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1.  Proceedings of the 2016 Childhood Arthritis and Rheumatology Research Alliance (CARRA) Scientific Meeting 
Fotis, Lampros | Shaikh, Nur | Baszis, Kevin | French, Anthony | Tarr, Phillip | Grevich, Sriharsha | Lee, Peggy | Ringold, Sarah | Leroux, Brian | Leahey, Hannah | Yuasa, Megan | Foster, Jessica | Sokolove, Jeremy | Lahey, Lauren | Robinson, William | Newsom, Joshua | Stevens, Anne | Karasawa, Rie | Tamaki, Mayumi | Tanaka, Megumi | Sato, Toshiko | Yudoh, Kazuo | Jarvis, James N. | Moncrieffe, Halima | Bennett, Mark F. | Tsoras, Monica | Luyrink, Lorie | Xu, Huan | Prahalad, Sampath | Morris, Paula | Dare, Jason | Nigrovic, Peter A. | Rosenkranz, Margalit | Becker, Mara | O’Neil, Kathleen M. | Griffin, Thomas | Lovell, Daniel J. | Grom, Alexei A. | Medvedovic, Mario | Thompson, Susan D. | Zhu, Lisha | Jiang, Kaiyu | Wong, Laiping | Buck, Michael J | Chen, Yanmin | Moncrieffe, Halima | Brungs, Laura | Liu, Tao | Wang, Ting | Jarvis, James N | Alsaeid, Khaled | Alfailakawi, Jasim | Alenezi, Hamid | Alsaeed, Hazim | Beukelman, Tim | Natter, Marc | Ilowite, Norm | Mieszkalski, Kelly | Burrell, Grendel | Best, Brian | Bristow, Helen | Carr, Shannon | Dennos, Anne | Kaufmann, Rachel | Kimura, Yukiko | Schanberg, Laura | Blier, Peter R. | Boneparth, Alexis | Wenderfer, Scott E. | Moorthy, L. Nandini | Radhakrishna, Suhas M. | Sagcal-Gironella, Anna Carmela P. | von Scheven, Emily | Gedik, Kader Cetin | Siddique, Salma | Aguiar, Cassyanne L. | Erkan, Doruk | Cohen, Ezra | Lee, Yvonne | Dossett, Michelle | Mehta, Darshan | Davis, Roger | Gilbert, Mileka | Goilav, Beatrice | Meidan, Esra | Hsu, Joyce | Boneparth, Alexis | Chua, Anabelle | Ardoin, Stacy | Wenderfer, Scott E. | Von Scheven, Emily | Ruth, Natasha M. | Hui-Yuen, Joyce | Gedik, Kader Cetin | Bermudez, Liza | Cook, Ashlea | Imundo, Lisa | Starr, Amy | Eichenfield, Andrew | Askanase, Anca | Janow, Ginger | Schanberg, Laura E. | Setoguchi, Soko | Hasselblad, Victor | Mellins, Elizabeth D. | Schneider, Rayfel | Kimura, Yukiko | Kimura, Yukiko | Grevich, Sriharsha | Beukelman, Timothy | Morgan, Esi | Graham, T. Brent | Ibarra, Maria | Ruas, Yonit Sterba | Klein-Gitelman, Marisa | Onel, Karen | Prahalad, Sampath | Punaro, Marilynn | Ringold, Sarah | Toib, Dana | Van Mater, Heather | Weiss, Jennifer E. | Weiss, Pamela F. | Mieszkalski, Kelly | Schanberg, Laura E. | Kwok, Timothy S. H. | Bisaillon, Jacinthe | Smith, Christine | Brosseau, Lucie | Stinson, Jennifer | Huber, Adam M. | Duffy, Ciaran M. | April, Karine Toupin | Lewandowski, Laura B. | Scott, Christiaan | Li, Suzanne C. | Torok, Kathryn S. | Rabinovich, C. Egla | Hong, Sandy D. | Becker, Mara L | Dedeoglu, Fatma | Ibarra, Maria F. | Ferguson, Polly J | Fuhbrigge, Rob C. | Stewart, Katie G. | Pope, Elena | Laxer, Ronald M. | Mason, Thomas G. | Higgins, Gloria C. | Li, Xiaohu | Punaro, Marilynn G. | Tomlinson, George | Pullenayegum, Eleanor | Matelski, John | Schanberg, Laura | Feldman, Brian M. | Manthiram, Kalpana | Correa, Hernan | Edwards, Kathryn | Oberle, Edward J. | Bayer, Michelle | Co, Dominic O. | Baris, Hatice Ezgi | Chiu, Yvonne | Huber, Adam | Kim, Susan | Oberle, Edward J. | Beukelman, Timothy | Orandi, Amir B. | Baszis, Kevin W. | Dharnidharka, Vikas | Hoeltzel, Mark F. | Reed, Ann | Huber, Adam | Tomlinson, George | Pullenayegum, Eleanor | Matelski, John | Goh, Y. Ingrid | Schanberg, Laura | Feldman, Brian M. | Schnabel, Anja | Range, Ursula | Hahn, Gabriele | Siepmann, Timo | Berner, Reinhard | Hedrich, Christian Michael | Stevens, Brandi | Torok, Kathryn S. | Li, Suzanne | Hershey, Nicole | Curran, Megan | Higgins, Gloria | Moore, Katharine | Rabinovich, Egla | Stevens, Anne M. | Stinson, Jennifer | Connelly, Mark | Huber, Adam | Luca, Nadia | Spiegel, Lynn | Tsimicalis, Argerie | Luca, Stephanie | Tajuddin, Naweed | Berard, Roberta | Barsalou, Julia | Campillo, Sarah | Dancey, Paul | Duffy, Ciaran | Feldman, Brian | Johnson, Nicole | McGrath, Patrick | Shiff, Natalie | Tse, Shirley | Tucker, Lori | Victor, Charles | Stinson, Jennifer | Lalloo, Chitra | Harris, Lauren | Cafazzo, Joseph | Spiegel, Lynn | Feldman, Brian | Luca, Nadia | Laxer, Ronald | Bullock, Danielle R. | Vehe, Richard K. | Zhang, Lei | Correll, Colleen K. | Ganguli, Suhas | Shenberger, Max | Korumilli, Ritesh | Gottlieb, Beth | Rodriguez, Martha | de Ranieri, Deirdre | Onel, Karen | Wagner-Weiner, Linda | Tesher, Melissa | Wojcicki, Elizabeth Roth | Maletta, Kristyn L. | Co, Dominic O. | Malloy, Marsha | Thomson, Sarah | Olson, Judyann C. | Wenderfer, Scott E. | Gilbert, Mileka | Hsu, Joyce | Sule, Sangeeta | Rubinstein, Tamar B. | Goilav, Beatrice | Okamura, Daryl M. | Chua, Annabelle | Greenbaum, Laurence A. | Lane, Jerome C. | von Scheven, Emily | Ardoin, Stacy P. | Ruth, Natasha M. | Woo, Jennifer M. P. | Malloy, Marsha M. | Jegers, James A. | Hahn, Dustin J. | Hintermeyer, Mary K. | Martinetti, Stacey M. | Heckel, Gretchen R. | Roth-Wojcicki, Elizabeth L. | Co, Dominic O.
Table of Contents
P1 Serologic evidence of gut-driven systemic inflammation in juvenile idiopathic arthritis
Lampros Fotis, Nur Shaikh, Kevin Baszis, Anthony French, Phillip Tarr
P2 Oral health and anti-citrullinated peptide antibodies (ACPA) in juvenile idiopathic arthritis
Sriharsha Grevich, Peggy Lee, Sarah Ringold, Brian Leroux, Hannah Leahey, Megan Yuasa, Jessica Foster, Jeremy Sokolove, Lauren Lahey, William Robinson, Joshua Newsom, Anne Stevens
P3 Novel autoantigens for endothelial cell antibodies in pediatric rheumatic diseases identified by proteomics
Rie Karasawa, Mayumi Tamaki, Megumi Tanaka, Toshiko Sato, Kazuo Yudoh, James N. Jarvis
P4 Transcriptional profiling reveals monocyte signature associated with JIA patient poor response to methotrexate
Halima Moncrieffe, Mark F. Bennett, Monica Tsoras, Lorie Luyrink, Huan Xu, Sampath Prahalad, Paula Morris, Jason Dare, Peter A. Nigrovic, Margalit Rosenkranz, Mara Becker, Kathleen M. O’Neil, Thomas Griffin, Daniel J. Lovell, Alexei A. Grom, Mario Medvedovic, Susan D. Thompson
P5 A multi-dimensional genomic map for polyarticular juvenile idiopathic arthritis
Lisha Zhu, Kaiyu Jiang, Laiping Wong, Michael J Buck, Yanmin Chen, Halima Moncrieffe, Laura Brungs, Tao Liu, Ting Wang, James N Jarvis
P6 Tocilizumab for treatment of children with refractory JIA
Khaled Alsaeid, Jasim Alfailakawi, Hamid Alenezi, Hazim Alsaeed
P7 Clinical characteristics of the initial patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry
Tim Beukelman, Marc Natter, Norm Ilowite, Kelly Mieszkalski, Grendel Burrell, Brian Best, Helen Bristow, Shannon Carr, Anne Dennos, Rachel Kaufmann, Yukiko Kimura, Laura Schanberg
P8 Comparative performance of small and large clinical centers in a comprehensive pediatric rheumatology disease registry
Peter R Blier
P9 Clinical characteristics of children with membranous lupus nephritis: The Childhood Arthritis and Rheumatology Research Alliance Legacy Registry
Alexis Boneparth, Scott E. Wenderfer, L. Nandini Moorthy, Suhas M. Radhakrishna, Anna Carmela P. Sagcal-Gironella, Emily von Scheven
P10 Rituximab use in pediatric lupus anticoagulant hypoprothrombinemia syndrome - a two center experience
Kader Cetin Gedik, Salma Siddique, Cassyanne L. Aguiar, Doruk Erkan
P11 Predictors of complementary and alternative medicine use and response in children with musculoskeletal conditions
Ezra Cohen, Yvonne Lee, Michelle Dossett, Darshan Mehta, Roger Davis
P12 Comparison of pediatric rheumatology and nephrology survey results for the treatment of refractory proliferative lupus nephritis and renal flare in juvenile SLE
Mileka Gilbert, Beatrice Goilav, Esra Meidan, Joyce Hsu, Alexis Boneparth, Anabelle Chua, Stacy Ardoin, Scott E. Wenderfer, Emily Von Scheven, Natasha M. Ruth
P13 Transitioning lupus patients from pediatric to adult rheumatology
Joyce Hui-Yuen, Kader Cetin Gedik, Liza Bermudez, Ashlea Cook, Lisa Imundo, Amy Starr, Andrew Eichenfield, Anca Askanase
P14 The systemic juvenile idiopathic arthritis cohort of the Childhood Arthritis & Rheumatology Research Alliance Registry
Ginger Janow, Laura E. Schanberg, Soko Setoguchi, Victor Hasselblad, Elizabeth D. Mellins, Rayfel Schneider, Yukiko Kimura, The CARRA Legacy Registry Investigators
P15 Results of the pilot study of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans for new-onset systemic juvenile idiopathic arthritis
Yukiko Kimura, Sriharsha Grevich, Timothy Beukelman, Esi Morgan, T Brent Graham, Maria Ibarra, Yonit Sterba Ruas, Marisa Klein-Gitelman, Karen Onel, Sampath Prahalad, Marilynn Punaro, Sarah Ringold, Dana Toib, Heather Van Mater, Jennifer E. Weiss, Pamela F. Weiss, Kelly Mieszkalski, Laura E. Schanberg
P16 A systemic review of pain relief modalities in juvenile idiopathic arthritis: First step in developing a novel decision support intervention
Timothy S. H. Kwok, Jacinthe Bisaillon, Christine Smith, Lucie Brosseau, Jennifer Stinson, Adam M. Huber, Ciaran M. Duffy, Karine Toupin April
P17 Barriers and facilitators to care retention for pediatric systemic lupus erythematous patients in South Africa: A qualitative study
Laura B Lewandowski, Christiaan Scott
P18 Evaluating the feasibility of conducting comparative effectiveness studies in juvenile Localized Scleroderma (jLS)
Suzanne C. Li, Kathryn S. Torok, C. Egla Rabinovich, Sandy D. Hong, Mara L Becker, Fatma Dedeoglu, Maria F. Ibarra, Polly J Ferguson, Rob C. Fuhbrigge, Katie G. Stewart, Elena Pope, Ronald M. Laxer, Thomas G. Mason, Gloria C. Higgins, Xiaohu Li, Marilynn G. Punaro, George Tomlinson, Eleanor Pullenayegum, John Matelski, Laura Schanberg, Brian M. Feldman
P19 Tonsillar histology in patients with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome
Kalpana Manthiram, Hernan Correa, Kathryn Edwards
P20 Clinical course of juvenile dermatomyositis presenting as skin predominant disease
Edward J. Oberle, Michelle Bayer, Dominic O. Co, Hatice Ezgi Baris, Yvonne Chiu, Adam Huber, Susan Kim
P21 A Survey of musculoskeletal ultrasound practices of pediatric rheumatologists in North America
Edward J Oberle, Timothy Beukelman
P22 Assessment, classification and treatment of calcinosis as a complication of juvenile dermatomyositis: A survey of pediatric rheumatologists by the Childhood Arthritis and Rheumatology Research Alliance
Amir B. Orandi, Kevin W. Baszis, Vikas Dharnidharka, Mark F. Hoeltzel, for the CARRA JDM Committee
P23 CARRA dermatomyositis CTP pilot study
Ann Reed, Adam Huber, George Tomlinson, Eleanor Pullenayegum, John Matelski, Y. Ingrid Goh, Laura Schanberg, Brian M. Feldman
P24 Unexpectedly high incidences and prolonged disease activity in children with chronic non-bacterial osteomyelitis (CNO) as compared to bacterial osteomyelitis
Anja Schnabel, Ursula Range, Gabriele Hahn, Timo Siepmann, Reinhard Berner, Christian Michael Hedrich
P25 Juvenile systemic sclerosis cohort within the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry: Follow up characteristics
Brandi Stevens, Kathryn S. Torok, Suzanne Li, Nicole Hershey, Megan Curran, Gloria Higgins, Katharine Moore, Egla Rabinovich, Anne M. Stevens, for the CARRA Registry Investigators
P26 Development and usability testing of an iPad and desktop psycho-educational game for children with Juvenile Idiopathic Arthritis and their parents
Jennifer Stinson, Mark Connelly, Adam Huber, Nadia Luca, Lynn Spiegel, Argerie Tsimicalis, Stephanie Luca, Naweed Tajuddin, Roberta Berard, Julia Barsalou, Sarah Campillo, Paul Dancey, Ciaran Duffy, Brian Feldman, Nicole Johnson, Patrick McGrath, Natalie Shiff, Shirley Tse, Lori Tucker, Charles Victor
P27 iCanCopeTM: User-centred design and development of a smartphone app to support self-management for youth with arthritis pain
Jennifer Stinson, Chitra Lalloo, Lauren Harris, Joseph Cafazzo, Lynn Spiegel, Brian Feldman, Nadia Luca, Ronald Laxer
P28 Accessing pediatric rheumatology care: Despite barriers, few parents prefer telemedicine
Danielle R. Bullock, Richard K. Vehe, Lei Zhang, Colleen K. Correll1
P29 Exploration of factors contributing to time to achieve clinically inactive disease (CID) in juvenile idiopathic arthritis (JIA): A preliminary report
Suhas Ganguli, Max Shenberger, Ritesh Korumilli, Beth Gottlieb
P30 Pediatric rheumatology referral patterns: Presenting complaints of new patients at a large, urban academic center
Martha Rodriguez, Deirdre de Ranieri, Karen Onel, Linda Wagner-Weiner, Melissa Tesher
P31 Quality improvement (QI) initiatives in childhood systemic lupus erythematosus (cSLE)
Elizabeth Roth Wojcicki, Kristyn L. Maletta, Dominic O. Co, Marsha Malloy, Sarah Thomson, Judyann C. Olson
P32 Proliferative lupus nephritis in juvenile SLE: Support from the pediatric nephrology community for the definitions of responsiveness and flare in the 2012 consensus treatment plans
Scott E. Wenderfer, Mileka Gilbert, Joyce Hsu, Sangeeta Sule, Tamar B. Rubinstein, Beatrice Goilav, Daryl M. Okamura, Annabelle Chua, Laurence A. Greenbaum, Jerome C. Lane, Emily von Scheven, Stacy P. Ardoin, Natasha M. Ruth
P33 The steroid taper app: Making of a mobile app
Jennifer M. P. Woo, Marsha M. Malloy, James A. Jegers, Dustin J. Hahn, Mary K. Hintermeyer, Stacey M. Martinetti, Gretchen R. Heckel, Elizabeth L. Roth-Wojcicki, Dominic O. Co
doi:10.1186/s12969-016-0098-0
PMCID: PMC4943514  PMID: 27409414
2.  Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus 
Clinical immunology (Orlando, Fla.)  2015;161(2):157-162.
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.
doi:10.1016/j.clim.2015.09.007
PMCID: PMC4658308  PMID: 26385092
systemic lupus erythematosus; leptin pathway; gene polymorphisms
3.  Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA 
Annals of the Rheumatic Diseases  2014;75(1):242-252.
Objectives
Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association.
Methods
Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR.
Results
The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10−4, OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10−7, OR 0.71; case-only pmeta=1.9×10−4, OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR.
Conclusions
These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.
doi:10.1136/annrheumdis-2014-205584
PMCID: PMC4717392  PMID: 25180293
Systemic Lupus Erythematosus; Autoantibodies; Gene Polymorphism; B cells
4.  Genetic Association of CD247 (CD3ζ) with SLE in a Large-Scale Multiethnic Study 
Genes and immunity  2015;16(2):142-150.
A classic T-cell phenotype in Systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters TCR signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multi-ethnic population. We typed 44 contiguous CD247 SNPs in 8 922 SLE patients and 8 077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99×10−4
doi:10.1038/gene.2014.73
PMCID: PMC4371129  PMID: 25569266
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. | 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.
Human Molecular Genetics  2014;24(2):582-596.
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.
doi:10.1093/hmg/ddu455
PMCID: PMC4275071  PMID: 25205108
Frontiers in Genetics  2015;5:450.
Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR) in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb) common haplotype marking a single causal variant that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3′ UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 × 10−10, OR 0.81 (0.75–0.86). Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 202 kb. Functionally, we found that PXK operates on the B-cell antigen receptor (BCR); we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.
doi:10.3389/fgene.2014.00450
PMCID: PMC4288052  PMID: 25620976
lupus; PXK; fine-mapping; B cells; BCR
Cellular and Molecular Immunology  2014;11(6):510-521.
The ovary is not an immunologically privileged organ, but a breakdown in tolerogenic mechanisms for ovary-specific antigens has disastrous consequences on fertility in women, and this is replicated in murine models of autoimmune disease. Isolated ovarian autoimmune disease is rare in women, likely due to the severity of the disease and the inability to transmit genetic information conferring the ovarian disease across generations. Nonetheless, autoimmune oophoritis is often observed in association with other autoimmune diseases, particularly autoimmune adrenal disease, and takes a toll on both society and individual health. Studies in mice have revealed at least two mechanisms that protect the ovary from autoimmune attack. These mechanisms include control of autoreactive T cells by thymus-derived regulatory T cells, as well as a role for the autoimmune regulator (AIRE), a transcriptional regulator that induces expression of tissue-restricted antigens in medullary thymic epithelial cells during development of T cells. Although the latter mechanism is incompletely defined, it is well established that failure of either results in autoimmune-mediated targeting and depletion of ovarian follicles. In this review, we will address the clinical features and consequences of autoimmune-mediated ovarian infertility in women, as well as the possible mechanisms of disease as revealed by animal models.
doi:10.1038/cmi.2014.97
PMCID: PMC4220844  PMID: 25327908
Arthritis and rheumatism  2012;64(11):3695-3705.
Objective
Systemic 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 more than 30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting the NF-κB signaling. In order to better understand the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway, we analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog, TNIP2, in case-control sets of diverse ethnic origins.
Methods
We fine-mapped TNIP1, TNIP2, and TAX1BP1 in a total of 8372 SLE cases and 7492 healthy controls from European-ancestry, African-American, Hispanic, East Asian, and African-American Gullah populations. Levels of TNIP1 mRNA and ABIN1 protein were analyzed using quantitative RT-PCR and Western blotting, respectively, in EBV-transformed human B cell lines.
Results
We found significant associations between genetic variants within TNIP1 and SLE but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified two independent risk haplotypes within TNIP1 in individuals of European-ancestry that were also present in African-American and Hispanic populations. These risk haplotypes produced lower levels of TNIP1 mRNA and ABIN1 protein suggesting they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression.
Conclusion
Our results confirmed 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.
doi:10.1002/art.34642
PMCID: PMC3485412  PMID: 22833143
PLoS Genetics  2013;9(10):e1003870.
Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.
Author Summary
Systemic lupus erythematosus (SLE), a debilitating autoimmune disease characterized by the production of pathogenic autoantibodies, has a strong genetic basis. Variants of the IL10 gene, which encodes cytokine interleukin-10 (IL-10) with known function of promoting B cell hyperactivity and autoantibody production, are associated with SLE and other autoimmune diseases, and serum IL-10 levels are elevated in SLE patients correlating with increased disease activity. In this study, to discover SLE-predisposing causal variant(s), we assessed variants within the genomic region containing IL10 and its gene family member IL19, IL20 and IL24 for association with SLE in case and control subjects from diverse ancestries. We identified SLE-associated SNP rs3122605 located at 9.2 kb upstream of IL10 as the most likely causal variant in subjects of European ancestry. The SLE-risk allele of rs3122605 was dose-dependently associated with elevated IL10 expression at both mRNA and protein levels in peripheral blood samples from SLE patients and controls, which could be explained, at least in part, by its preferential binding to Elk-1, a transcription factor activated in B cells during active disease of SLE patients. Elk-1-mediated IL-10 overexpression could be downregulated by inhibiting activation of mitogen-activated protein kinases, suggesting a potential therapeutic target for SLE.
doi:10.1371/journal.pgen.1003870
PMCID: PMC3794920  PMID: 24130510
The Journal of rheumatology  2013;40(6):842-849.
Objective
Little 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. This study analyzed variation in reactive intermediate genes for association with SLE in two populations with African ancestry.
Methods
A total of 244 SNPs 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) and. Single-marker, haplotype, and two-locus interaction tests were computed for these populations.
Results
The glutathione reductase gene GSR (rs2253409, P=0.0014, OR [95% CI]=1.26 [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 [95%CI]=2.10 [1.23–3.59]) and nitric oxide synthase gene NOS1 (rs561712, P=0.0072, OR [95%CI]=0.62 [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 [95%CI]=1.26 [1.10–1.44]). Haplotype and two-locus interaction analyses also uncovered different loci in each population.
Conclusion
These results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.
doi:10.3899/jrheum.120989
PMCID: PMC3735344  PMID: 23637325
systemic lupus erythematosus; African Americans; genetic association studies; oxygen compounds; single nucleotide polymorphism
PLoS Genetics  2013;9(7):e1003554.
We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P = 1.71×10−34, OR = 1.43[1.26–1.60]) and rs1234317-T (P = 1.16×10−28, OR = 1.38[1.24–1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5′ region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5′ risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.
Author Summary
Systemic lupus erythematosus (SLE/lupus) is a complex disease in which the body's immune cells cause inflammation in one or more systems to cause the associated morbidity. Hormones, the environment and genes are all causal contributors to SLE and over the past several years the genetic component of SLE has been firmly established. Several genes which are regulators of the immune system are associated with disease risk. We have established one of these, the tumour-necrosis family superfamily member 4 (TNFSF4) gene, as a lupus susceptibility gene in Northern Europeans. A major obstacle in pinpointing the marker(s) at TNFSF4 which best explain the risk of SLE has been the strong correlation (linkage disequilibrium, LD) between adjacent markers across the TNFSF4 region in this population. To address this, we have typed polymorphisms in several populations in addition to the European groups. The mixed ancestry of these populations gives a different LD pattern than that found in Europeans, presenting a method of pinpointing the section of the TNFSF4 region which results in SLE susceptibility. The Non-European populations have allowed identification of a polymorphism likely to regulate expression of TNFSF4 to increase susceptibility to SLE.
doi:10.1371/journal.pgen.1003554
PMCID: PMC3715547  PMID: 23874208
Arthritis and Rheumatism  2012;64(6):1960-1969.
Objective
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. TRAF6 is a candidate gene for SLE, which has a major role in several signaling pathways that are important for immunity and organ development.
Methods
Fifteen single-nucleotide polymorphisms (SNPs), across TRAF6 were evaluated in 7,490 SLE 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 with 95% confidence intervals were calculated.
Results
Evidence of associations in multiple SNPs was detected. 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 in Q-statistic). In addition, rs540386 previously reported to be associated with RA was found to be in LD with these two SNPs (r2= 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). 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 were detected in one available SNP rs5030437 with Z score magnitude of 2.28 (p=0.02) under a dominant model.
Conclusion
Our data indicate the presence of association of TRAF6 with SLE in agreement with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.
doi:10.1002/art.34361
PMCID: PMC3380425  PMID: 22231568
TRAF6; polymorphism; systemic lupus erythematosus
Annals of the Rheumatic Diseases  2011;71(5):694-699.
Objectives
Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci.
Methods
A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex–gene interaction was further validated using parametric and nonparametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients.
Results
A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P = 4.52×10−8) A significant sex–gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men.
Conclusions
The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.
doi:10.1136/annrheumdis-2011-200385
PMCID: PMC3324666  PMID: 22110124
Annals of the rheumatic diseases  2012;72(3):437-444.
Objectives
The 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.
Methods
We fine-mapped ≥136 SNPs in a ~227kb region on Xq28, containing IRAK1, MECP2 and 7 adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15,783 case-control subjects derived from 4 different ancestral groups.
Results
Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at P<5×10−8 with consistent association in subjects with African ancestry. Of these, 6 SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all 4 ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest P value in trans-ancestral meta-analysis (Pmeta=1.3×10−27, OR=1.43), and thus was considered to be the most-likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (P=0.0012) and healthy controls (P=0.0064).
Conclusion
These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.
doi:10.1136/annrheumdis-2012-201851
PMCID: PMC3567234  PMID: 22904263
Systemic Lupus Erythematosus; Gene Polymorphism; Xq28; IRAK1; MECP2
PLoS Genetics  2013;9(2):e1003336.
We previously reported that the G allele of rs3853839 at 3′untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10−10, odds ratio (OR) (95%CI) = 1.27 (1.17–1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5×10−11, OR = 1.24 [1.18–1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3′UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R2 = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3′UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta = 2.0×10−19, OR = 1.25 [1.20–1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.
Author Summary
Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease contributed to by excessive innate immune activation involving toll-like receptors (TLRs, particularly TLR7/8/9) and type I interferon (IFN) signaling pathways. TLR7 responds against RNA–containing nuclear antigens and activates IFN-α pathway, playing a pivotal role in the development of SLE. While a genomic duplication of Tlr7 promotes lupus-like disease in the Y-linked autoimmune accelerator (Yaa) murine model, the lack of common copy number variations at TLR7 in humans led us to identify a functional single nucleotide polymorphism (SNP), rs3853839 at 3′ UTR of the TLR7 gene, associated with SLE susceptibility in Eastern Asians. In this study, we fine-mapped the TLR7-TLR8 region and confirmed rs3853839 exhibiting the strongest association with SLE in European Americans, African Americans, and Amerindian/Hispanics. Individuals carrying the risk G allele of rs3853839 exhibited increased TLR7 expression at the both mRNA and protein level and decreased transcript degradation. MicroRNA-3148 (miR-3148) downregulated the expression of non-risk allele (C) containing transcripts preferentially, suggesting a likely mechanism for increased TLR7 levels in risk-allele carriers. This trans-ancestral mapping provides evidence for the global association with SLE risk at rs3853839, which resides in a microRNA–gene regulatory site affecting TLR7 expression.
doi:10.1371/journal.pgen.1003336
PMCID: PMC3585142  PMID: 23468661
Arthritis and Rheumatism  2012;64(2):485-492.
Objective
Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis is established in lupus. We test for gene-gene interactions in a number of known lupus susceptibility loci.
Methods
Eighteen SNPs tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 lupus patients and 3,818 normal healthy controls of European descent. Epistasis was tested using a 2-step approach utilizing both parametric and non-parametric methods. The false discovery rate (FDR) method was used to correct for multiple testing.
Results
We detected and confirmed gene-gene interactions between the HLA region and CTLA4, IRF5, and ITGAM, and between PDCD1 and IL21 in lupus patients. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (Interaction odds ratio=1.19, z-score= 3.95, P= 7.8×10−5 (FDR≤0.05), PMDR= 5.9×10−45). Importantly, our data suggest that in lupus patients the presence of the HLA lupus-risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus-risk allele in IRF5 (rs2070197) by 17% and 16%, respectively (P= 0.0028 and 0.0047).
Conclusion
We provide evidence for gene-gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability.
doi:10.1002/art.33354
PMCID: PMC3268866  PMID: 21952918
Maternal microchimerism (MMc) has been purported to play a role in the pathogenesis of autoimmunity, but how a small number of foreign cells could contribute to chronic, systemic inflammation has not been explained. Reports of peripheral blood cells differentiating into tissue-specific cell types may shed light on the problem in that chimeric maternal cells could act as target cells within tissues. We investigated MMc in tissues from seven male infants. Female cells, presumed maternal, were characterized by simultaneous immunohistochemistry and fluorescence in situ hybridization for X- and Y-chromosomes. Maternal cells constituted 0.017 to 1.9% of parenchymal cells and were found in all infants in liver, pancreas, lung, kidney, bladder, skin, and spleen. Maternal cells were differentiated: maternal hepatocytes in liver, renal tubular cells in kidney, and β-islet cells in pancreas. Maternal cells were not found in areas of tissue injury or inflammatory infiltrate. Maternal hematopoietic cells were found only in hearts from patients with neonatal lupus. Thus, differentiated maternal cells are present in multiple tissue types and occur independently of inflammation or tissue injury. Loss of tolerance to maternal parenchymal cells could lead to organ-specific “auto” inflammatory disease and elimination of maternal cells in areas of inflammation.
doi:10.2350/08-07-0499.1
PMCID: PMC2783488  PMID: 18939886
fetal development; maternal microchimerism; differentiation; stem cells; pregnancy
Genes and immunity  2012;13(5):380-387.
Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni corrected threshold (P < 1 × 10−4). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P = 0.0004) and UBCH7 protein expression (P = 0.0068). The results suggest that variants carried on the SLE associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.
doi:10.1038/gene.2012.6
PMCID: PMC3411915  PMID: 22476155
Systemic Lupus Erythematosus; UBE2L3; Multi Ethnic Association Study; UBCH7 Expression
Annals of the rheumatic diseases  2012;71(11):1809-1814.
Objective
Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin αΜ (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM.
Methods
The authors examined several markers in the ICAM1–ICAM4–ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case–control study of 17 481 unrelated participants from four ancestry populations. The single marker association and gene–gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed.
Results
The A-allele of ICAM1–ICAM4–ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (ORmeta=1.16, 95% CI 1.11 to 1.22; p=4.88×10−10 and ORmeta=1.67, 95% CI 1.55 to 1.79; p=3.32×10−46, respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91×10−5).
Conclusion
These findings are the first to suggest that an ICAM–integrin-mediated pathway contributes to susceptibility to SLE.
doi:10.1136/annrheumdis-2011-201110
PMCID: PMC3466387  PMID: 22523428
Arthritis and rheumatism  2011;63(9):2755-2763.
Objective
T cells from patients with SLE express increased amounts of PP2Ac which contribute to decreased production of IL-2. Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac.
Methods
We conducted a trans-ethnic study consisting of 8,695 SLE cases and 7,308 controls from four different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across the PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time PCR.
Results
A 32-kb haplotype comprised of multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans (HA), European Americans (EA) and Asians but not in African-Americans (AA). Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, EA and HA populations (pmeta=3.8×10−7, OR=1.3[1.14–1.31]). In EA, the largest ethnic dataset, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-dsDNA and anti-RNP antibodies. PPP2CA expression was approximately 2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying GG genotype (p = 0.008).
Conclusion
Our data provide the first evidence for an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in EA, HA and Asians.
doi:10.1002/art.30452
PMCID: PMC3163110  PMID: 21590681
Genes and Immunity  2011;13(3):232-238.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and organ damage. Lupus nephritis (LN) is one of the most severe manifestations of SLE. Multiple studies reported associations between renal diseases and variants in the non-muscle myosin heavy chain 9 (MYH9) and the neighboring apolipoprotein L 1 (APOL1) genes. We evaluated 167 variants spanning MYH9 for association with LN in a multiethnic sample. The two previously identified risk variants in APOL1 were also tested for association with LN in European-Americans (EAs) (N = 579) and African-Americans (AAs) (N = 407). Multiple peaks of association exceeding a Bonferroni corrected p-value of p < 2.03 × 10−3 were observed between LN and MYH9 in EAs (N=4620), with the most pronounced association at rs2157257 (p = 4.7 × 10−4; odds ratio [OR]=1.205). A modest effect with MYH9 was also detected in Gullah (rs8136069, p = 0.0019, OR = 2.304). No association between LN and MYH9 was found in AAs, Asians, Amerindians or Hispanics. This study provides the first investigation of MYH9 in LN in non-Africans and of APOL1 in LN in any population and presents novel insight into the potential role of MYH9 in LN in EAs.
doi:10.1038/gene.2011.82
PMCID: PMC3330160  PMID: 22189356
MYH9; APOL1; lupus nephritis; systemic lupus erythematosus; multiethnic association study

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