Corinne, Keystone, Edward C., Bykerk, Vivian P., Hirschfield, Gideon, Xie, Gang, Ng, Wan-Fai, Nordmark, Gunnel, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L., Rischmueller, Maureen, Rohrer, Michael, Segal, Barbara M., Vyse, Timothy J., Wahren-Herlenius, Marie, Witte, Torsten, Pons-Estel, Bernardo, Alarcón-Riquelme, Marta E., Guthridge, Joel M., James, Judith A., Lessard, Christopher J., Kelly, Jennifer A., Thompson, Susan D., Gaffney, Patrick M., Montgomery, Courtney G., Edberg, Jeffrey C., Kimberly, Robert P., Alarcón, Graciela S., Langefeld, Carl L., Gilkeson, Gary S., Kamen, Diane L., Tsao, Betty P., McCune, Joseph W., Salmon, Jane E., Merrill, Joan T., Weisman, Michael H., Wallace, Daniel J., Utset, Tammy O., Bottinger, Erwin P., Amos, Christopher I., Siminovitch, Katherine A., Mariette, Xavier, Sivils, Kathy L., Harley, John B., and Scofield, Hal R.

Published
2016
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10. Identification of Susceptibility Loci in IL6, RPS9/LILRB3, and an Intergenic Locus on Chromosome 21q22 in Takayasu Arteritis in a Genome-Wide Association Study

Author

Renauer, Paul A., Saruhan-Direskeneli, Guher, Coit, Patrick, Adler, Adam, Aksu, Kenan, Keser, Gokhan, Alibaz-Oner, Fatma, Aydin, Sibel Z., Kamali, Sevil, Inanc, Murat, Carette, Simon, Cuthbertson, David, Hoffman, Gary S., Akar, Servet, Onen, Fatos, Akkoc, Nurullah, Khalidi, Nader A., Koening, Curry, Karadag, Omer, Kiraz, Sedat, Langford, Carol A., Maksimowicz-McKinnon, Kathleen, McAlear, Carol A., Ozbalkan, Zeynep, Ates, Askin, Karaaslan, Yasar, Duzgun, Nursen, Monach, Paul A., Ozer, Huseyin T. E., Erken, Eren, Ozturk, Mehmet A., Yazici, Ayten, Cefle, Ayse, Onat, Ahmet Mesut, Kisacik, Bunyamin, Pagnoux, Christian, Kasifoglu, Timucin, Seyahi, Emire, Fresko, Izzet, Seo, Philip, Sreih, Antoine G., Warrington, Kenneth J., Ytterberg, Steven R., Cobankara, Veli, Cunninghame-Graham, Deborah S., Vyse, Timothy J., Pamuk, Omer N., Tunc, Ercan S., Dalkilic, Ediz, Bicakcigil, Muge, Yentur, Sibel P., Wren, Jonathan D., Merkel, Peter A., Direskeneli, Haner, and Sawalha, Amr H.

Published
2015
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11. Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

Author

Günther, Claudia, Kind, Barbara, Reijns, Martin A.M., Berndt, Nicole, Martinez-Bueno, Manuel, Wolf, Christine, Tüngler, Victoria, Chara, Osvaldo, Lee, Young Ae, Hübner, Norbert, Bicknell, Louise, Blum, Sophia, Krug, Claudia, Schmidt, Franziska, Kretschmer, Stefanie, Koss, Sarah, Astell, Katy R., Ramantani, Georgia, Bauerfeind, Anja, Morris, David L., Cunninghame Graham, Deborah S., Bubeck, Doryen, Leitch, Andrea, Ralston, Stuart H., Blackburn, Elizabeth A., Gahr, Manfred, Witte, Torsten, Vyse, Timothy J., Melchers, Inga, Mangold, Elisabeth, Nöthen, Markus M., Aringer, Martin, Kuhn, Annegret, Lüthke, Kirsten, Unger, Leonore, Bley, Annette, Lorenzi, Alice, Isaacs, John D., Alexopoulou, Dimitra, Conrad, Karsten, Dahl, Andreas, Roers, Axel, Alarcon-Riquelme, Marta E., Jackson, Andrew P., and Lee-Kirsch, Min Ae

Published
2015
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12. Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study

Author

Ortiz-Fernandez, Lourdes, Saruhan-Direskeneli, Guher, Alibaz-Oner, Fatma, Kaymaz-Tahra, Sema, Coit, Patrick, Kong, Xiufang, Kiprianos, Allan P., Maughan, Robert T., Aydin, Sibel Z., Aksu, Kenan, Keser, Gokhan, Kamali, Sevil, Inanc, Murat, Springer, Jason, Akar, Servet, Onen, Fatos, Akkoc, Nurullah, Khalidi, Nader A., Koening, Curry, Karadag, Omer, Kiraz, Sedat, Forbess, Lindsy, Langford, Carol A., McAlear, Carol A., Ozbalkan, Zeynep, Yavuz, Sule, Cetin, Gozde Yildirim, Alpay-Kanitez, Nilufer, Chung, Sharon, Ates, Askin, Karaaslan, Yasar, McKinnon-Maksimowicz, Kathleen, Monach, Paul A., Ozer, Huseyin T. E., Seyahi, Emire, Fresko, Izzet, Cefle, Ayse, Seo, Philip, Warrington, Kenneth J., Ozturk, Mehmet A., Ytterberg, Steven R., Cobankara, Veli, Onat, Ahmet Mesut, Duzgun, Nursen, Bicakcigil, Muge, Yentur, Sibel P., Lally, Lindsay, Manfredi, Angelo A., Baldissera, Elena, Erken, Eren, Yazici, Ayten, Kisacik, Bunyamin, Kasifoglu, Timucin, Dalkilic, Ediz, Cuthbertson, David, Pagnoux, Christian, Sreih, Antoine, Reales, Guillermo, Wallace, Chris, Wren, Jonathan D., Cunninghame-Graham, Deborah S., Vyse, Timothy J., Sun, Ying, Chen, Huiyong, Grayson, Peter C., Tombetti, Enrico, Jiang, Lindi, Mason, Justin C., Merkel, Peter A., Direskeneli, Haner, Sawalha, Amr H., Ortiz-Fernandez, Lourdes, Saruhan-Direskeneli, Guher, Alibaz-Oner, Fatma, Kaymaz-Tahra, Sema, Coit, Patrick, Kong, Xiufang, Kiprianos, Allan P., Maughan, Robert T., Aydin, Sibel Z., Aksu, Kenan, Keser, Gokhan, Kamali, Sevil, Inanc, Murat, Springer, Jason, Akar, Servet, Onen, Fatos, Akkoc, Nurullah, Khalidi, Nader A., Koening, Curry, Karadag, Omer, Kiraz, Sedat, Forbess, Lindsy, Langford, Carol A., McAlear, Carol A., Ozbalkan, Zeynep, Yavuz, Sule, Cetin, Gozde Yildirim, Alpay-Kanitez, Nilufer, Chung, Sharon, Ates, Askin, Karaaslan, Yasar, McKinnon-Maksimowicz, Kathleen, Monach, Paul A., Ozer, Huseyin T. E., Seyahi, Emire, Fresko, Izzet, Cefle, Ayse, Seo, Philip, Warrington, Kenneth J., Ozturk, Mehmet A., Ytterberg, Steven R., Cobankara, Veli, Onat, Ahmet Mesut, Duzgun, Nursen, Bicakcigil, Muge, Yentur, Sibel P., Lally, Lindsay, Manfredi, Angelo A., Baldissera, Elena, Erken, Eren, Yazici, Ayten, Kisacik, Bunyamin, Kasifoglu, Timucin, Dalkilic, Ediz, Cuthbertson, David, Pagnoux, Christian, Sreih, Antoine, Reales, Guillermo, Wallace, Chris, Wren, Jonathan D., Cunninghame-Graham, Deborah S., Vyse, Timothy J., Sun, Ying, Chen, Huiyong, Grayson, Peter C., Tombetti, Enrico, Jiang, Lindi, Mason, Justin C., Merkel, Peter A., Direskeneli, Haner, and Sawalha, Amr H.

Abstract

Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 x 10(-s)) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.

Published
2021
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15. Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study

Author

Ortiz-Fernández, Lourdes, primary, Saruhan-Direskeneli, Güher, additional, Alibaz-Oner, Fatma, additional, Kaymaz-Tahra, Sema, additional, Coit, Patrick, additional, Kong, Xiufang, additional, Kiprianos, Allan P., additional, Maughan, Robert T., additional, Aydin, Sibel Z., additional, Aksu, Kenan, additional, Keser, Gokhan, additional, Kamali, Sevil, additional, Inanc, Murat, additional, Springer, Jason, additional, Akar, Servet, additional, Onen, Fatos, additional, Akkoc, Nurullah, additional, Khalidi, Nader A., additional, Koening, Curry, additional, Karadag, Omer, additional, Kiraz, Sedat, additional, Forbess, Lindsy, additional, Langford, Carol A., additional, McAlear, Carol A., additional, Ozbalkan, Zeynep, additional, Yavuz, Sule, additional, Çetin, Gozde Yildirim, additional, Alpay-Kanitez, Nilufer, additional, Chung, Sharon, additional, Ates, Askin, additional, Karaaslan, Yasar, additional, McKinnon-Maksimowicz, Kathleen, additional, Monach, Paul A., additional, Ozer, Hüseyin T.E., additional, Seyahi, Emire, additional, Fresko, Izzet, additional, Cefle, Ayse, additional, Seo, Philip, additional, Warrington, Kenneth J., additional, Ozturk, Mehmet A., additional, Ytterberg, Steven R., additional, Cobankara, Veli, additional, Onat, Ahmet Mesut, additional, Duzgun, Nurşen, additional, Bıcakcıgil, Muge, additional, Yentür, Sibel P., additional, Lally, Lindsay, additional, Manfredi, Angelo A., additional, Baldissera, Elena, additional, Erken, Eren, additional, Yazici, Ayten, additional, Kısacık, Bünyamin, additional, Kaşifoğlu, Timuçin, additional, Dalkilic, Ediz, additional, Cuthbertson, David, additional, Pagnoux, Christian, additional, Sreih, Antoine, additional, Reales, Guillermo, additional, Wallace, Chris, additional, Wren, Jonathan D., additional, Cunninghame-Graham, Deborah S., additional, Vyse, Timothy J., additional, Sun, Ying, additional, Chen, Huiyong, additional, Grayson, Peter C., additional, Tombetti, Enrico, additional, Jiang, Lindi, additional, Mason, Justin C., additional, Merkel, Peter A., additional, Direskeneli, Haner, additional, and Sawalha, Amr H., additional

Published
2021
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18. Genome-wide assessment of genetic risk for systemic lupus erythematosus and disease severity

Author

Chen, Lingyan, primary, Wang, Yong-Fei, primary, Liu, Lu, primary, Bielowka, Adrianna, primary, Ahmed, Rahell, primary, Zhang, Huoru, primary, Tombleson, Phil, primary, Roberts, Amy L, primary, Odhams, Christopher A, primary, Cunninghame Graham, Deborah S, primary, Zhang, Xuejun, primary, Yang, Wanling, primary, Vyse, Timothy J, primary, and Morris, David L, primary

Published
2020
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21. Review: Abnormal B Cell Development in Systemic Lupus Erythematosus:What the Genetics Tell Us

Author

Karrar, Sarah and Cunninghame Graham, Deborah S.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell dysfunction, production of autoantibodies directed toward cellular and nuclear components, and multiorgan damage caused by immune complex deposition and inflammation within affected tissues 1. It largely affects women of childbearing age (the third and fourth decades of life) and is associated with significant morbidity and mortality.In healthy individuals, B cells with autoreactive receptors are selected out during B cell maturation, starting at the initial stages of B cell receptor (BCR) development in the bone marrow and continuing through to the fine tuning that occurs in activated mature B cells in secondary lymphoid tissue. Studies in lupus patients as well as mouse models indicate that these processes are altered in SLE.The etiology of the disease is complex and its phenotype is highly heterogeneous, but genetic susceptibility is thought to contribute as much as 60% of disease risk 2. Although rare monogenic causes do exist, heredity in SLE is complex, with multiple common variants contributing to disease, with patients having to achieve a certain “genetic threshold” for disease risk. This genetic risk, in combination with environmental factors (exposure to ultraviolet sunlight, smoking, and infections including Epstein‐Barr virus have all been implicated), leads to development of the disease 1. In this review, we summarize some of the B cell anomalies in SLE and incorporate evidence from studies in humans and mouse models, together with data from genetic association studies, to explain the mechanisms behind B cell dysregulation in SLE.

Published
2018

22. Genome-wide assessment of genetic risk for systemic lupus erythematosus and disease severity

Author

Chen, Lingyan, primary, Wang, Yong-Fei, additional, Liu, Lu, additional, Bielowka, Adrianna, additional, Ahmed, Rahell, additional, Zhang, Huoru, additional, Tombleson, Phil, additional, Roberts, Amy L, additional, Odhams, Christopher A, additional, Cunninghame Graham, Deborah S, additional, Zhang, Xuejun, additional, Yang, Wangling, additional, Vyse, Timothy J, additional, and Morris, David L, additional

Published
2019
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23. Correction: Klinefelters syndrome (47,XXY) is in excess among men with Sjogrens syndrome (vol 168, pg 25, 2016)

Author

Harris, Valerie M., Sharma, Rohan, Cavett, Joshua, Kurien, Biji T., Liu, Ke, Koelsch, Kristi A., Rasmussen, Astrid, Radfar, Lida, Lewis, David, Stone, Donald U., Kaufman, C. Erick, Li, Shibo, Segal, Barbara, Wallace, Daniel J., Weisman, Michael H., Venuturupalli, Swamy, Kelly, Jennifer A., Alarcon-Riquelme, Marta E., Pons-Estel, Bernardo, Jonsson, Roland, Lu, Xianglan, Gottenberg, Jacques-Eric, Anaya, Juan-Manuel, Cunninghame-Graham, Deborah S., Huang, Andrew J. W., Brennan, Michael T., Hughes, Pamela, Alevizos, Ilias, Miceli-Richard, Corinne, Keystone, Edward C., Bykerk, Vivian P., Hirschfield, Gideon, Xie, Gang, Siminovitch, Katherine A., Ng, Wan-Fai, Nordmark, Gunnel, Bucher, Sara Magnusson, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L., Rischmueller, Maureen, Rohrer, Michael, Wahren-Herlenius, Marie, Witte, Torsten, Mariette, Xavier, Lessard, Christopher J., Harley, John B., Sivils, Kathy L., Scofield, R. Hal, Harris, Valerie M., Sharma, Rohan, Cavett, Joshua, Kurien, Biji T., Liu, Ke, Koelsch, Kristi A., Rasmussen, Astrid, Radfar, Lida, Lewis, David, Stone, Donald U., Kaufman, C. Erick, Li, Shibo, Segal, Barbara, Wallace, Daniel J., Weisman, Michael H., Venuturupalli, Swamy, Kelly, Jennifer A., Alarcon-Riquelme, Marta E., Pons-Estel, Bernardo, Jonsson, Roland, Lu, Xianglan, Gottenberg, Jacques-Eric, Anaya, Juan-Manuel, Cunninghame-Graham, Deborah S., Huang, Andrew J. W., Brennan, Michael T., Hughes, Pamela, Alevizos, Ilias, Miceli-Richard, Corinne, Keystone, Edward C., Bykerk, Vivian P., Hirschfield, Gideon, Xie, Gang, Siminovitch, Katherine A., Ng, Wan-Fai, Nordmark, Gunnel, Bucher, Sara Magnusson, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L., Rischmueller, Maureen, Rohrer, Michael, Wahren-Herlenius, Marie, Witte, Torsten, Mariette, Xavier, Lessard, Christopher J., Harley, John B., Sivils, Kathy L., and Scofield, R. Hal

Abstract

n/a, Funding Agencies|BLRD VA [I01 BX001451]

Published
2018
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25. Corrigendum to “Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome” [Clin. Immunol. 168 (2016) 25–29]

Author

Harris, Valerie M., primary, Sharma, Rohan, additional, Cavett, Joshua, additional, Kurien, Biji T., additional, Liu, Ke, additional, Koelsch, Kristi A., additional, Rasmussen, Astrid, additional, Radfar, Lida, additional, Lewis, David, additional, Stone, Donald U., additional, Kaufman, C. Erick, additional, Li, Shibo, additional, Segal, Barbara, additional, Wallace, Daniel J., additional, Weisman, Michael H., additional, Venuturupalli, Swamy, additional, Kelly, Jennifer A., additional, Alarcon-Riquelme, Marta E., additional, Pons-Estel, Bernardo, additional, Jonsson, Roland, additional, Lu, Xianglan, additional, Gottenberg, Jacques-Eric, additional, Anaya, Juan-Manuel, additional, Cunninghame-Graham, Deborah S., additional, Huang, Andrew J.W., additional, Brennan, Michael T., additional, Hughes, Pamela, additional, Alevizos, Ilias, additional, Miceli-Richard, Corinne, additional, Keystone, Edward C., additional, Bykerk, Vivian P., additional, Hirschfield, Gideon, additional, Xie, Gang, additional, Siminovitch, Katherine A., additional, Ng, Wan-Fai, additional, Nordmark, Gunnel, additional, Bucher, Sara Magnusson, additional, Eriksson, Per, additional, Omdal, Roald, additional, Rhodus, Nelson L., additional, Rischmueller, Maureen, additional, Rohrer, Michael, additional, Wahren-Herlenius, Marie, additional, Witte, Torsten, additional, Mariette, Xavier, additional, Lessard, Christopher J., additional, Harley, John B., additional, Sivils, Kathy L., additional, and Scofield, R. Hal, additional

Published
2018
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26. Rare X Chromosome Abnormalities in Systemic Lupus Erythematosus and Sjögren's Syndrome

Author

Sharma, Rohan, Harris, Valerie M., Cavett, Joshua, Kurien, Biji T., Liu, Ke, Koelsch, Kristi A., Fayaaz, Anum, Chaudhari, Kaustubh S., Radfar, Lida, Lewis, David, Stone, Donald U., Kaufman, C. Erick, Li, Shibo, Segal, Barbara, Wallace, Daniel J., Weisman, Michael H., Venuturupalli, Swamy, Kelly, Jennifer A., Pons-Estel, Bernardo, Jonsson, Roland, Lu, Xianglan, Gottenberg, Jacques-Eric, Anaya, Juan-Manuel, Cunninghame-Graham, Deborah S., Huang, Andrew J. W., Brennan, Michael T., Hughes, Pamela, Alevizos, Ilias, Miceli-Richard, Corinne, Keystone, Edward C., Bykerk, Vivian P., Hirschfield, Gideon, Nordmark, Gunnel, Bucher, Sara Magnusson, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L., Rischmueller, Maureen, Rohrer, Michael, Wahren-Herlenius, Marie, Witte, Torsten, Alarcon-Riquelme, Marta, Mariette, Xavier, Lessard, Christopher J., Harley, John B., Ng, Wan-Fai, Rasmussen, Astrid, Sivils, Kathy L., Scofield, R. Hal, Sharma, Rohan, Harris, Valerie M., Cavett, Joshua, Kurien, Biji T., Liu, Ke, Koelsch, Kristi A., Fayaaz, Anum, Chaudhari, Kaustubh S., Radfar, Lida, Lewis, David, Stone, Donald U., Kaufman, C. Erick, Li, Shibo, Segal, Barbara, Wallace, Daniel J., Weisman, Michael H., Venuturupalli, Swamy, Kelly, Jennifer A., Pons-Estel, Bernardo, Jonsson, Roland, Lu, Xianglan, Gottenberg, Jacques-Eric, Anaya, Juan-Manuel, Cunninghame-Graham, Deborah S., Huang, Andrew J. W., Brennan, Michael T., Hughes, Pamela, Alevizos, Ilias, Miceli-Richard, Corinne, Keystone, Edward C., Bykerk, Vivian P., Hirschfield, Gideon, Nordmark, Gunnel, Bucher, Sara Magnusson, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L., Rischmueller, Maureen, Rohrer, Michael, Wahren-Herlenius, Marie, Witte, Torsten, Alarcon-Riquelme, Marta, Mariette, Xavier, Lessard, Christopher J., Harley, John B., Ng, Wan-Fai, Rasmussen, Astrid, Sivils, Kathy L., and Scofield, R. Hal

Abstract

Objective: Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE) are related by clinical and serologic manifestations as well as genetic risks. Both diseases are more commonly found in women than in men, at a ratio of similar to 10 to 1. Common X chromosome aneuploidies, 47,XXY and 47,XXX, are enriched among men and women, respectively, in either disease, suggesting a dose effect on the X chromosome. Methods: We examined cohorts of SS and SLE patients by constructing intensity plots of X chromosome single-nucleotide polymorphism alleles, along with determining the karyotype of selected patients. Results: Among similar to 2,500 women with SLE, we found 3 patients with a triple mosaic, consisting of 45,X/46,XX/47,XXX. Among similar to 2,100 women with SS, 1 patient had 45,X/46,XX/47,XXX, with a triplication of the distal p arm of the X chromosome in the 47,XXX cells. Neither the triple mosaic nor the partial triplication was found among the controls. In another SS cohort, we found a mother/daughter pair with partial triplication of this same region of the X chromosome. The triple mosaic occurs in similar to 1 in 25,000-50,000 live female births, while partial triplications are even rarer. Conclusion: Very rare X chromosome abnormalities are present among patients with either SS or SLE and may inform the location of a gene(s) that mediates an X dose effect, as well as critical cell types in which such an effect is operative.

Published
2017
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27. Identification of a Sjögrens syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons

Author

Li, He, Ragna Reksten, Tove, Ice, John A., Kelly, Jennifer A., Adrianto, Indra, Rasmussen, Astrid, Wang, Shaofeng, He, Bo, Grundahl, Kiely M., Glenn, Stuart B., Miceli-Richard, Corinne, Bowman, Simon, Lester, Sue, Eriksson, Per, Eloranta, Maija-Leena, Brun, Johan G., Goransson, Lasse G., Harboe, Erna, Guthridge, Joel M., Kaufman, Kenneth M., Kvarnstrom, Marika, Cunninghame Graham, Deborah S., Patel, Ketan, Adler, Adam J., Darise Farris, A., Brennan, Michael T., Chodosh, James, Gopalakrishnan, Rajaram, Weisman, Michael H., Venuturupalli, Swamy, Wallace, Daniel J., Hefner, Kimberly S., Houston, Glen D., Huang, Andrew J. W., Hughes, Pamela J., Lewis, David M., Radfar, Lida, Vista, Evan S., Edgar, Contessa E., Rohrer, Michael D., Stone, Donald U., Vyse, Timothy J., Harley, John B., Gaffney, Patrick M., James, Judith A., Turner, Sean, Alevizos, Ilias, Anaya, Juan-Manuel, Rhodus, Nelson L., Segal, Barbara M., Montgomery, Courtney G., Hal Scofield, R., Kovats, Susan, Mariette, Xavier, Ronnblom, Lars, Witte, Torsten, Rischmueller, Maureen, Wahren-Herlenius, Marie, Omdal, Roald, Jonsson, Roland, Ng, Wan-Fai, Nordmark, Gunnel, Lessard, Christopher J., Sivils, Kathy L., Li, He, Ragna Reksten, Tove, Ice, John A., Kelly, Jennifer A., Adrianto, Indra, Rasmussen, Astrid, Wang, Shaofeng, He, Bo, Grundahl, Kiely M., Glenn, Stuart B., Miceli-Richard, Corinne, Bowman, Simon, Lester, Sue, Eriksson, Per, Eloranta, Maija-Leena, Brun, Johan G., Goransson, Lasse G., Harboe, Erna, Guthridge, Joel M., Kaufman, Kenneth M., Kvarnstrom, Marika, Cunninghame Graham, Deborah S., Patel, Ketan, Adler, Adam J., Darise Farris, A., Brennan, Michael T., Chodosh, James, Gopalakrishnan, Rajaram, Weisman, Michael H., Venuturupalli, Swamy, Wallace, Daniel J., Hefner, Kimberly S., Houston, Glen D., Huang, Andrew J. W., Hughes, Pamela J., Lewis, David M., Radfar, Lida, Vista, Evan S., Edgar, Contessa E., Rohrer, Michael D., Stone, Donald U., Vyse, Timothy J., Harley, John B., Gaffney, Patrick M., James, Judith A., Turner, Sean, Alevizos, Ilias, Anaya, Juan-Manuel, Rhodus, Nelson L., Segal, Barbara M., Montgomery, Courtney G., Hal Scofield, R., Kovats, Susan, Mariette, Xavier, Ronnblom, Lars, Witte, Torsten, Rischmueller, Maureen, Wahren-Herlenius, Marie, Omdal, Roald, Jonsson, Roland, Ng, Wan-Fai, Nordmark, Gunnel, Lessard, Christopher J., and Sivils, Kathy L.

Abstract

Sjogrens syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2-5-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 x 10(-14)). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (P-meta = 2.59 x 10(-9); odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3 end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease., Funding Agencies|NIH [P50AR0608040, 1R01AR065953, 5R01DE015223, 5RC2AR058959, 5P01AR049084, 5P30AR053483, 5U19AI082714, U19AI056363, 1R01DE018209, 5R01DE018209, 8P20GM103456, 1P30GM110766, 1R03AR065786, 5R37AI024717, 5P01AI083194, 7S10RR027190-02, 1U01AI101934, U54GM104938, S10RR026735, 5P30GM103510]; National Institute of Dental and Craniofacial Research; US Department of Veterans Affairs IM MA 9; USA Department of Defense [PR094002]; American College of Rheumatology Research and Education Foundation/Abbott Health Professional Graduate Student Preceptorship Award; Oklahoma Medical Research Foundation; Sjogrens Syndrome Foundation; Phileona Foundation; French ministry of health: PHRC [2006-AOM06133]; French ministry of research [ANR-2010-BLAN-1133]

Published
2017
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28. 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., Carlsson Almlof, Jonas, Acevedo-Vasquez, Eduardo M., Alarcon, 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., Rantapaa Dahlqvist, Solbritt, DAlfonso, Sandra, Martins Da Silva, Berta, de la Rua Figueroa, Inigo, Doria, Andrea, Edberg, Jeffrey C., Endreffy, Emoke, Esquivel-Valerio, Jorge A., Fortin, Paul R., Freedman, Barry I., Frostegard, Johan, Garcia, Mercedes A., Garcia de la Torre, Ignacio, Gilkeson, Gary S., Gladman, Dafna D., Gunnarsson, Iva, Guthridge, Joel M., Huggins, Jennifer L., James, Judith A., Kallenberg, Cees G. M., Kamen, Diane L., Karp, David R., Kaufman, Kenneth M., Kottyan, Leah C., Kovacs, Laszlo, Laustrup, Helle, Lauwerys, Bernard R., Li, Quan-Zhen, Maradiaga-Cecena, Marco A., Martin, Javier, McCune, Joseph M., McWilliams, David R., Merrill, Joan T., Miranda, Pedro, Moctezuma, Jose 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, Jose M., Aguilar-Salinas, Carlos A., Scherbarth, Hugo R., Scorza, Raffaella, Seldin, Michael F., Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D., Toloza, Sergio M. A., Truedsson, Lennart, Tusie-Luna, Teresa, Vasconcelos, Carlos, Vila, Luis M., Wallace, Daniel J., Weisman, Michael H., Wither, Joan E., Bhangale, Tushar, Oksenberg, Jorge R., Rioux, John D., Gregersen, Peter K., Syvanen, Ann-Christine, Ronnblom, Lars, Criswell, Lindsey A., Jacob, Chaim O., Sivils, Kathy L., Tsao, Betty P., Schanberg, Laura E., Behrens, Timothy W., Silverman, Earl D., Alarcon-Riquelme, Marta E., Kimberly, Robert P., Harley, John B., Wakeland, Edward K., Graham, Robert R., Gaffney, Patrick M., Vyse, Timothy J., 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., Carlsson Almlof, Jonas, Acevedo-Vasquez, Eduardo M., Alarcon, 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., Rantapaa Dahlqvist, Solbritt, DAlfonso, Sandra, Martins Da Silva, Berta, de la Rua Figueroa, Inigo, Doria, Andrea, Edberg, Jeffrey C., Endreffy, Emoke, Esquivel-Valerio, Jorge A., Fortin, Paul R., Freedman, Barry I., Frostegard, Johan, Garcia, Mercedes A., Garcia de la Torre, Ignacio, Gilkeson, Gary S., Gladman, Dafna D., Gunnarsson, Iva, Guthridge, Joel M., Huggins, Jennifer L., James, Judith A., Kallenberg, Cees G. M., Kamen, Diane L., Karp, David R., Kaufman, Kenneth M., Kottyan, Leah C., Kovacs, Laszlo, Laustrup, Helle, Lauwerys, Bernard R., Li, Quan-Zhen, Maradiaga-Cecena, Marco A., Martin, Javier, McCune, Joseph M., McWilliams, David R., Merrill, Joan T., Miranda, Pedro, Moctezuma, Jose 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, Jose M., Aguilar-Salinas, Carlos A., Scherbarth, Hugo R., Scorza, Raffaella, Seldin, Michael F., Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D., Toloza, Sergio M. A., Truedsson, Lennart, Tusie-Luna, Teresa, Vasconcelos, Carlos, Vila, Luis M., Wallace, Daniel J., Weisman, Michael H., Wither, Joan E., Bhangale, Tushar, Oksenberg, Jorge R., Rioux, John D., Gregersen, Peter K., Syvanen, Ann-Christine, Ronnblom, Lars, Criswell, Lindsey A., Jacob, Chaim O., Sivils, Kathy L., Tsao, Betty P., Schanberg, Laura E., Behrens, Timothy W., Silverman, Earl D., Alarcon-Riquelme, Marta E., Kimberly, Robert P., Harley, John B., Wakeland, Edward K., Graham, Robert R., Gaffney, Patrick M., and Vyse, Timothy J.

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 (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P amp;lt; 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE., Funding Agencies|Alliance for Lupus Research; Arthritis Research UK Special Strategic Award [19289]; George Koukis; National Institute for Health Research (NIHR) Biomedical Research Centre based at Guys and St Thomas NHS Foundation Trust; Kings College London; NIH [AR049084]; International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN) [AI083194, CA141700, AR058621]; Proyecto de Excelencia; Consejeria de Andalucia; MUSC [UL1RR029882, 5P60AR062755]; US National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH) [K01 AR067280, P60 AR062755, N01AR22265]; APPLE Investigators; NIAMS/NIH [P50-AR055503]; RILITE foundation; Genentech; [AR043814]; [AR-065626]; [AR060366]; [MD007909]; [AI107176]; [AR-057172]; [RC2 AR058959]; [U19 A1082714]; [R01 AR063124]; [P30 GM110766]; [R01 AR056360]; [P60 AR053308]; [R01AR43727]; [NIH AR 043727]; [069572]

Published
2017
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29. X Chromosome Dose and Sex Bias in Autoimmune Diseases:Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome

Author

Liu, Ke, Kurien, Biji T, Zimmerman, Sarah L, Kaufman, Kenneth M, Taft, Diana H, Kottyan, Leah C, Lazaro, Sara, Weaver, Carrie A, Ice, John A, Adler, Adam J, Chodosh, James, Radfar, Lida, Rasmussen, Astrid, Stone, Donald U, Lewis, David M, Li, Shibo, Koelsch, Kristi A, Igoe, Ann, Talsania, Mitali, Kumar, Jay, Maier-Moore, Jacen S, Harris, Valerie M, Gopalakrishnan, Rajaram, Jonsson, Roland, Lessard, James A, Lu, Xianglan, Gottenberg, Jacques-Eric, Anaya, Juan-Manuel, Cunninghame-Graham, Deborah S, Huang, Andrew J W, Brennan, Michael T, Hughes, Pamela, Illei, Gabor G, Miceli-Richard, Corinne, Keystone, Edward C, Bykerk, Vivian P, Hirschfield, Gideon, Xie, Gang, Ng, Wan-Fai, Nordmark, Gunnel, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L, Rischmueller, Maureen, Rohrer, Michael, Segal, Barbara M, Vyse, Timothy J, Wahren-Herlenius, Marie, Witte, Torsten, Pons-Estel, Bernardo, Alarcon-Riquelme, Marta E, Guthridge, Joel M, James, Judith A, Lessard, Christopher J, Kelly, Jennifer A, Thompson, Susan D, Gaffney, Patrick M, Montgomery, Courtney G, Edberg, Jeffrey C, Kimberly, Robert P, Alarcón, Graciela S, Langefeld, Carl L, Gilkeson, Gary S, Kamen, Diane L, Tsao, Betty P, McCune, W Joseph, Salmon, Jane E, Merrill, Joan T, Weisman, Michael H, Wallace, Daniel J, Utset, Tammy O, Bottinger, Erwin P, Amos, Christopher I, Siminovitch, Katherine A, Mariette, Xavier, Sivils, Kathy L, Harley, John B, and Scofield, R Hal

Subjects
Gene dosage, Liver Cirrhosis, Sarcoidosis, Sex Chromosome Disorders of Sex Development, Case control study, Trisomy, Major clinical study, XXX, Article, Fluorescence, Chromosomes, Autoimmune Diseases, X chromosome, Systemic lupus erythematosus, Rheumatoid, Autoimmune disease, Prevalence, Live birth, Humans, Rheumatoid arthritis, Sex Distribution, Sex Chromosome Aberrations, In Situ Hybridization, Priority journal, Lupus Erythematosus, Fluorescence in situ hybridization, Arthritis, Systemic, Biliary, Quality control, Polymerase chain reaction, Single nucleotide polymorphism, Sjogren's Syndrome, Primary biliary cirrhosis, Sex chromosome aberration, Case-Control Studies, Female, Sex, Karyotype 47, Controlled study, Sex ratio, Human
Abstract

Objective More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ?1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. Methods All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. Results We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients. Conclusion The estimated prevalence of SLE and SS in women with 47,XXX was ?2.5 and ?2.9 times higher, respectively, than that in women with 46,XX and ?25 and ?41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity. © 2016, American College of Rheumatology.

Published
2016

31. Genome-wide association study identifies susceptibility loci in IL6, RPS9/LILRB3, and an intergenic locus on chromosome 21q22 in Takayasu’s arteritis

Author

Renauer, Paul, Saruhan-Direskeneli, Guher, Coit, Patrick, Adler, Adam, Aksu, Kenan, Keser, Gokhan, Alibaz-Oner, Fatma, Aydin, Sibel Z., Kamali, Sevil, Inanc, Murat, Carette, Simon, Cuthbertson, David, Hoffman, Gary S., Akar, Servet, Onen, Fatos, Akkoc, Nurullah, Khalidi, Nader A., Koening, Curry, Karadag, Omer, Kiraz, Sedat, Langford, Carol A., Maksimowicz-McKinnon, Kathleen, McAlear, Carol A., Ozbalkan, Zeynep, Ates, Askin, Karaaslan, Yasar, Duzgun, Nursen, Monach, Paul A., Ozer, Huseyin TE, Erken, Eren, Ozturk, Mehmet A., Yazici, Ayten, Cefle, Ayse, Onat, A. Mesut, Kisacik, Bunyamin, Pagnoux, Christian, Kasifoglu, Timucin, Seyahi, Emire, Fresko, Izzet, Seo, Philip, Sreih, Antoine, Warrington, Kenneth J., Ytterberg, Steven R., Cobankara, Veli, Cunninghame-Graham, Deborah S., Vyse, Timothy J., Pamuk, Omer N., Tunc, Ercan, Dalkilic, Ediz, Bicakcigil, Muge, Yentur, Sibel P., Wren, Jonathan D., Merkel, Peter A., Direskeneli, Haner, and Sawalha, Amr H.

Subjects
Ribosomal Proteins, Turkey, Chromosomes, Human, Pair 21, Interleukin-6, Ribosomal Protein S9, Takayasu Arteritis, Article, White People, Cohort Studies, Antigens, CD, Case-Control Studies, North America, Odds Ratio, Humans, Genetic Predisposition to Disease, Receptors, Immunologic, Genome-Wide Association Study
Abstract

Takayasu arteritis is a rare large vessel vasculitis with incompletely understood etiology. This study was undertaken to perform the first unbiased genome-wide association analysis of Takayasu arteritis.Two independent cohorts of patients with Takayasu arteritis from Turkey and North America were included in our study. The Turkish cohort consisted of 559 patients and 489 controls, and the North American cohort consisted of 134 patients and 1,047 controls of European ancestry. Genotyping was performed using the Omni1-Quad and Omni2.5 genotyping arrays. Genotyping data were subjected to rigorous quality control measures and subsequently analyzed to discover genetic susceptibility loci for Takayasu arteritis.We identified genetic susceptibility loci for Takayasu arteritis with a genome-wide level of significance in IL6 (rs2069837) (odds ratio [OR] 2.07, P = 6.70 × 10(-9)), RPS9/LILRB3 (rs11666543) (OR 1.65, P = 2.34 × 10(-8)), and an intergenic locus on chromosome 21q22 (rs2836878) (OR 1.79, P = 3.62 × 10(-10)). The genetic susceptibility locus in RPS9/LILRB3 lies within the leukocyte receptor complex gene cluster on chromosome 19q13.4, and the disease risk variant in this locus correlates with reduced expression of multiple genes including the inhibitory leukocyte immunoglobulin-like receptor gene LILRB3 (P = 2.29 × 10(-8)). In addition, we identified candidate susceptibility genes with suggestive levels of association (P1 × 10(-5)) with Takayasu arteritis, including PCSK5, LILRA3, PPM1G/NRBP1, and PTK2B.Our findings indicate novel genetic susceptibility loci for Takayasu arteritis and uncover potentially important aspects of the pathophysiology of this form of vasculitis.

Published
2015

32. X Chromosome Dose and Sex Bias in Autoimmune Diseases : Increased 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome

Author

Liu, Ke, Kurien, Biji T, Zimmerman, Sarah L, Kaufman, Kenneth M, Taft, Diana H, Kottyan, Leah C, Lazaro, Sara, Weaver, Carrie A, Ice, John A, Adler, Adam J, Chodosh, James, Radfar, Lida, Rasmussen, Astrid, Stone, Donald U, Lewis, David M, Li, Shibo, Koelsch, Kristi A, Igoe, Ann, Talsania, Mitali, Kumar, Jay, Maier-Moore, Jacen S, Harris, Valerie M, Gopalakrishnan, Rajaram, Jonsson, Roland, Lessard, James A, Lu, Xianglan, Gottenberg, Jacques-Eric, Anaya, Juan-Manuel, Cunninghame-Graham, Deborah S, Huang, Andrew J W, Brennan, Michael T, Hughes, Pamela, Illei, Gabor G, Miceli-Richard, Corinne, Keystone, Edward C, Bykerk, Vivian P, Hirschfield, Gideon, Xie, Gang, Ng, Wan-Fai, Nordmark, Gunnel, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L, Rischmueller, Maureen, Rohrer, Michael, Segal, Barbara M, Vyse, Timothy J, Wahren-Herlenius, Marie, Witte, Torsten, Pons-Estel, Bernardo, Alarcon-Riquelme, Marta E, Guthridge, Joel M, James, Judith A, Lessard, Christopher J, Kelly, Jennifer A, Thompson, Susan D, Gaffney, Patrick M, Montgomery, Courtney G, Edberg, Jeffrey C, Kimberly, Robert P, Alarcón, Graciela S, Langefeld, Carl L, Gilkeson, Gary S, Kamen, Diane L, Tsao, Betty P, McCune, W Joseph, Salmon, Jane E, Merrill, Joan T, Weisman, Michael H, Wallace, Daniel J, Utset, Tammy O, Bottinger, Erwin P, Amos, Christopher I, Siminovitch, Katherine A, Mariette, Xavier, Sivils, Kathy L, Harley, John B, Scofield, R Hal, Liu, Ke, Kurien, Biji T, Zimmerman, Sarah L, Kaufman, Kenneth M, Taft, Diana H, Kottyan, Leah C, Lazaro, Sara, Weaver, Carrie A, Ice, John A, Adler, Adam J, Chodosh, James, Radfar, Lida, Rasmussen, Astrid, Stone, Donald U, Lewis, David M, Li, Shibo, Koelsch, Kristi A, Igoe, Ann, Talsania, Mitali, Kumar, Jay, Maier-Moore, Jacen S, Harris, Valerie M, Gopalakrishnan, Rajaram, Jonsson, Roland, Lessard, James A, Lu, Xianglan, Gottenberg, Jacques-Eric, Anaya, Juan-Manuel, Cunninghame-Graham, Deborah S, Huang, Andrew J W, Brennan, Michael T, Hughes, Pamela, Illei, Gabor G, Miceli-Richard, Corinne, Keystone, Edward C, Bykerk, Vivian P, Hirschfield, Gideon, Xie, Gang, Ng, Wan-Fai, Nordmark, Gunnel, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L, Rischmueller, Maureen, Rohrer, Michael, Segal, Barbara M, Vyse, Timothy J, Wahren-Herlenius, Marie, Witte, Torsten, Pons-Estel, Bernardo, Alarcon-Riquelme, Marta E, Guthridge, Joel M, James, Judith A, Lessard, Christopher J, Kelly, Jennifer A, Thompson, Susan D, Gaffney, Patrick M, Montgomery, Courtney G, Edberg, Jeffrey C, Kimberly, Robert P, Alarcón, Graciela S, Langefeld, Carl L, Gilkeson, Gary S, Kamen, Diane L, Tsao, Betty P, McCune, W Joseph, Salmon, Jane E, Merrill, Joan T, Weisman, Michael H, Wallace, Daniel J, Utset, Tammy O, Bottinger, Erwin P, Amos, Christopher I, Siminovitch, Katherine A, Mariette, Xavier, Sivils, Kathy L, Harley, John B, and Scofield, R Hal

Abstract

OBJECTIVE: More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX, 1 in ∼1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls. METHODS: We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR). RESULTS: We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ∼404 SLE women and ∼344 SS women. 47,XXX was present in excess among SLE and SS subjects. CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was respectively ∼2.5 and ∼2.9 times higher than in 46,XX women and ∼25 and ∼41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity. This article is protected by copyright. All rights reserved.

Published
2016
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33. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus

Author

Morris, David L, Sheng, Yujun, Zhang, Yan, Wang, Yong-Fei, Zhu, Zhengwei, Tombleson, Philip, Chen, Lingyan, Cunninghame Graham, Deborah S, Bentham, James, Roberts, Amy L, Chen, Ruoyan, Zuo, Xianbo, Wang, Tingyou, Wen, Leilei, Yang, Chao, Liu, Lu, Yang, Lulu, Li, Feng, Huang, Yuanbo, Yin, Xianyong, Yang, Sen, Rönnblom, Lars, Fürnrohr, Barbara G, Voll, Reinhard E, Schett, Georg, Costedoat-Chalumeau, Nathalie, Gaffney, Patrick M, Lau, Yu Lung, Zhang, Xuejun, Yang, Wanling, Cui, Yong, Vyse, Timothy J, Morris, David L, Sheng, Yujun, Zhang, Yan, Wang, Yong-Fei, Zhu, Zhengwei, Tombleson, Philip, Chen, Lingyan, Cunninghame Graham, Deborah S, Bentham, James, Roberts, Amy L, Chen, Ruoyan, Zuo, Xianbo, Wang, Tingyou, Wen, Leilei, Yang, Chao, Liu, Lu, Yang, Lulu, Li, Feng, Huang, Yuanbo, Yin, Xianyong, Yang, Sen, Rönnblom, Lars, Fürnrohr, Barbara G, Voll, Reinhard E, Schett, Georg, Costedoat-Chalumeau, Nathalie, Gaffney, Patrick M, Lau, Yu Lung, Zhang, Xuejun, Yang, Wanling, Cui, Yong, and Vyse, Timothy J

Abstract

Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.

Published
2016
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34. Mapping eQTLs With RNA-Seq Reveals Novel SLE Susceptibility Genes, Non-Coding RNAs, and Alternative-Splicing Events That Are Concealed Using Microarrays

Author

Odhams, Christopher A., primary, Cortini, Andrea, additional, Chen, Lingyan, additional, Roberts, Amy L., additional, Vinuela, Ana, additional, Buil, Alfonso, additional, Small, Kerrin S., additional, Dermitzakis, Emmanouil T., additional, Morris, David L., additional, Vyse, Timothy J., additional, and Cunninghame Graham, Deborah S., additional

Published
2016
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36. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus

Author

Morris, David L, primary, Sheng, Yujun, additional, Zhang, Yan, additional, Wang, Yong-Fei, additional, Zhu, Zhengwei, additional, Tombleson, Philip, additional, Chen, Lingyan, additional, Cunninghame Graham, Deborah S, additional, Bentham, James, additional, Roberts, Amy L, additional, Chen, Ruoyan, additional, Zuo, Xianbo, additional, Wang, Tingyou, additional, Wen, Leilei, additional, Yang, Chao, additional, Liu, Lu, additional, Yang, Lulu, additional, Li, Feng, additional, Huang, Yuanbo, additional, Yin, Xianyong, additional, Yang, Sen, additional, Rönnblom, Lars, additional, Fürnrohr, Barbara G, additional, Voll, Reinhard E, additional, Schett, Georg, additional, Costedoat–Chalumeau, Nathalie, additional, Gaffney, Patrick M, additional, Lau, Yu Lung, additional, Zhang, Xuejun, additional, Yang, Wanling, additional, Cui, Yong, additional, and Vyse, Timothy J, additional

Published
2016
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37. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

Author

Bentham, James, Morris, David L, Cunninghame Graham, Deborah S, Pinder, Christopher L, Tombleson, Philip, Behrens, Timothy W, Martín, Javier, Fairfax, Benjamin P, Knight, Julian C, Chen, Lingyan, Replogle, Joseph, Syvänen, Ann-Christine, Rönnblom, Lars, Graham, Robert R, Wither, Joan E, Rioux, John D, Alarcón-Riquelme, Marta E, Vyse, Timothy J, Bentham, James, Morris, David L, Cunninghame Graham, Deborah S, Pinder, Christopher L, Tombleson, Philip, Behrens, Timothy W, Martín, Javier, Fairfax, Benjamin P, Knight, Julian C, Chen, Lingyan, Replogle, Joseph, Syvänen, Ann-Christine, Rönnblom, Lars, Graham, Robert R, Wither, Joan E, Rioux, John D, Alarcón-Riquelme, Marta E, and Vyse, Timothy J

Abstract

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

Published
2015
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38. Klinefelter's Syndrome (47,XXY) Among Men with Sjogren's Syndrome

Author

Harris, Valerie M., Cavett, Joshua, Kurien, Biji, Liu, Ke, Koelsch, Kristi A., Radfar, Lida, Lewis, David M., Stone, Donald U., Li, Shibo, Segal, Barbara, Wallace, Daniel J., Weisman, Michael H., Kelly, Jennifer A., Alarcon-Riquelme, Marta, Pons-Estel, Bernado, Jonsson, Roland, Lu, Xianglan, Gottenberg, Jacques, Anaya, Juan-Manuel, Cunninghame-Graham, Deborah S., Keystone, Edward C., Huang, Andrew J. W., Brennan, Michael T., Hughes, Pamela, Illei, G., Miceli, Corinne, Bykerk, V. P., Hirschfield, Gideon, Xie, Gang, Ng, Wan-Fai, Nordmark, Gunnel, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L., Rischmueller, Maureen, Rohrer, Michael D., Wahren-Herlenius, Marie, Witte, Torsten, Mariette, Xavier, Lessard, Christopher, Harley, John B., Sivils, Kathy L., Scofield, Robert Hal, Harris, Valerie M., Cavett, Joshua, Kurien, Biji, Liu, Ke, Koelsch, Kristi A., Radfar, Lida, Lewis, David M., Stone, Donald U., Li, Shibo, Segal, Barbara, Wallace, Daniel J., Weisman, Michael H., Kelly, Jennifer A., Alarcon-Riquelme, Marta, Pons-Estel, Bernado, Jonsson, Roland, Lu, Xianglan, Gottenberg, Jacques, Anaya, Juan-Manuel, Cunninghame-Graham, Deborah S., Keystone, Edward C., Huang, Andrew J. W., Brennan, Michael T., Hughes, Pamela, Illei, G., Miceli, Corinne, Bykerk, V. P., Hirschfield, Gideon, Xie, Gang, Ng, Wan-Fai, Nordmark, Gunnel, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L., Rischmueller, Maureen, Rohrer, Michael D., Wahren-Herlenius, Marie, Witte, Torsten, Mariette, Xavier, Lessard, Christopher, Harley, John B., Sivils, Kathy L., and Scofield, Robert Hal

Published
2015
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39. Identification of Novel Sjogren's Syndrome Risk Loci in the Regions of TNFAIP3 and PRDM1

Author

Lessard, Christopher J., Li, He, Ice, John, Adrianto, Indra, Rasmussen, Astrid, Grundahl, Kiely, Kelly, Jennifer A., Miceli, Corinne, Bowman, Simon, Lester, Susan, Brun, Johan G., Goransson, Lasse G., Harboe, Erna, Guthridge, Joel M., Kaufman, Kenneth M., Eriksson, Per, Eloranta, Maija-Leena, Kvarnstrom, Marika, Cunninghame-Graham, Deborah S., Farris, A. Darise, Brennan, Michael T., Chodosh, James, Gopalakrishnan, Raj, Huang, Andrew J. W., Hughes, Pamela, Lewis, David M., Radfar, Lida, Rohrer, Michael D., Stone, Donald U., Vyse, Timothy J., Gaffney, Patrick M., James, Judith A., Harley, John B., Omdal, Roald, Wahren-Herlenius, Marie, Illei, Gabor G., Witte, Torsten, Jonsson, Roland, Rischmueller, Maureen, Ronnblom, Lars, Mariette, Xavier, Anaya, Juan-Manuel, Ng, Wan-Fai, Nordmark, Gunnel, Montgomery, Courtney G., Rhodus, Nelson L., Segal, Barbara M., Scofield, R. Hal, Sivils, Kathy L., Lessard, Christopher J., Li, He, Ice, John, Adrianto, Indra, Rasmussen, Astrid, Grundahl, Kiely, Kelly, Jennifer A., Miceli, Corinne, Bowman, Simon, Lester, Susan, Brun, Johan G., Goransson, Lasse G., Harboe, Erna, Guthridge, Joel M., Kaufman, Kenneth M., Eriksson, Per, Eloranta, Maija-Leena, Kvarnstrom, Marika, Cunninghame-Graham, Deborah S., Farris, A. Darise, Brennan, Michael T., Chodosh, James, Gopalakrishnan, Raj, Huang, Andrew J. W., Hughes, Pamela, Lewis, David M., Radfar, Lida, Rohrer, Michael D., Stone, Donald U., Vyse, Timothy J., Gaffney, Patrick M., James, Judith A., Harley, John B., Omdal, Roald, Wahren-Herlenius, Marie, Illei, Gabor G., Witte, Torsten, Jonsson, Roland, Rischmueller, Maureen, Ronnblom, Lars, Mariette, Xavier, Anaya, Juan-Manuel, Ng, Wan-Fai, Nordmark, Gunnel, Montgomery, Courtney G., Rhodus, Nelson L., Segal, Barbara M., Scofield, R. Hal, and Sivils, Kathy L.

Published
2015
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40. The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.

Author

Kottyan, Leah C., Zoller, Erin E., Bene, Jessica, Lu, Xiaoming, Kelly, Jennifer A., Rupert, Andrew M., Lessard, Christopher J., Vaughn, Samuel E., Marion, Miranda, Weirauch, Matthew T., Namjou, Bahram, Adler, Adam, Rasmussen, Astrid, Glenn, Stuart, Montgomery, Courtney G., Hirschfield, Gideon M., Xie, Gang, Coltescu, Catalina, Amos, Chris, Li, He, Ice, John A., Nath, Swapan K., Mariette, Xavier, Bowman, Simon, Rischmueller, Maureen, Lester, Sue, Brun, Johan G., Gøransson, Lasse G., Harboe, Erna, Omdal, Roald, Cunninghame-Graham, Deborah S., Vyse, Tim, Miceli-Richard, Corinne, Brennan, Michael T., Lessard, James A., Wahren-Herlenius, Marie, Kvarnström, Marika, Illei, Gabor G., Witte, Torsten, Jonsson, Roland, Eriksson, Per, Nordmark, Gunnel, Ng, Wan-Fai, Anaya, Juan-Manuel, Rhodus, Nelson N., Segal, Barbara M., Merrill, Joan T., James, Judith A., Guthridge, Joel M., Hal Scofield, R, Alarcon-Riquelme, Marta, Bae, Sang-Cheol, Boackle, Susan A., Criswell, Lindsey A., Gilkeson, Gary, Kamen, Diane L, Jacob, Chaim O., Kimberly, Robert, Brown, Elizabeth, Edberg, Jeffrey, Alarcón, Graciela S., Reveille, John D., Vilá, Luis M., Petri, Michelle, Ramsey-Goldman, Rosalind, Freedman, Barry I., Niewold, Timothy, Stevens, Anne M., Tsao, Betty P., Ying, Jun, Mayes, Maureen D., Gorlova, Olga Y., Wakeland, Ward, Radstake, Timothy, Martin, Ezequiel, Martin, Javier, Siminovitch, Katherine, Moser Sivils, Kathy L., Gaffney, Patrick M., Langefeld, Carl D., Harley, John B., Kaufman, Kenneth M., Kottyan, Leah C., Zoller, Erin E., Bene, Jessica, Lu, Xiaoming, Kelly, Jennifer A., Rupert, Andrew M., Lessard, Christopher J., Vaughn, Samuel E., Marion, Miranda, Weirauch, Matthew T., Namjou, Bahram, Adler, Adam, Rasmussen, Astrid, Glenn, Stuart, Montgomery, Courtney G., Hirschfield, Gideon M., Xie, Gang, Coltescu, Catalina, Amos, Chris, Li, He, Ice, John A., Nath, Swapan K., Mariette, Xavier, Bowman, Simon, Rischmueller, Maureen, Lester, Sue, Brun, Johan G., Gøransson, Lasse G., Harboe, Erna, Omdal, Roald, Cunninghame-Graham, Deborah S., Vyse, Tim, Miceli-Richard, Corinne, Brennan, Michael T., Lessard, James A., Wahren-Herlenius, Marie, Kvarnström, Marika, Illei, Gabor G., Witte, Torsten, Jonsson, Roland, Eriksson, Per, Nordmark, Gunnel, Ng, Wan-Fai, Anaya, Juan-Manuel, Rhodus, Nelson N., Segal, Barbara M., Merrill, Joan T., James, Judith A., Guthridge, Joel M., Hal Scofield, R, Alarcon-Riquelme, Marta, Bae, Sang-Cheol, Boackle, Susan A., Criswell, Lindsey A., Gilkeson, Gary, Kamen, Diane L, Jacob, Chaim O., Kimberly, Robert, Brown, Elizabeth, Edberg, Jeffrey, Alarcón, Graciela S., Reveille, John D., Vilá, Luis M., Petri, Michelle, Ramsey-Goldman, Rosalind, Freedman, Barry I., Niewold, Timothy, Stevens, Anne M., Tsao, Betty P., Ying, Jun, Mayes, Maureen D., Gorlova, Olga Y., Wakeland, Ward, Radstake, Timothy, Martin, Ezequiel, Martin, Javier, Siminovitch, Katherine, Moser Sivils, Kathy L., Gaffney, Patrick M., Langefeld, Carl D., Harley, John B., and Kaufman, Kenneth M.

Abstract

Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögrens syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.

Published
2015
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41. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

Author

Bentham, James, primary, Morris, David L, additional, Cunninghame Graham, Deborah S, additional, Pinder, Christopher L, additional, Tombleson, Philip, additional, Behrens, Timothy W, additional, Martín, Javier, additional, Fairfax, Benjamin P, additional, Knight, Julian C, additional, Chen, Lingyan, additional, Replogle, Joseph, additional, Syvänen, Ann-Christine, additional, Rönnblom, Lars, additional, Graham, Robert R, additional, Wither, Joan E, additional, Rioux, John D, additional, Alarcón-Riquelme, Marta E, additional, and Vyse, Timothy J, additional

Published
2015
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42. Identification of Susceptibility Loci inIL6,RPS9/LILRB3, and an Intergenic Locus on Chromosome 21q22 in Takayasu Arteritis in a Genome-Wide Association Study

Author

Renauer, Paul A., primary, Saruhan-Direskeneli, Guher, additional, Coit, Patrick, additional, Adler, Adam, additional, Aksu, Kenan, additional, Keser, Gokhan, additional, Alibaz-Oner, Fatma, additional, Aydin, Sibel Z., additional, Kamali, Sevil, additional, Inanc, Murat, additional, Carette, Simon, additional, Cuthbertson, David, additional, Hoffman, Gary S., additional, Akar, Servet, additional, Onen, Fatos, additional, Akkoc, Nurullah, additional, Khalidi, Nader A., additional, Koening, Curry, additional, Karadag, Omer, additional, Kiraz, Sedat, additional, Langford, Carol A., additional, Maksimowicz-McKinnon, Kathleen, additional, McAlear, Carol A., additional, Ozbalkan, Zeynep, additional, Ates, Askin, additional, Karaaslan, Yasar, additional, Duzgun, Nursen, additional, Monach, Paul A., additional, Ozer, Huseyin T. E., additional, Erken, Eren, additional, Ozturk, Mehmet A., additional, Yazici, Ayten, additional, Cefle, Ayse, additional, Onat, Ahmet Mesut, additional, Kisacik, Bunyamin, additional, Pagnoux, Christian, additional, Kasifoglu, Timucin, additional, Seyahi, Emire, additional, Fresko, Izzet, additional, Seo, Philip, additional, Sreih, Antoine G., additional, Warrington, Kenneth J., additional, Ytterberg, Steven R., additional, Cobankara, Veli, additional, Cunninghame-Graham, Deborah S., additional, Vyse, Timothy J., additional, Pamuk, Omer N., additional, Tunc, S. Ercan, additional, Dalkilic, Ediz, additional, Bicakcigil, Muge, additional, Yentur, Sibel P., additional, Wren, Jonathan D., additional, Merkel, Peter A., additional, Direskeneli, Haner, additional, and Sawalha, Amr H., additional

Published
2015
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43. Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

Author

Günther, Claudia, primary, Kind, Barbara, additional, Reijns, Martin A.M., additional, Berndt, Nicole, additional, Martinez-Bueno, Manuel, additional, Wolf, Christine, additional, Tüngler, Victoria, additional, Chara, Osvaldo, additional, Lee, Young Ae, additional, Hübner, Norbert, additional, Bicknell, Louise, additional, Blum, Sophia, additional, Krug, Claudia, additional, Schmidt, Franziska, additional, Kretschmer, Stefanie, additional, Koss, Sarah, additional, Astell, Katy R., additional, Ramantani, Georgia, additional, Bauerfeind, Anja, additional, Morris, David L., additional, Cunninghame Graham, Deborah S., additional, Bubeck, Doryen, additional, Leitch, Andrea, additional, Ralston, Stuart H., additional, Blackburn, Elizabeth A., additional, Gahr, Manfred, additional, Witte, Torsten, additional, Vyse, Timothy J., additional, Melchers, Inga, additional, Mangold, Elisabeth, additional, Nöthen, Markus M., additional, Aringer, Martin, additional, Kuhn, Annegret, additional, Lüthke, Kirsten, additional, Unger, Leonore, additional, Bley, Annette, additional, Lorenzi, Alice, additional, Isaacs, John D., additional, Alexopoulou, Dimitra, additional, Conrad, Karsten, additional, Dahl, Andreas, additional, Roers, Axel, additional, Alarcon-Riquelme, Marta E., additional, Jackson, Andrew P., additional, and Lee-Kirsch, Min Ae, additional

Published
2014
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44. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome

Author

Lessard, Christopher J, Li, He, Adrianto, Indra, Ice, John A, Rasmussen, Astrid, Grundahl, Kiely M, Kelly, Jennifer A, Dozmorov, Mikhail G, Miceli-Richard, Corinne, Bowman, Simon, Lester, Sue, Eriksson, Per, Eloranta, Maija-Leena, Brun, Johan G, Gøransson, Lasse G, Harboe, Erna, Guthridge, Joel M, Kaufman, Kenneth M, Kvarnström, Marika, Jazebi, Helmi, Cunninghame Graham, Deborah S, Grandits, Martha E, Nazmul-Hossain, Abu N M, Patel, Ketan, Adler, Adam J, Maier-Moore, Jacen S, Farris, A Darise, Brennan, Michael T, Lessard, James A, Chodosh, James, Gopalakrishnan, Rajaram, Hefner, Kimberly S, Houston, Glen D, Huang, Andrew J W, Hughes, Pamela J, Lewis, David M, Radfar, Lida, Rohrer, Michael D, Stone, Donald U, Wren, Jonathan D, Vyse, Timothy J, Gaffney, Patrick M, James, Judith A, Omdal, Roald, Wahren-Herlenius, Marie, Illei, Gabor G, Witte, Torsten, Jonsson, Roland, Rischmueller, Maureen, Rönnblom, Lars, Nordmark, Gunnel, Ng, Wan-Fai, Mariette, Xavier, Anaya, Juan-Manuel, Rhodus, Nelson L, Segal, Barbara M, Scofield, R Hal, Montgomery, Courtney G, Harley, John B, Sivils, Kathy L, Lessard, Christopher J, Li, He, Adrianto, Indra, Ice, John A, Rasmussen, Astrid, Grundahl, Kiely M, Kelly, Jennifer A, Dozmorov, Mikhail G, Miceli-Richard, Corinne, Bowman, Simon, Lester, Sue, Eriksson, Per, Eloranta, Maija-Leena, Brun, Johan G, Gøransson, Lasse G, Harboe, Erna, Guthridge, Joel M, Kaufman, Kenneth M, Kvarnström, Marika, Jazebi, Helmi, Cunninghame Graham, Deborah S, Grandits, Martha E, Nazmul-Hossain, Abu N M, Patel, Ketan, Adler, Adam J, Maier-Moore, Jacen S, Farris, A Darise, Brennan, Michael T, Lessard, James A, Chodosh, James, Gopalakrishnan, Rajaram, Hefner, Kimberly S, Houston, Glen D, Huang, Andrew J W, Hughes, Pamela J, Lewis, David M, Radfar, Lida, Rohrer, Michael D, Stone, Donald U, Wren, Jonathan D, Vyse, Timothy J, Gaffney, Patrick M, James, Judith A, Omdal, Roald, Wahren-Herlenius, Marie, Illei, Gabor G, Witte, Torsten, Jonsson, Roland, Rischmueller, Maureen, Rönnblom, Lars, Nordmark, Gunnel, Ng, Wan-Fai, Mariette, Xavier, Anaya, Juan-Manuel, Rhodus, Nelson L, Segal, Barbara M, Scofield, R Hal, Montgomery, Courtney G, Harley, John B, and Sivils, Kathy L

Abstract

Sjögren's syndrome is a common autoimmune disease (affecting ~0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjögren's syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (Pmeta = 7.65 × 10−114), we establish associations with IRF5-TNPO3 (Pmeta = 2.73 × 10−19), STAT4 (Pmeta = 6.80 × 10−15), IL12A (Pmeta = 1.17 × 10−10), FAM167A-BLK (Pmeta = 4.97 × 10−10), DDX6-CXCR5 (Pmeta = 1.10 × 10−8) and TNIP1 (Pmeta = 3.30 × 10−8). We also observed suggestive associations (Pmeta < 5 × 10−5) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjögren's syndrome.

Published
2013
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45. Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus

Author

Cunninghame Graham, Deborah S, Morris, David L, Bhangale, Tushar R, Criswell, Lindsey A, Syvänen, Ann-Christine, Rönnblom, Lars, Behrens, Timothy W, Graham, Robert R, Vyse, Timothy J, Cunninghame Graham, Deborah S, Morris, David L, Bhangale, Tushar R, Criswell, Lindsey A, Syvänen, Ann-Christine, Rönnblom, Lars, Behrens, Timothy W, Graham, Robert R, and Vyse, Timothy J

Abstract

Systemic lupus erythematosus (SLE) is a complex trait characterised by the production of a range of auto-antibodies and a diverse set of clinical phenotypes. Currently, ∼8% of the genetic contribution to SLE in Europeans is known, following publication of several moderate-sized genome-wide (GW) association studies, which identified loci with a strong effect (OR>1.3). In order to identify additional genes contributing to SLE susceptibility, we conducted a replication study in a UK dataset (870 cases, 5,551 controls) of 23 variants that showed moderate-risk for lupus in previous studies. Association analysis in the UK dataset and subsequent meta-analysis with the published data identified five SLE susceptibility genes reaching genome-wide levels of significance (P(comb)<5×10(-8)): NCF2 (P(comb) = 2.87×10(-11)), IKZF1 (P(comb) = 2.33×10(-9)), IRF8 (P(comb) = 1.24×10(-8)), IFIH1 (P(comb) = 1.63×10(-8)), and TYK2 (P(comb) = 3.88×10(-8)). Each of the five new loci identified here can be mapped into interferon signalling pathways, which are known to play a key role in the pathogenesis of SLE. These results increase the number of established susceptibility genes for lupus to ∼30 and validate the importance of using large datasets to confirm associations of loci which moderately increase the risk for disease.

Published
2011
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46. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus

Author

Graham, R. Robert, 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, Cunninghame Graham, Deborah S., Onofrio, Robert, Petri, Michelle, Gunnarsson, Iva, Svenungsson, Elisabeth, Rönnblom, Lars, Nordmark, Gunnel, Gregersen, Peter K., Moser, Kathy, Gaffney, Patrick M., Criswell, Lindsey A., Vyse, Timothy J., Syvänen, Ann-Christine, Altshuler, David M., Graham, R. Robert, 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, Cunninghame Graham, Deborah S., Onofrio, Robert, Petri, Michelle, Gunnarsson, Iva, Svenungsson, Elisabeth, Rönnblom, Lars, Nordmark, Gunnel, Gregersen, Peter K., Moser, Kathy, Gaffney, Patrick M., Criswell, Lindsey A., Vyse, Timothy J., Syvänen, Ann-Christine, and Altshuler, David M.

Abstract

Systematic genome-wide studies to map genomic regions associated with human diseases are becoming more practical. Increasingly, efforts will be focused on the identification of the specific functional variants responsible for the disease. The challenges of identifying causal variants include the need for complete ascertainment of genetic variants and the need to consider the possibility of multiple causal alleles. We recently reported that risk of systemic lupus erythematosus (SLE) is strongly associated with a common SNP in IFN regulatory factor 5 (IRF5), and that this variant altered spicing in a way that might provide a functional explanation for the reproducible association to SLE risk. Here, by resequencing and genotyping in patients with SLE, we find evidence for three functional alleles of IRF5: the previously described exon 1B splice site variant, a 30-bp in-frame insertion/deletion variant of exon 6 that alters a proline-, glutamic acid-, serine- and threonine-rich domain region, and a variant in a conserved polyA+ signal sequence that alters the length of the 3' UTR and stability of IRF5 mRNAs. Haplotypes of these three variants define at least three distinct levels of risk to SLE. Understanding how combinations of variants influence IRF5 function may offer etiological and therapeutic insights in SLE; more generally, IRF5 and SLE illustrates how multiple common variants of the same gene can together influence risk of common disease.

Published
2007
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47. CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation

Author

Manjarrez-Orduño, Nataly, primary, Marasco, Emiliano, additional, Chung, Sharon A, additional, Katz, Matthew S, additional, Kiridly, Jenna F, additional, Simpfendorfer, Kim R, additional, Freudenberg, Jan, additional, Ballard, David H, additional, Nashi, Emil, additional, Hopkins, Thomas J, additional, Cunninghame Graham, Deborah S, additional, Lee, Annette T, additional, Coenen, Marieke J H, additional, Franke, Barbara, additional, Swinkels, Dorine W, additional, Graham, Robert R, additional, Kimberly, Robert P, additional, Gaffney, Patrick M, additional, Vyse, Timothy J, additional, Behrens, Timothy W, additional, Criswell, Lindsey A, additional, Diamond, Betty, additional, and Gregersen, Peter K, additional

Published
2012
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