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528 results on '"Kaufman, Kenneth M."'

1. Shared and distinct interactions of type 1 and type 2 Epstein-Barr Nuclear Antigen 2 with the human genome

Author

Viel, Kenyatta C. M. F., Parameswaran, Sreeja, Donmez, Omer A., Forney, Carmy R., Hass, Matthew R., Yin, Cailing, Jones, Sydney H., Prosser, Hayley K., Diouf, Arame A., Gittens, Olivia E., Edsall, Lee E., Chen, Xiaoting, Rowden, Hope, Dunn, Katelyn A., Guo, Rui, VonHandorf, Andrew, Leong, Merrin Man Long, Ernst, Kevin, Kaufman, Kenneth M., Lawson, Lucinda P., Gewurz, Ben, Zhao, Bo, Kottyan, Leah C., and Weirauch, Matthew T.

Published
2024
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3. Validation of low-coverage whole-genome sequencing for mitochondrial DNA variants suggests mitochondrial DNA as a genetic cause of preterm birth.

Author

Yang, Zeyu, Slone, Jesse, Wang, Xinjian, Zhan, Jack, Huang, Yongbo, Namjou, Bahram, Kaufman, Kenneth M, Pauciulo, Michael, Harley, John B, Muglia, Louis J, Chepelev, Iouri, and Huang, Taosheng

Subjects
Mitochondria, Humans, Premature Birth, DNA, Mitochondrial, Infant, Infant, Newborn, Genome, Mitochondrial, Whole Genome Sequencing, human genetics, low-coverage whole-genome sequencing, mitochondrial disease, mitochondrial genome, preterm birth, Perinatal Period - Conditions Originating in Perinatal Period, Genetics, Pediatric Research Initiative, Infant Mortality, Preterm, Low Birth Weight and Health of the Newborn, Human Genome, Pediatric, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Aetiology, Reproductive health and childbirth, Good Health and Well Being, Clinical Sciences, Genetics & Heredity
Abstract

Preterm birth (PTB), or birth that occurs earlier than 37 weeks of gestational age, is a major contributor to infant mortality and neonatal hospitalization. Mutations in the mitochondrial genome (mtDNA) have been linked to various rare mitochondrial disorders and may be a contributing factor in PTB given that maternal genetic factors have been strongly linked to PTB. However, to date, no study has found a conclusive connection between a particular mtDNA variant and PTB. Given the high mtDNA copy number per cell, an automated pipeline was developed for detecting mtDNA variants using low-coverage whole-genome sequencing (lcWGS) data. The pipeline was first validated against samples of known heteroplasmy, and then applied to 929 samples from a PTB cohort from diverse ethnic backgrounds with an average gestational age of 27.18 weeks (range: 21-30). Our new pipeline successfully identified haplogroups and a large number of mtDNA variants in this large PTB cohort, including 8 samples carrying known pathogenic variants and 47 samples carrying rare mtDNA variants. These results confirm that lcWGS can be utilized to reliably identify mtDNA variants. These mtDNA variants may make a contribution toward preterm birth in a small proportion of live births.

Published
2021

4. Complement genes contribute sex-biased vulnerability in diverse disorders.

Author

Kamitaki, Nolan, Sekar, Aswin, Handsaker, Robert E, de Rivera, Heather, Tooley, Katherine, Morris, David L, Taylor, Kimberly E, Whelan, Christopher W, Tombleson, Philip, Loohuis, Loes M Olde, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Boehnke, Michael, Kimberly, Robert P, Kaufman, Kenneth M, Harley, John B, Langefeld, Carl D, Seidman, Christine E, Pato, Michele T, Pato, Carlos N, Ophoff, Roel A, Graham, Robert R, Criswell, Lindsey A, Vyse, Timothy J, and McCarroll, Steven A

Subjects
Schizophrenia Working Group of the Psychiatric Genomics Consortium, Humans, Sjogren's Syndrome, Lupus Erythematosus, Systemic, Genetic Predisposition to Disease, HLA Antigens, Major Histocompatibility Complex, Sex Characteristics, Haplotypes, Alleles, Adult, Middle Aged, Complement C3, Complement C4, Female, Male, Young Adult, Lupus, Brain Disorders, Schizophrenia, Biotechnology, Genetics, Mental Health, Autoimmune Disease, 2.1 Biological and endogenous factors, Inflammatory and immune system, General Science & Technology
Abstract

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

Published
2020

5. Large-scale genome-wide association study of coronary artery disease in genetically diverse populations

Author

Tcheandjieu, Catherine, Zhu, Xiang, Hilliard, Austin T., Clarke, Shoa L., Napolioni, Valerio, Ma, Shining, Lee, Kyung Min, Fang, Huaying, Chen, Fei, Lu, Yingchang, Tsao, Noah L., Raghavan, Sridharan, Koyama, Satoshi, Gorman, Bryan R., Vujkovic, Marijana, Klarin, Derek, Levin, Michael G., Sinnott-Armstrong, Nasa, Wojcik, Genevieve L., Plomondon, Mary E., Maddox, Thomas M., Waldo, Stephen W., Bick, Alexander G., Pyarajan, Saiju, Huang, Jie, Song, Rebecca, Ho, Yuk-Lam, Buyske, Steven, Kooperberg, Charles, Haessler, Jeffrey, Loos, Ruth J. F., Do, Ron, Verbanck, Marie, Chaudhary, Kumardeep, North, Kari E., Avery, Christy L., Graff, Mariaelisa, Haiman, Christopher A., Le Marchand, Loïc, Wilkens, Lynne R., Bis, Joshua C., Leonard, Hampton, Shen, Botong, Lange, Leslie A., Giri, Ayush, Dikilitas, Ozan, Kullo, Iftikhar J., Stanaway, Ian B., Jarvik, Gail P., Gordon, Adam S., Hebbring, Scott, Namjou, Bahram, Kaufman, Kenneth M., Ito, Kaoru, Ishigaki, Kazuyoshi, Kamatani, Yoichiro, Verma, Shefali S., Ritchie, Marylyn D., Kember, Rachel L., Baras, Aris, Lotta, Luca A., Kathiresan, Sekar, Hauser, Elizabeth R., Miller, Donald R., Lee, Jennifer S., Saleheen, Danish, Reaven, Peter D., Cho, Kelly, Gaziano, J. Michael, Natarajan, Pradeep, Huffman, Jennifer E., Voight, Benjamin F., Rader, Daniel J., Chang, Kyong-Mi, Lynch, Julie A., Damrauer, Scott M., Wilson, Peter W. F., Tang, Hua, Sun, Yan V., Tsao, Philip S., O’Donnell, Christopher J., and Assimes, Themistocles L.

Published
2022
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6. Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery

Author

Zhou, Tian, Zhu, Xinyi, Ye, Zhizhong, Wang, Yong-Fei, Yao, Chao, Xu, Ning, Zhou, Mi, Ma, Jianyang, Qin, Yuting, Shen, Yiwei, Tang, Yuanjia, Yin, Zhihua, Xu, Hong, Zhang, Yutong, Zang, Xiaoli, Ding, Huihua, Yang, Wanling, Guo, Ya, Harley, John B., Namjou, Bahram, Kaufman, Kenneth M., Kottyan, Leah C., Weirauch, Matthew T., Hou, Guojun, and Shen, Nan

Published
2022
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7. Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHL as linkers between mitochondrial dysfunction and eosinophilic esophagitis.

Author

Sherrill, Joseph D, Kc, Kiran, Wang, Xinjian, Wen, Ting, Chamberlin, Adam, Stucke, Emily M, Collins, Margaret H, Abonia, J Pablo, Peng, Yanyan, Wu, Qiang, Putnam, Philip E, Dexheimer, Phillip J, Aronow, Bruce J, Kottyan, Leah C, Kaufman, Kenneth M, Harley, John B, Huang, Taosheng, and Rothenberg, Marc E

Subjects
T-Lymphocytes, Mitochondria, Fibroblasts, Epithelial Cells, Humans, Ketoglutarate Dehydrogenase Complex, Oxidoreductases, Ketone Oxidoreductases, Oxidoreductases Acting on CH-CH Group Donors, Proteins, RNA, Small Interfering, Interleukin-13, Cytokines, Up-Regulation, Mutation, Adult, Child, Female, Male, Eosinophilic Esophagitis, Exome Sequencing, Allergy, Cellular immune response, Immunology, Inflammation, Human Genome, Food Allergies, Clinical Research, Genetics, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Whole Exome Sequencing
Abstract

Eosinophilic esophagitis (EoE) is an allergic inflammatory esophageal disorder with a complex underlying genetic etiology often associated with other comorbidities. Using whole-exome sequencing (WES) of 63 patients with EoE and 60 unaffected family members and family-based trio analysis, we sought to uncover rare coding variants. WES analysis identified 5 rare, damaging variants in dehydrogenase E1 and transketolase domain-containing 1 (DHTKD1). Rare variant burden analysis revealed an overabundance of putative, potentially damaging DHTKD1 mutations in EoE (P = 0.01). Interestingly, we also identified 7 variants in the DHTKD1 homolog oxoglutarate dehydrogenase-like (OGDHL). Using shRNA-transduced esophageal epithelial cells and/or patient fibroblasts, we further showed that disruption of normal DHTKD1 or OGDHL expression blunts mitochondrial function. Finally, we demonstrated that the loss of DHTKD1 expression increased ROS production and induced the expression of viperin, a gene previously shown to be involved in production of Th2 cytokines in T cells. Viperin had increased expression in esophageal biopsies of EoE patients compared with control individuals and was upregulated by IL-13 in esophageal epithelial cells. These data identify a series of rare genetic variants implicating DHTKD1 and OGDHL in the genetic etiology of EoE and underscore a potential pathogenic role for mitochondrial dysfunction in EoE.

Published
2018

8. Human cytomegalovirus extensively re-organizes the human genome, diminishing TEAD1 transcription factor activity

Author

Sayeed, Khund, primary, Parameswaran, Sreeja, additional, Beucler, Matthew J., additional, Edsall, Lee E., additional, VonHandorf, Andrew, additional, Crowther, Audrey, additional, Donmez, Omer A., additional, Hass, Matthew R., additional, Richards, Scott, additional, Forney, Carmy R., additional, Wright, Jay, additional, Leong, Merrin ML, additional, Murray-Nerger, Laura A., additional, Gewurz, Benjamin E, additional, Kaufman, Kenneth M., additional, Harley, John B., additional, Zhao, Bo, additional, Miller, William E., additional, Kottyan, Leah C., additional, and Weirauch, Matthew T, additional

Published
2024
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9. Genome-wide association study evaluating single-nucleotide polymorphisms and outcomes in patients with advanced stage serous ovarian or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study

Author

Moore, Kathleen N, Tritchler, David, Kaufman, Kenneth M, Lankes, Heather, Quinn, Michael CJ, Consortium, on behalf of the Ovarian Cancer Association, Van Le, Linda, Berchuck, Andrew, Backes, Floor J, Tewari, Krishnansu S, Lee, Roger B, Kesterson, Joshua P, Wenham, Robert M, Armstrong, Deborah K, Krivak, Thomas C, Bookman, Michael A, and Birrer, Michael J

Subjects
Cancer, Human Genome, Prevention, Genetics, Rare Diseases, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Cystadenocarcinoma, Serous, Female, Genome-Wide Association Study, Humans, Middle Aged, Neoplasm Staging, Ovarian Neoplasms, Peritoneal Neoplasms, Polymorphism, Single Nucleotide, Prognosis, Randomized Controlled Trials as Topic, Genome-wide association, Advanced stage serous ovarian, Primary peritoneal cancer, Ovarian Cancer Association Consortium, Oncology and Carcinogenesis, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis
Abstract

ObjectiveThis study evaluated single nucleotide polymorphisms (SNPs) associated with progression free (PFS) and overall survival (OS) in patients with advanced stage serous EOC.MethodsPatients enrolled in GOG-172 and 182 who provided specimens for translational research and consent were included. Germline DNA was evaluated with the Illumina's HumanOMNI1-Quad beadchips and scanned using Illumina's iScan optical imaging system. SNPs with allele frequency>0.05 and genotyping rate>0.98 were included. Analysis of SNPs for PFS and OS was done using Cox regression. Statistical significance was determined using Bonferroni corrected p-values with genomic control adjustment.ResultsThe initial GWAS analysis included 1,124,677 markers in 396 patients. To obtain the final data set, quality control checks were performed and limited to serous tumors and self-identified Caucasian race. In total 636,555 SNPs and 289 patients passed all the filters. The pre-specified statistical level of significance was 7.855e-08. No SNPs met this criteria for PFS or OS, however, two SNPs were close to significance (rs10899426 p-2.144e-08) (rs6256 p-9.774e-07) for PFS and 2 different SNPs were identified (rs295315 p-7.536e-07; rs17693104 p-7.734e-07) which were close to significance for OS.ConclusionsUsing the pre-specified level of significance of 1×10-08, we did not identify any SNPs of statistical significance for OS or PFS, however several were close. The SNP's identified in this GWAS study will require validation and these preliminary findings may lead to identification of novel pathways and biomarkers.

Published
2017

10. 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

11. Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus

Author

Zhao, Jian, Wu, Hui, Langefeld, Carl D, Kaufman, Kenneth M, Kelly, Jennifer A, Bae, Sang-Cheol, networks, Marta E Alarcón-Riquelme for the BIOLUPUS and GENLES, Alarcón, Graciela S, Anaya, Juan-Manuel, Criswell, Lindsey A, Freedman, Barry I, Kamen, Diane L, Gilkeson, Gary S, Jacob, Chaim O, James, Judith A, Merrill, Joan T, Gaffney, Patrick M, Sivils, Kathy Moser, Niewold, Timothy B, Petri, Michelle A, Song, Seung Taek, Jeong, Hye-jin, Ramsey-Goldman, Rosalind, Reveille, John D, Scofield, R Hal, Stevens, Anne M, Boackle, Susan A, Vilá, Luis M, Chang, Deh-Ming, Song, Yeong Wook, Vyse, Timothy J, Harley, John B, Brown, Elizabeth E, Edberg, Jeffrey C, Kimberly, Robert P, Hahn, Bevra H, Grossman, Jennifer M, Tsao, Betty P, and La Cava, Antonio

Subjects
Biomedical and Clinical Sciences, Immunology, Clinical Research, Autoimmune Disease, Genetic Testing, Genetics, Lupus, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Case-Control Studies, Genetic Predisposition to Disease, Genotype, Humans, Leptin, Lupus Erythematosus, Systemic, Polymorphism, Single Nucleotide, Systemic lupus erythematosus, Leptin pathway, Gene polymorphisms, Marta E. Alarcón-Riquelme for the BIOLUPUS and GENLES networks
Abstract

Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.

Published
2015

12. Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis

Author

Shoda, Tetsuo, Kaufman, Kenneth M., Wen, Ting, Caldwell, Julie M., Osswald, Garrett A., Purnima, Pathre, Zimmermann, Nives, Collins, Margaret H., Rehn, Kira, Foote, Heather, Eby, Michael D., Zhang, Wenying, Ben-Baruch Morgenstern, Netali, Ballaban, Adina Y., Habel, Jeff E., Kottyan, Leah C., Abonia, J. Pablo, Mukkada, Vincent A., Putnam, Philip E., Martin, Lisa J., and Rothenberg, Marc E.

Published
2021
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13. Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression

Author

Lu, Xiaoming, Zoller, Erin E, Weirauch, Matthew T, Wu, Zhiguo, Namjou, Bahram, Williams, Adrienne H, Ziegler, Julie T, Comeau, Mary E, Marion, Miranda C, Glenn, Stuart B, Adler, Adam, Shen, Nan, Nath, Swapan K, Stevens, Anne M, Freedman, Barry I, Tsao, Betty P, Jacob, Chaim O, Kamen, Diane L, Brown, Elizabeth E, Gilkeson, Gary S, Alarcón, Graciela S, Reveille, John D, Anaya, Juan-Manuel, James, Judith A, Sivils, Kathy L, Criswell, Lindsey A, Vilá, Luis M, Alarcón-Riquelme, Marta E, Petri, Michelle, Scofield, R Hal, Kimberly, Robert P, Ramsey-Goldman, Rosalind, Bin Joo, Young, Choi, Jeongim, Bae, Sang-Cheol, Boackle, Susan A, Graham, Deborah Cunninghame, Vyse, Timothy J, Guthridge, Joel M, Gaffney, Patrick M, Langefeld, Carl D, Kelly, Jennifer A, Greis, Kenneth D, Kaufman, Kenneth M, Harley, John B, and Kottyan, Leah C

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Biotechnology, Lupus, Autoimmune Disease, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Alleles, Animals, Asian People, Bayes Theorem, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Lupus Erythematosus, Systemic, Mice, Protein Binding, Proto-Oncogene Protein c-ets-1, STAT1 Transcription Factor, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1.

Published
2015

14. 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

15. 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

17. Variable Association of Reactive Intermediate Genes with Systemic Lupus Erythematosus in Populations with Different African Ancestry

Author

Ramos, Paula S, Oates, James C, Kamen, Diane L, Williams, Adrienne H, Gaffney, Patrick M, Kelly, Jennifer A, Kaufman, Kenneth M, Kimberly, Robert P, Niewold, Timothy B, Jacob, Chaim O, Tsao, Betty P, Alarcón, Graciela S, Brown, Elizabeth E, Edberg, Jeffrey C, Petri, Michelle A, Ramsey-Goldman, Rosalind, Reveille, John D, Vilá, Luis M, James, Judith A, Guthridge, Joel M, Merrill, Joan T, Boackle, Susan A, Freedman, Barry I, Scofield, R Hal, Stevens, Anne M, Vyse, Timothy J, Criswell, Lindsey A, Moser, Kathy L, Alarcón-Riquelme, Marta E, Langefeld, Carl D, Harley, John B, and Gilkeson, Gary S

Subjects
Autoimmune Disease, Lupus, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Adult, Alleles, Black People, Electron Transport Complex I, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Genotype, Glutathione Reductase, Haplotypes, Humans, Lupus Erythematosus, Systemic, NADH Dehydrogenase, Nitric Oxide Synthase Type I, Polymorphism, Single Nucleotide, SYSTEMIC LUPUS ERYTHEMATOSUS, AFRICAN AMERICANS, OXYGEN COMPOUNDS, GENETIC ASSOCIATION STUDIES, SINGLE-NUCLEOTIDE POLYMORPHISM, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology
Abstract

ObjectiveLittle is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate-related genes biological candidates for disease susceptibility. We analyzed variation in reactive intermediate genes for association with SLE in 2 populations with African ancestry.MethodsA total of 244 single-nucleotide polymorphisms (SNP) from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls). Single-marker, haplotype, and 2-locus interaction tests were computed for these populations.ResultsThe glutathione reductase gene GSR (rs2253409; p = 0.0014, OR 1.26, 95% CI 1.09-1.44) was the most significant single SNP association in AA. In the Gullah, the NADH dehydrogenase NDUFS4 (rs381575; p = 0.0065, OR 2.10, 95% CI 1.23-3.59) and NO synthase gene NOS1 (rs561712; p = 0.0072, OR 0.62, 95% CI 0.44-0.88) were most strongly associated with SLE. When both populations were analyzed together, GSR remained the most significant effect (rs2253409; p = 0.00072, OR 1.26, 95% CI 1.10-1.44). Haplotype and 2-locus interaction analyses also uncovered different loci in each population.ConclusionThese results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.

Published
2013

18. Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups

Author

Kaufman, Kenneth M, Zhao, Jian, Kelly, Jennifer A, Hughes, Travis, Adler, Adam, Sanchez, Elena, Ojwang, Joshua O, Langefeld, Carl D, Ziegler, Julie T, Williams, Adrienne H, Comeau, Mary E, Marion, Miranda C, Glenn, Stuart B, Cantor, Rita M, Grossman, Jennifer M, Hahn, Bevra H, Song, Yeong Wook, Yu, Chack-Yung, James, Judith A, Guthridge, Joel M, Brown, Elizabeth E, Alarcón, Graciela S, Kimberly, Robert P, Edberg, Jeffrey C, Ramsey-Goldman, Rosalind, Petri, Michelle A, Reveille, John D, Vilá, Luis M, Anaya, Juan-Manuel, Boackle, Susan A, Stevens, Anne M, Freedman, Barry I, Criswell, Lindsey A, Group, Bernardo A Pons-Estel on behalf of the Argentine Collaborative, Lee, Joo-Hyun, Lee, Ji-Seon, Chang, Deh-Ming, Scofield, R Hal A, Gilkeson, Gary S, Merrill, Joan T, Niewold, Timothy B, Vyse, Timothy James, Bae, Sang-Cheol, network, Marta E Alarcón-Riquelme on behalf of the BIOLUPUS, Jacob, Chaim O, Sivils, Kathy Moser, Gaffney, Patrick M, Harley, John B, Sawalha, Amr H, and Tsao, Betty P

Subjects
Human Genome, Autoimmune Disease, Lupus, Genetics, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Base Sequence, Chromosome Mapping, Chromosomes, Human, X, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Interleukin-1 Receptor-Associated Kinases, Lupus Erythematosus, Systemic, Methyl-CpG-Binding Protein 2, Molecular Sequence Data, Polymorphism, Single Nucleotide, Racial Groups, Real-Time Polymerase Chain Reaction, Risk Factors, Argentine Collaborative Group, BIOLUPUS network, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology
Abstract

ObjectivesThe Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE.MethodsWe fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups.ResultsMultiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p

Published
2013

19. Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus

Author

Adrianto, Indra, Wang, Shaofeng, Wiley, Graham B, Lessard, Christopher J, Kelly, Jennifer A, Adler, Adam J, Glenn, Stuart B, Williams, Adrienne H, Ziegler, Julie T, Comeau, Mary E, Marion, Miranda C, Wakeland, Benjamin E, Liang, Chaoying, Kaufman, Kenneth M, Guthridge, Joel M, Alarcón‐Riquelme, Marta E, Networks, BIOLUPUS and GENLES, Alarcón, Graciela S, Anaya, Juan‐Manuel, Bae, Sang‐Cheol, Kim, Jae‐Hoon, Bin Joo, Young, Boackle, Susan A, Brown, Elizabeth E, Petri, Michelle A, Ramsey‐Goldman, Rosalind, Reveille, John D, Vilá, Luis M, Criswell, Lindsey A, Edberg, Jeffrey C, Freedman, Barry I, Gilkeson, Gary S, Jacob, Chaim O, James, Judith A, Kamen, Diane L, Kimberly, Robert P, Martín, Javier, Merrill, Joan T, Niewold, Timothy B, Pons‐Estel, Bernardo A, Scofield, R Hal, Stevens, Anne M, Tsao, Betty P, Vyse, Timothy J, Langefeld, Carl D, Harley, John B, Wakeland, Edward K, Moser, Kathy L, Montgomery, Courtney G, and Gaffney, Patrick M

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Human Genome, Lupus, Autoimmune Disease, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Adaptor Proteins, Signal Transducing, Black or African American, Asian, B-Lymphocytes, Cell Line, Transformed, DNA-Binding Proteins, Female, Genetic Markers, Genetic Predisposition to Disease, Haplotypes, Hispanic or Latino, Humans, Intracellular Signaling Peptides and Proteins, Lupus Erythematosus, Systemic, Male, Neoplasm Proteins, Polymorphism, Single Nucleotide, Risk Factors, United States, White People, BIOLUPUS and GENLES Networks, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway.MethodsWe analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively.ResultsWe found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression.ConclusionOur results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.

Published
2012

20. Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian–European populations

Author

Sánchez, Elena, Rasmussen, Astrid, Riba, Laura, Acevedo‐Vasquez, Eduardo, Kelly, Jennifer A, Langefeld, Carl D, Williams, Adrianne H, Ziegler, Julie T, Comeau, Mary E, Marion, Miranda C, La Torre, Ignacio García‐De, Maradiaga‐Ceceña, Marco A, Cardiel, Mario H, Esquivel‐Valerio, Jorge A, Rodriguez‐Amado, Jacqueline, Moctezuma, José Francisco, Miranda, Pedro, Perandones, Carlos E, Castel, Cecilia, Laborde, Hugo A, Alba, Paula, Musuruana, Jorge L, Goecke, I Annelise, Anaya, Juan‐Manuel, Kaufman, Kenneth M, Adler, Adam, Glenn, Stuart B, Brown, Elizabeth E, Alarcón, Graciela S, Kimberly, Robert P, Edberg, Jeffrey C, Vilá, Luis M, Criswell, Lindsey A, Gilkeson, Gary S, Niewold, Timothy B, Martín, Javier, Vyse, Timothy J, Boackle, Susan A, Ramsey‐Goldman, Rosalind, Scofield, R Hal, Petri, Michelle, Merrill, Joan T, Reveille, John D, Tsao, Betty P, Orozco, Lorena, Baca, Vicente, Moser, Kathy L, Gaffney, Patrick M, James, Judith A, Harley, John B, Tusié‐Luna, Teresa, Pons‐Estel, Bernardo A, Jacob, Chaim O, and Alarcón‐Riquelme, Marta E

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Health Sciences, Genetics, Autoimmune Disease, Clinical Research, Lupus, Kidney Disease, American Indian or Alaska Native, Inflammatory and immune system, Adolescent, Adult, Child, Female, Genetic Predisposition to Disease, Genotype, Humans, Indians, North American, Indians, South American, Lupus Erythematosus, Systemic, Lupus Nephritis, Male, Middle Aged, Morbidity, Prevalence, Risk Factors, Socioeconomic Factors, White People, Young Adult, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveAmerican Indian-Europeans, Asians, and African Americans have an excess morbidity from systemic lupus erythematosus (SLE) and a higher prevalence of lupus nephritis than do Caucasians. The aim of this study was to analyze the relationship between genetic ancestry and sociodemographic characteristics and clinical features in a large cohort of American Indian-European SLE patients.MethodsA total of 2,116 SLE patients of American Indian-European origin and 4,001 SLE patients of European descent for whom we had clinical data were included in the study. Genotyping of 253 continental ancestry-informative markers was performed on the Illumina platform. Structure and Admixture software were used to determine genetic ancestry proportions of each individual. Logistic regression was used to test the association between genetic ancestry and sociodemographic and clinical characteristics. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs).ResultsThe average American Indian genetic ancestry of 2,116 SLE patients was 40.7%. American Indian genetic ancestry conferred increased risks of renal involvement (P < 0.0001, OR 3.50 [95% CI 2.63- 4.63]) and early age at onset (P < 0.0001). American Indian ancestry protected against photosensitivity (P < 0.0001, OR 0.58 [95% CI 0.44-0.76]), oral ulcers (P < 0.0001, OR 0.55 [95% CI 0.42-0.72]), and serositis (P < 0.0001, OR 0.56 [95% CI 0.41-0.75]) after adjustment for age, sex, and age at onset. However, age and sex had stronger effects than genetic ancestry on malar rash, discoid rash, arthritis, and neurologic involvement.ConclusionIn general, American Indian genetic ancestry correlates with lower sociodemographic status and increases the risk of developing renal involvement and SLE at an earlier age.

Published
2012

21. Evaluation of TRAF6 in a large multiancestral lupus cohort

Author

Namjou, Bahram, Choi, Chan‐Bum, Harley, Isaac TW, Alarcón‐Riquelme, Marta E, Network, BIOLUPUS, Kelly, Jennifer A, Glenn, Stuart B, Ojwang, Joshua O, Adler, Adam, Kim, Kwangwoo, Gallant, Caroline J, Boackle, Susan A, Criswell, Lindsey A, Kimberly, Robert P, Brown, Elizabeth E, Edberg, Jeffrey, Alarcón, Graciela S, Stevens, Anne M, Jacob, Chaim O, Gilkeson, Gary S, Kamen, Diane L, Tsao, Betty P, Anaya, Juan‐Manuel, Kim, Eun‐Mi, Park, So‐Yeon, Sung, Yoon‐Kyoung, Guthridge, Joel M, Merrill, Joan T, Petri, Michelle, Ramsey‐Goldman, Rosalind, Vilá, Luis M, Niewold, Timothy B, Martin, Javier, Pons‐Estel, Bernardo A, Network, Genoma en Lupus, Vyse, Timothy J, Freedman, Barry I, Moser, Kathy L, Gaffney, Patrick M, Williams, Adrienne H, Comeau, Mary E, Reveille, John D, Kang, Changwon, James, Judith A, Scofield, R Hal, Langefeld, Carl D, Kaufman, Kenneth M, Harley, John B, and Bae, Sang‐Cheol

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Lupus, Clinical Research, Arthritis, Autoimmune Disease, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Alleles, Case-Control Studies, Cohort Studies, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Lupus Erythematosus, Systemic, Male, Polymorphism, Single Nucleotide, TNF Receptor-Associated Factor 6, BIOLUPUS Network, Genoma en Lupus Network, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveSystemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development.MethodsFifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated.ResultsEvidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 × 10(-5) and P = 4.73 × 10(-5) , respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r(2) = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 × 10(-4) , OR 0.89 [95% CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 × 10(-6) , OR 0.57 [95% CI 0.45-0.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model.ConclusionOur data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.

Published
2012

22. A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap.

Author

Ramos, Paula S, Criswell, Lindsey A, Moser, Kathy L, Comeau, Mary E, Williams, Adrienne H, Pajewski, Nicholas M, Chung, Sharon A, Graham, Robert R, Zidovetzki, Raphael, Kelly, Jennifer A, Kaufman, Kenneth M, Jacob, Chaim O, Vyse, Timothy J, Tsao, Betty P, Kimberly, Robert P, Gaffney, Patrick M, Alarcón-Riquelme, Marta E, Harley, John B, Langefeld, Carl D, and International Consortium on the Genetics of Systemic Erythematosus

Subjects
International Consortium on the Genetics of Systemic Erythematosus, Humans, Arthritis, Rheumatoid, Colitis, Ulcerative, Crohn Disease, Lupus Erythematosus, Systemic, Diabetes Mellitus, Type 1, Autoimmune Diseases, Genetic Predisposition to Disease, Receptors, Interleukin, Case-Control Studies, Cohort Studies, Polymorphism, Single Nucleotide, European Continental Ancestry Group, OX40 Ligand, Interleukin-2 Receptor alpha Subunit, Genome-Wide Association Study, Genetic Pleiotropy, V-Set Domain-Containing T-Cell Activation Inhibitor 1, Arthritis, Rheumatoid, Colitis, Ulcerative, Lupus Erythematosus, Systemic, Diabetes Mellitus, Type 1, Receptors, Interleukin, Polymorphism, Single Nucleotide, Genetics, Developmental Biology
Abstract

In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non-Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, P = 2.02×10(-06)) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohn's disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non-MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases.

Published
2011

27. Characterization of Human Telomerase Complex

Author

Ramakrishnan, Shyam, Sharma, Harsh W., Farris, A. Darise, Kaufman, Kenneth M., Harley, John B., Collins, Kathleen, Van Venrooij, Walther J., Martin, Mitchell L., and Narayanan, Ramaswamy

Published
1997

28. HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

Author

British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group, Childhood Arthritis Prospective Study (CAPS) Group, Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators, Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group, Biologically Based Outcome Predictors in JIA (BBOP) Group, International Childhood Arthritis Genetics (INCHARGE) Consortium, Ombrello, Michael J., Remmers, Elaine F., Tachmazidou, Ioanna, Grom, Alexei, Foell, Dirk, Haas, Johannes-Peter, Martini, Alberto, Gattorno, Marco, Özen, Seza, Prahalad, Sampath, Zeft, Andrew S., Bohnsack, John F., Mellins, Elizabeth D., Ilowite, Norman T., Russo, Ricardo, Len, Claudio, Hilario, Maria Odete E., Oliveira, Sheila, Yeung, Rae S.M., Rosenberg, Alan, Wedderburn, Lucy R., Anton, Jordi, Schwarz, Tobias, Hinks, Anne, Bilginer, Yelda, Park, Jane, Cobb, Joanna, Satorius, Colleen L., Han, Buhm, Baskin, Elizabeth, Signa, Sara, Duerr, Richard H., Achkar, J. P., Kamboh, M. Ilyas, Kaufman, Kenneth M., Kottyan, Leah C., Pinto, Dalila, Scherer, Stephen W., Alarcón-Riquelme, Marta E., Docampo, Elisa, Estivill, Xavier, Gül, Ahmet, de Bakker, Paul I. W., Raychaudhuri, Soumya, Langefeld, Carl D., Thompson, Susan, Zeggini, Eleftheria, Thomson, Wendy, Kastner, Daniel L., and Woo, Patricia

Published
2015

29. 1401 A Genome Wide Association Scan of SLE genetic risk in a cohort of African-American persons

Author

Harley, Isaac TW, primary, Sun, Celi, additional, Williams, Adrienne H, additional, Ziegler, Julie T, additional, Comeau, Mary E, additional, Marion, Miranda C, additional, Glenn, Stuart B, additional, Adler, Adam, additional, Frank-Pearce, Summer G, additional, Shen, Nan, additional, Kelly, Jennifer A, additional, Namjou-Khales, Bahram, additional, Petri, Michelle, additional, Alarcon-Riquelme, Marta, additional, Joseph McCune, W, additional, Gaffney, Patrick, additional, Sivils, Kathy, additional, Salmon, Jane E, additional, Weisman, Michael H, additional, Edberg, Jeffrey C, additional, Brown, Elizabeth E, additional, Utset, Tammy, additional, Criswell, Lindsey A, additional, Jacob, Chaim O, additional, Tsao, Betty, additional, Vyse, Timothy J, additional, James, Judith A, additional, Gilkeson, Gary S, additional, Kamen, Diane L, additional, Montgomery, Courtney, additional, Merrill, Joan T, additional, Nath, Swapan K, additional, Laurynenka, Viktoryia, additional, Chepelev, Iouri, additional, Harris-Lewis, Valerie, additional, Hal Scofield, R, additional, Kimberly, Robert P, additional, Langefeld, Carl D, additional, Harley, John B, additional, and Kaufman, Kenneth M, additional

Published
2022
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30. The US Department of Veterans Affairs Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD): A Biorepository Addressing National Health Threats

Author

Harley, John B, primary, Pyarajan, Saiju, additional, Partan, Elizabeth S, additional, Epstein, Lauren, additional, Wertheim, Jason A, additional, Diwan, Abhinav, additional, Woods, Christopher W, additional, Davey, Victoria, additional, Blair, Sharlene, additional, Clark, Dennis H, additional, Kaufman, Kenneth M, additional, Khan, Shagufta, additional, Chepelev, Iouri, additional, Devine, Alexander, additional, Cameron, Perry, additional, McCann, Monica F, additional, Ammons, Mary Cloud B, additional, Bolz, Devin D, additional, Battles, Jane K, additional, Curtis, Jeffrey L, additional, Holodniy, Mark, additional, Marconi, Vincent C, additional, Searles, Charles D, additional, Beenhouwer, David O, additional, Brown, Sheldon T, additional, Moorman, Jonathan P, additional, Yao, Zhi Q, additional, Rodriguez-Barradas, Maria C, additional, Mohapatra, Shyam, additional, Molina De Rodriguez, Osmara Y, additional, Padiernos, Emerson B, additional, McIndoo, Eric R, additional, Price, Emily, additional, Burgoyne, Hailey M, additional, Robey, Ian, additional, Schwenke, Dawn C, additional, Shive, Carey L, additional, Przygodzki, Ronald M, additional, Ramoni, Rachel B, additional, Krull, Holly K, additional, and Bonomo, Robert A, additional

Published
2022
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32. Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase

Author

Jacob, Chaim O., Eisenstein, Miriam, Dinauer, Mary C., Ming, Wenyu, Liu, Qiang, John, Sutha, Quismorio,, Francesco P., Reiff, Andreas, Myones, Barry L., Kaufman, Kenneth M., McCurdy, Deborah, Harley, John B., Silverman, Earl, Kimberly, Robert P., Vyse, Timothy J., Gaffney, Patrick M., Moser, Kathy L., Klein-Gitelman, Marisa, Wagner-Weiner, Linda, Langefeld, Carl D., Armstrong, Don L., and Zidovetzki, Raphael

Published
2012

33. Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus

Author

Shen, Nan, Fu, Qiong, Deng, Yun, Qian, Xiaoxia, Zhao, Jian, Kaufman, Kenneth M., Wu, Yee Ling, Yu, C. Yung, Tang, Yuanjia, Chen, Ji-Yih, Yang, Wanling, Wong, Maida, Kawasaki, Aya, Tsuchiya, Naoyuki, Sumida, Takayuki, Kawaguchi, Yasushi, Howe, Hwee Siew, Mok, Mo Yin, Bang, So-Young, Liu, Fei-Lan, Chang, Deh-Ming, Takasaki, Yoshinari, Hashimoto, Hiroshi, Harley, John B., Guthridge, Joel M., Grossman, Jennifer M., Cantor, Rita M., Song, Yeong Wook, Bae, Sang-Cheol, Chen, Shunle, Hahn, Bevra H., Lau, Yu Lung, Tsao, Betty P., and Smith, Kenneth G. C.

Published
2010

34. Identification of IRAK1 as a Risk Gene with Critical Role in the Pathogenesis of Systemic Lupus Erythematosus

Author

Jacob, Chaim O., Zhu, Jiankun, Armstrong, Don L., Yan, Mei, Han, Jie, Zhou, Xin J., Thomas, James A., Reiff, Andreas, Myones, Barry L., Ojwang, Joshua O., Kaufman, Kenneth M., Klein-Gitelman, Marisa, McCurdy, Deborah, Wagner-Weiner, Linda, Silverman, Earl, Ziegler, Julie, Kelly, Jennifer A., Merrill, Joan T., Harley, John B., Ramsey-Goldman, Rosalind, Vila, Luis M., Bae, Sang-Cheol, Vyse, Timothy J., Gilkeson, Gary S., Gaffney, Patrick M., Moser, Kathy L., Langefeld, Carl D., Zidovetzki, Raphael, Mohan, Chandra, and Vitetta, Ellen S.

Published
2009
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36. 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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38. Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture

Author

Alarcón-Riquelme, Marta E., Ziegler, Julie T., Molineros, Julio, Howard, Timothy D., Moreno-Estrada, Andrés, Sánchez-Rodríguez, Elena, Ainsworth, Hannah C., Ortiz-Tello, Patricia, Comeau, Mary E., Rasmussen, Astrid, Kelly, Jennifer A., Adler, Adam, Acevedo-Vázquez, Eduardo M., Mariano Cucho-Venegas, Jorge, García-De la Torre, Ignacio, Cardiel, Mario H., Miranda, Pedro, Catoggio, Luis J., Maradiaga-Ceceña, Marco, Gaffney, Patrick M., Vyse, Timothy J., Criswell, Lindsey A., Tsao, Betty P., Sivils, Kathy L., Bae, Sang-Cheol, James, Judith A., Kimberly, Robert P., Kaufman, Kenneth M., Harley, John B., Esquivel-Valerio, Jorge A., Moctezuma, José F., García, Mercedes A., Berbotto, Guillermo A., Babini, Alejandra M., Scherbarth, Hugo, Toloza, Sergio, Baca, Vicente, Nath, Swapan K., Aguilar Salinas, Carlos, Orozco, Lorena, Tusié-Luna, Teresa, Zidovetzki, Raphael, Pons-Estel, Bernardo A., Langefeld, Carl D., and Jacob, Chaim O.

Published
2016
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39. Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA

Author

Zhao, Jian, Giles, Brendan M, Taylor, Rhonda L, Yette, Gabriel A, Lough, Kara M, Ng, Han Leng, Abraham, Lawrence J, Wu, Hui, Kelly, Jennifer A, Glenn, Stuart B, Adler, Adam J, Williams, Adrienne H, Comeau, Mary E, Ziegler, Julie T, Marion, Miranda, Alarcón-Riquelme, Marta E, Alarcón, Graciela S, Anaya, Juan-Manuel, Bae, Sang-Cheol, Kim, Dam, Lee, Hye-Soon, Criswell, Lindsey A, Freedman, Barry I, Gilkeson, Gary S, Guthridge, Joel M, Jacob, Chaim O, James, Judith A, Kamen, Diane L, Merrill, Joan T, Sivils, Kathy Moser, Niewold, Timothy B, Petri, Michelle A, Ramsey-Goldman, Rosalind, Reveille, John D, Scofield, R Hal, Stevens, Anne M, Vilá, Luis M, Vyse, Timothy J, Kaufman, Kenneth M, Harley, John B, Langefeld, Carl D, Gaffney, Patrick M, Brown, Elizabeth E, Edberg, Jeffrey C, Kimberly, Robert P, Ulgiati, Daniela, Tsao, Betty P, and Boackle, Susan A

Published
2016
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46. CRISPRa screen on a genetic risk locus shared by multiple autoimmune diseases identifies a dysfunctional enhancer that affects IRF8 expression through cooperative lncRNA and DNA methylation machinery

Author

Zhou, Tian, primary, Zhu, Xinyi, additional, Ye, Zhizhong, additional, Wang, Yongfei, additional, Yao, Chao, additional, Xu, Ning, additional, Zhou, Mi, additional, Ma, Jianyang, additional, Qin, Yuting, additional, Shen, Yiwei, additional, Tang, Yuanjia, additional, Yin, Zhihua, additional, Xu, Hong, additional, Zhang, Yutong, additional, Zang, Xiaoli, additional, Ding, Huihua, additional, Yang, Wanling, additional, Guo, Ya, additional, Harley, John B., additional, Namjou, Bahram, additional, Kaufman, Kenneth M., additional, Kottyan, Leah C., additional, Weirauch, Matthew T., additional, Hou, Guojun, additional, and Shen, Nan, additional

Published
2021
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47. Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations

Author

Kim-Howard, Xana, Sun, Celi, Molineros, Julio E., Maiti, Amit K., Chandru, Hema, Adler, Adam, Wiley, Graham B., Kaufman, Kenneth M., Kottyan, Leah, Guthridge, Joel M., Rasmussen, Astrid, Kelly, Jennifer, Sánchez, Elena, Raj, Prithvi, Li, Quan-Zhen, Bang, So-Young, Lee, Hye-Soon, Kim, Tae-Hwan, Kang, Young Mo, Suh, Chang-Hee, Chung, Won Tae, Park, Yong-Beom, Choe, Jung-Yoon, Shim, Seung Cheol, Lee, Shin-Seok, Han, Bok-Ghee, Olsen, Nancy J., Karp, David R., Moser, Kathy, Pons-Estel, Bernardo A., Wakeland, Edward K., James, Judith A., Harley, John B., Bae, Sang-Cheol, Gaffney, Patrick M., Alarcón-Riquelme, Marta, Acevedo, Eduardo, La Torre, Ignacio García-De, Maradiaga-Ceceña, Marco A., Cardiel, Mario H., Esquivel-Valerio, Jorge A., Rodriguez-Amado, Jacqueline, Moctezuma, José Francisco, Miranda, Pedro, Perandones, Carlos, Aires, Buenos, Castel, Cecilia, Laborde, Hugo A., Alba, Paula, Musuruana, Jorge, Goecke, Annelise, Foster, Carola, Orozco, Lorena, Baca, Vicente, Looger, Loren L., and Nath, Swapan K.

Published
2014
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49. Proteasome degradation of GRK2 during ischemia and ventricular tachyarrhythmias in a canine model of myocardial infarction

Author

Yu, Xichun, Huang, shijun, Patterson, Eugene, Garrett, Marion W., Kaufman, Kenneth M., Metcalf, Jordan P., Zhu, Meili, Dunn, Samuel T., and Kem, David C.

Subjects
Cardiac arrest -- Research, Arrhythmia -- Research, Heart attack -- Research, G proteins, Biological sciences
Abstract

Arrhythmia-prone subepicardial border zone (EBZ) tissue demonstrates decreased G protein receptor kinase 2 (GRK2) activity and increased sensitivity to isoproterenol 6-24 h after coronary artery ligation (CAL) in the dog. With the use of a semiquantitative immunofluorescence technique, the relative fluorescence intensity (RF) of GRK2 in EBZ decreased to 24% of that in a remote site (RS) (P < 0.01, n = 30 cells from 3 dogs), whereas GRK5 RF did not change. Confocal studies of cardiac tissue from transgenic mice overexpressing GRK2 validated the use of a semilogarithmic relationship between RF and GRK2 activity. As shown with the use of quantitative real-time RT-PCR, both GRK2 and GRK5 mRNA were not decreased at 24 h in EBZ (n = 6 dogs) relative to RS control, indicating that the decrease of GRK2 in the EBZ is likely due to posttranscriptional degradation following CAL. Pretreatment of six dogs with the selective proteasome inhibitor bortezomib provided 100% (EBZ) and 50% (infarct) protection against loss of GRK2 at 24 h. There was an absence of rapid (>300 beats/min) and very rapid (>360 beats/min) ventricular triplets that are highly predictive of sudden cardiac death during ECG monitoring in the bortezomib-pretreated animals in contrast to nonpretreated infarcted animals. We have demonstrated that the dramatic decrease in GRK2 in cardiac ischemic tissue can bc largely blocked by prior proteasome blockade and that this is associated with significant cardioprotection against malignant ventricular tachyarrhythmias. [beta]-adrenergic receptor; G protein receptor kinase 2; sudden cardiac death; ventricular arrhythmias; immunofluorescence microscopy

Published
2005

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