Peter K Gregersen

Publications (171)2230.75 Total impact

• Article: Relationship between air pollution and positivity of RA-related autoantibodies in individuals without established RA: a report on SERA.

  Ryan W Gan, Kevin D Deane, Gary O Zerbe, M Kristen Demoruelle, Michael H Weisman, Jane H Buckner, Peter K Gregersen, Ted R Mikuls, James R O'Dell, Richard M Keating, V Michael Holers, Jill M Norris
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  ABSTRACT: INTRODUCTION: Studies suggest that respiratory exposures including smoking, proximity to traffic and air pollution might be associated with development of rheumatoid arthritis (RA). RA-related autoantibodies are predictive of the development of RA. OBJECTIVE: We evaluated the relationship between RA-related autoantibodies and exposure to particulate matter (PM), a measure of air pollution of interest to health, in individuals without RA. METHODS: The Studies of the Etiology of Rheumatoid Arthritis (SERA) is a multicentre study following first-degree relatives (FDRs) of a proband with RA. FDRs are without the 1987 ACR (American College of Rheumatology) classifiable RA at enrolment and are followed for the development of RA-related autoimmunity. RA-related autoantibody outcomes as well as tender and swollen joint outcomes were assessed. Exposure to PM was assigned using ambient air pollution monitoring data and interpolated with inverse distance weighting spatial analyses using Geographic Information Systems. PM exposures were linked to FDR's residential zip codes. RESULTS: RA-related autoantibodies as well as tender or swollen joints are not associated with ambient PM concentrations. DISCUSSION: While other respiratory exposures may be associated with increased risk of RA, our data suggest that ambient PM is not associated with autoantibodies and joint signs among individuals without RA, but at increased risk of developing RA.
  Annals of the rheumatic diseases 04/2013; · 8.11 Impact Factor
• Article: Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

  Jing Cui, Eli A. Stahl, Saedis Saevarsdottir, Corinne Miceli, Dorothee Diogo, Gosia Trynka, Towfique Raj, Maša Umiċeviċ Mirkov, Helena Canhao, Katsunori Ikari, [......], Philip L. De Jager, Soumya Raychaudhuri, Michael E. Weinblatt, Peter K. Gregersen, Xavier Mariette, Anne Barton, Leonid Padyukov, Marieke J. H. Coenen, Elizabeth W. Karlson, Robert M. Plenge
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  ABSTRACT: Author Summary There are no genetic predictors of response to one of the most widely used classes of drugs in the treatment of rheumatoid arthritis—biological modifiers of the inflammatory cytokine tumor necrosis factor-alpha (or anti-TNF therapy). To identify genetic predictors, we performed the largest genome-wide association study (GWAS) to date as part of an international collaboration. In our study, which included 2,706 RA patients treated with one of three anti-TNF drugs, the most significant finding was restricted to RA patients treated with etanercept ( P = 8×10⁻⁸), a drug that acts as a soluble receptor to bind circulating cytokine and prevents TNF from binding to its cell surface receptor. The associated variant influences expression of a nearby immune-related gene, CD84 , whose expression is correlated with disease activity in RA patients. Together, our data support a model in which genomic factors related to CD84</
  PLoS Genet. 03/2013; 9(3):e1003394.
• Source

  Available from: Katsunori Ikari

  Article: Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis.

  Jing Cui, Eli A Stahl, Saedis Saevarsdottir, Corinne Miceli, Dorothee Diogo, Gosia Trynka, Towfique Raj, Maša Umiċeviċ Mirkov, Helena Canhao, Katsunori Ikari, [......], Philip L De Jager, Soumya Raychaudhuri, Michael E Weinblatt, Peter K Gregersen, Xavier Mariette, Anne Barton, Leonid Padyukov, Marieke J H Coenen, Elizabeth W Karlson, Robert M Plenge
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  ABSTRACT: Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10(-8)), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.
  PLoS Genetics 03/2013; 9(3):e1003394. · 8.69 Impact Factor
• Article: Absolute pitch exhibits phenotypic and genetic overlap with synesthesia.

  Peter K Gregersen, Elena Kowalsky, Annette Lee, Simon Baron-Cohen, Simon E Fisher, Julian E Asher, David Ballard, Jan Freudenberg, Wentian Li
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  ABSTRACT: Absolute pitch (AP) and synesthesia are two uncommon cognitive traits that reflect increased neuronal connectivity and have been anecdotally reported to occur together in an individual. Here we systematically evaluate the occurrence of synesthesia in a population of 768 subjects with documented AP. Out of these 768 subjects, 151 (20.1%) reported synesthesia, most commonly with color. These self-reports of synesthesia were validated in a subset of 21 study subjects, using an established methodology. We further carried out combined linkage analysis of 53 multiplex families with AP and 36 multiplex families with synesthesia. We observed a peak NPL LOD = 4.68 on chromosome 6q, as well as evidence of linkage on chromosome 2, using a dominant model. These data establish the close phenotypic and genetic relationship between AP and synesthesia. The chromosome 6 linkage region contains 73 genes; several leading candidate genes involved in neurodevelopment were investigated by exon resequencing. However, further studies will be required to definitively establish the identity of the causative gene(s) in the region.
  Human Molecular Genetics 03/2013; · 7.64 Impact Factor
• Article: MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus.

  Yun Deng, Jian Zhao, Daisuke Sakurai, Kenneth M Kaufman, Jeffrey C Edberg, Robert P Kimberly, Diane L Kamen, Gary S Gilkeson, Chaim O Jacob, R Hal Scofield, [......], Anne M Stevens, Susan A Boackle, Rita M Cantor, Weiling Chen, Jeniffer M Grossman, Bevra H Hahn, John B Harley, Marta E Alarcόn-Riquelme, Elizabeth E Brown, Betty P Tsao
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  ABSTRACT: We previously reported that the G allele of rs3853839 at 3'untranslated region (UTR) of Toll-like receptor 7 () was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [ = 6.5×10, 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 region exhibiting consistent and independent association with SLE ( = 7.5×10, OR = 1.24 [1.18-1.34]). The risk G allele was associated with significantly increased levels of mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. 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 expression. Indeed, miR-3148 levels were inversely correlated with transcript levels in PBMCs from SLE patients and controls (R = 0.255, = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by 3'UTR segment bearing the C allele ( = 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 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries ( = 2.0×10, OR = 1.25 [1.20-1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.
  PLoS Genetics 02/2013; 9(2):e1003336. · 8.69 Impact Factor
• Article: Regulation of dendritic cell activation by microRNA let-7c and BLIMP1.

  Sun Jung Kim, Peter K Gregersen, Betty Diamond
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  ABSTRACT: Mice with a DC-specific deletion of the transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp1) exhibit a lupus-like phenotype, secondary to enhanced DC production of IL-6. Here we explored further phenotypic changes in Blimp1-deficient DCs, the molecular mechanism underlying these changes, and their relevance to human disease. Blimp1-deficient DCs exhibited elevated expression of MHC II, and exposure to TLR agonists increased secretion of proinflammatory cytokines. This phenotype reflects enhanced expression of the microRNA let-7c, which is regulated by BLIMP1. Let-7c reciprocally inhibited Blimp1 and also blocked LPS-induced suppressor of cytokine signaling-1 (SOCS1) expression, contributing to the proinflammatory phenotype of Blimp1-deficient DCs. DCs from Blimp1 SLE-risk allele carriers exhibited analogous phenotypic changes, including decreased BLIMP1 expression, increased let-7c expression, and increased expression of proinflammatory cytokines. These results suggest that let-7c regulates DC phenotype and confirm the importance of BLIMP1 in maintaining tolerogenic DCs in both mice and humans.
  The Journal of clinical investigation 01/2013; · 15.39 Impact Factor
• Article: Rare, Low-Frequency, and Common Variants in the Protein-Coding Sequence of Biological Candidate Genes from GWASs Contribute to Risk of Rheumatoid Arthritis.

  Dorothée Diogo, Fina Kurreeman, Eli A Stahl, Katherine P Liao, Namrata Gupta, Jeffrey D Greenberg, Manuel A Rivas, Brendan Hickey, Jason Flannick, Brian Thomson, [......], Alexandra Zhernakova, John Bowes, Steve Eyre, Katherine A Siminovitch, Peter K Gregersen, Jane Worthington, Lars Klareskog, Leonid Padyukov, Soumya Raychaudhuri, Robert M Plenge
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  ABSTRACT: The extent to which variants in the protein-coding sequence of genes contribute to risk of rheumatoid arthritis (RA) is unknown. In this study, we addressed this issue by deep exon sequencing and large-scale genotyping of 25 biological candidate genes located within RA risk loci discovered by genome-wide association studies (GWASs). First, we assessed the contribution of rare coding variants in the 25 genes to the risk of RA in a pooled sequencing study of 500 RA cases and 650 controls of European ancestry. We observed an accumulation of rare nonsynonymous variants exclusive to RA cases in IL2RA and IL2RB (burden test: p = 0.007 and p = 0.018, respectively). Next, we assessed the aggregate contribution of low-frequency and common coding variants to the risk of RA by dense genotyping of the 25 gene loci in 10,609 RA cases and 35,605 controls. We observed a strong enrichment of coding variants with a nominal signal of association with RA (p < 0.05) after adjusting for the best signal of association at the loci (p(enrichment) = 6.4 × 10(-4)). For one locus containing CD2, we found that a missense variant, rs699738 (c.798C>A [p.His266Gln]), and a noncoding variant, rs624988, reside on distinct haplotypes and independently contribute to the risk of RA (p = 4.6 × 10(-6)). Overall, our results indicate that variants (distributed across the allele-frequency spectrum) within the protein-coding portion of a subset of biological candidate genes identified by GWASs contribute to the risk of RA. Further, we have demonstrated that very large sample sizes will be required for comprehensively identifying the independent alleles contributing to the missing heritability of RA.
  The American Journal of Human Genetics 12/2012; · 10.60 Impact Factor
• Article: Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis.

  Masa Umicevic Mirkov, Jing Cui, Sita H Vermeulen, Eli A Stahl, Erik J M Toonen, Remco R Makkinje, Annette T Lee, Tom W J Huizinga, Renee Allaart, Anne Barton, [......], Pilar Barrera, Timothy R D J Radstake, Piet L C M van Riel, Hans Scheffer, Barbara Franke, Han G Brunner, Robert M Plenge, Peter K Gregersen, Henk-Jan Guchelaar, Marieke J H Coenen
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  ABSTRACT: BACKGROUND: Treatment strategies blocking tumour necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently, there are no means of identifying these patients before treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patients with RA using a genome-wide association approach. METHODS: We conducted a multistage, genome-wide association study with a primary analysis of 2 557 253 single-nucleotide polymorphisms (SNPs) in 882 patients with RA receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with p<10(-3) were selected for replication in 1821 patients from three independent cohorts. Pathway analysis including all SNPs with p<10(-3) was performed using Ingenuity. RESULTS: 772 markers showed evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p value in the overall meta-analysis compared with the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four cohorts studied. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology. CONCLUSIONS: Using a multistage strategy, we have identified eight genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections.
  Annals of the rheumatic diseases 12/2012; · 8.11 Impact Factor
• Article: Identification of the NF-κB activating protein-like locus as a risk locus for rheumatoid arthritis.

  Gang Xie, Yue Lu, Ye Sun, Steven Shiyang Zhang, Edward Clark Keystone, Peter K Gregersen, Robert M Plenge, Christopher I Amos, Katherine A Siminovitch
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  ABSTRACT: OBJECTIVE: To fine-map the NF-κB activating protein-like (NKAPL) locus identified in a prior genome-wide study as a possible rheumatoid arthritis (RA) risk locus and thereby delineate additional variants with stronger and/or independent disease association. METHODS: Genotypes for 101 SNPs across the NKAPL locus on chromosome 6p22.1 were obtained on 1368 Canadian RA cases and 1471 controls. Single marker associations were examined using logistic regression and the most strongly associated NKAPL locus SNPs then typed in another Canadian and a US-based RA case/control cohort. RESULTS: Fine-mapping analyses identified six NKAPL locus variants in a single haplotype block showing association with p≤5.6×10(-8) in the combined Canadian cohort. Among these SNPs, rs35656932 in the zinc finger 193 gene and rs13208096 in the NKAPL gene remained significant after conditional logistic regression, contributed independently to risk for disease, and were replicated in the US cohort (P(comb)=4.24×10(-10) and 2.44×10(-9), respectively). These associations remained significant after conditioning on SNPs tagging the HLA-shared epitope (SE) DRB1*0401 allele and were significantly stronger in the HLA-SE negative versus positive subgroup, with a significant negative interaction apparent between HLA-DRB1 SE and NKAPL risk alleles. CONCLUSIONS: By illuminating additional NKAPL variants with highly significant effects on risk that are distinct from, but interactive with those arising from the HLA-DRB1 locus, our data conclusively identify NKAPL as an RA susceptibility locus.
  Annals of the rheumatic diseases 12/2012; · 8.11 Impact Factor
• Article: High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.

  Steve Eyre, John Bowes, Dorothée Diogo, Annette Lee, Anne Barton, Paul Martin, Alexandra Zhernakova, Eli Stahl, Sebastien Viatte, Kate McAllister, [......], Miguel A Gonzalez-Gay, Luis Rodriguez-Rodriguez, Lisbeth Arlsetig, Javier Martin, Solbritt Rantapää-Dahlqvist, Robert M Plenge, Soumya Raychaudhuri, Lars Klareskog, Peter K Gregersen, Jane Worthington
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  ABSTRACT: Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.
  Nature Genetics 11/2012; · 35.53 Impact Factor
• Article: Genome-wide association study reveals novel genetic determinants of DNA repair capacity in lung cancer.

  Li-E Wang, Olga Y Gorlova, Jun Ying, Yawei Qiao, Shih-Feng Weng, Annette T Lee, Peter K Gregersen, Margaret R Spitz, Christopher I Amos, Qingyi Wei
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  ABSTRACT: Suboptimal cellular DNA repair capacity (DRC) has been shown to be associated with enhanced cancer risk, but genetic variants affecting the DRC phenotype have not been comprehensively investigated. In this study, with the available DRC phenotype data, we analyzed correlations between the DRC phenotype and genotypes detected by the Illumina 317K platform in 1,774 individuals of European ancestry from a Texas lung cancer genome-wide association study. The discovery phase was followed by a replication in an independent set of 1,374 cases and controls of European ancestry. We applied a generalized linear model with SNPs as predictors and DRC (a continuous variable) as the outcome. Covariates of age, sex, pack-years of smoking, DRC assay-related variables and case-control status of the study participants were adjusted in the model. We validated that reduced DRC was associated with an increased risk of lung cancer in both independent datasets. Several suggestive loci that contributed to the DRC phenotype were defined in ERCC2/XPD, PHACTR2 and DUSP1. In summary, we determined that DRC is an independent risk factor for lung cancer and we defined several genetic loci contributing to DRC phenotype.
  Cancer Research 10/2012; · 7.86 Impact Factor
• Article: Unraveling Multiple MHC Gene Associations with Systemic Lupus Erythematosus: Model Choice Indicates a Role for HLA Alleles and Non-HLA Genes in Europeans.

  David L Morris, Kimberly E Taylor, Michelle M A Fernando, Joanne Nititham, Marta E Alarcón-Riquelme, Lisa F Barcellos, Timothy W Behrens, Chris Cotsapas, Patrick M Gaffney, Robert R Graham, [......], Peter K Gregersen, John B Harley, Stephen L Hauser, Geoffrey Hom, Carl D Langefeld, Janelle A Noble, John D Rioux, Michael F Seldin, Lindsey A Criswell, Timothy J Vyse
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  ABSTRACT: We have performed a meta-analysis of the major-histocompatibility-complex (MHC) region in systemic lupus erythematosus (SLE) to determine the association with both SNPs and classical human-leukocyte-antigen (HLA) alleles. More specifically, we combined results from six studies and well-known out-of-study control data sets, providing us with 3,701 independent SLE cases and 12,110 independent controls of European ancestry. This study used genotypes for 7,199 SNPs within the MHC region and for classical HLA alleles (typed and imputed). Our results from conditional analysis and model choice with the use of the Bayesian information criterion show that the best model for SLE association includes both classical loci (HLA-DRB1(∗)03:01, HLA-DRB1(∗)08:01, and HLA-DQA1(∗)01:02) and two SNPs, rs8192591 (in class III and upstream of NOTCH4) and rs2246618 (MICB in class I). Our approach was to perform a stepwise search from multiple baseline models deduced from a priori evidence on HLA-DRB1 lupus-associated alleles, a stepwise regression on SNPs alone, and a stepwise regression on HLA alleles. With this approach, we were able to identify a model that was an overwhelmingly better fit to the data than one identified by simple stepwise regression either on SNPs alone (Bayes factor [BF] > 50) or on classical HLA alleles alone (BF > 1,000).
  The American Journal of Human Genetics 10/2012; · 10.60 Impact Factor
• Article: CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation.

  Nataly Manjarrez-Orduño, Emiliano Marasco, Sharon A Chung, Matthew S Katz, Jenna F Kiridly, Kim R Simpfendorfer, Jan Freudenberg, David H Ballard, Emil Nashi, Thomas J Hopkins, [......], Barbara Franke, Dorine W Swinkels, Robert R Graham, Robert P Kimberly, Patrick M Gaffney, Timothy J Vyse, Timothy W Behrens, Lindsey A Criswell, Betty Diamond, Peter K Gregersen
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  ABSTRACT: The c-Src tyrosine kinase, Csk, physically interacts with the intracellular phosphatase Lyp (encoded by PTPN22) and can modify the activation state of downstream Src kinases, such as Lyn, in lymphocytes. We identified an association of CSK with systemic lupus erythematosus (SLE) and refined its location to the intronic polymorphism rs34933034 (odds ratio (OR) = 1.32; P = 1.04 × 10(-9)). The risk allele at this SNP is associated with increased CSK expression and augments inhibitory phosphorylation of Lyn. In carriers of the risk allele, there is increased B-cell receptor (BCR)-mediated activation of mature B cells, as well as higher concentrations of plasma immunoglobulin M (IgM), relative to individuals with the non-risk haplotype. Moreover, the fraction of transitional B cells is doubled in the cord blood of carriers of the risk allele, due to an expansion of late transitional cells in a stage targeted by selection mechanisms. This suggests that the Lyp-Csk complex increases susceptibility to lupus at multiple maturation and activation points in B cells.
  Nature Genetics 10/2012; · 35.53 Impact Factor
• Article: European genetic ancestry is associated with a decreased risk of lupus nephritis.

  Ilana B Richman, Kimberly E Taylor, Sharon A Chung, Laura Trupin, Michelle Petri, Edward Yelin, Robert R Graham, Annette Lee, Timothy W Behrens, Peter K Gregersen, Michael F Seldin, Lindsey A Criswell
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  ABSTRACT: African Americans, East Asians, and Hispanics with systemic lupus erythematosus (SLE) are more likely to develop renal disease than are SLE patients of European descent. This study was undertaken to investigate whether European genetic ancestry protects against the development of lupus nephritis, with the aim of exploring the genetic and socioeconomic factors that might explain this effect. This was a cross-sectional study of SLE patients from a multiethnic case collection. Participants were genotyped for 126 single-nucleotide polymorphisms (SNPs) informative for ancestry. A subset of participants was also genotyped for 80 SNPs in 14 candidate genes for renal disease in SLE. Logistic regression was used to test the association between European ancestry and renal disease. Analyses were adjusted for continental ancestries, socioeconomic status (SES), and candidate genes. Participants (n = 1,906) had, on average, 62.4% European, 15.8% African, 11.5% East Asian, 6.5% Amerindian, and 3.8% South Asian ancestry. Among the participants, 656 (34%) had renal disease. A 10% increase in the proportion of European ancestry estimated in each participant was associated with a 15% reduction in the odds of having renal disease, after adjustment for disease duration and sex (odds ratio 0.85, 95% confidence interval 0.82-0.87; P = 1.9 × 10(-30) ). Adjustment for other genetic ancestries, measures of SES, or SNPs in the genes most associated with renal disease (IRF5 [rs4728142], BLK [rs2736340], STAT4 [rs3024912], and HLA-DRB1*0301 and DRB1*1501) did not substantively alter this relationship. European ancestry is protective against the development of renal disease in SLE, an effect that is independent of other genetic ancestries, candidate risk alleles, and socioeconomic factors.
  Arthritis & Rheumatism 10/2012; 64(10):3374-82. · 7.87 Impact Factor
• Article: GWAS implicates a role for quantitative immune traits and threshold effects in risk for human autoimmune disorders.

  Peter K Gregersen, Betty Diamond, Robert M Plenge
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  ABSTRACT: Genome wide association studies in human autoimmune disorders have provided a long list of alleles with rather modest degrees of risk. A large fraction of these associations are probably owing to either quantitative differences in gene expression or amino acid changes that regulate quantitative aspects of the immune response. While functional studies are still lacking for most of these associations, we present examples of autoimmune disease risk alleles that influence quantitative changes in lymphocyte activation, cytokine signaling and dendritic cell function. The analysis of immune quantitative traits associated with autoimmune loci is clearly going to be an important component of understanding the pathogenesis of autoimmunity. This will require both new and more efficient ways of characterizing the normal immune system, as well as large population resources in which genotype-phenotype correlations can be convincingly demonstrated. Future development of new therapies will depend on understanding the mechanistic underpinnings of immune regulation by these new risk loci.
  Current opinion in immunology 09/2012; 24(5):538-43. · 10.88 Impact Factor
• Article: Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants.

  Brian D Juran, Gideon M Hirschfield, Pietro Invernizzi, Elizabeth J Atkinson, Yafang Li, Gang Xie, Roman Kosoy, Michael Ransom, Ye Sun, Ilaria Bianchi, [......], Cynthia Levy, Andre Franke, Peter K Gregersen, Fabrizio Bossa, M Eric Gershwin, Mariza Deandrade, Christopher I Amos, Konstantinos N Lazaridis, Michael F Seldin, Katherine A Siminovitch
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  ABSTRACT: To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.
  Human Molecular Genetics 08/2012; · 7.64 Impact Factor
• Article: Multiple cytokines and chemokines are associated with rheumatoid arthritis-related autoimmunity in first-degree relatives without rheumatoid arthritis: Studies of the Aetiology of Rheumatoid Arthritis (SERA).

  Jan M Hughes-Austin, Kevin D Deane, Lezlie A Derber, Jason R Kolfenbach, Gary O Zerbe, Jeremy Sokolove, Lauren J Lahey, Michael H Weisman, Jane H Buckner, Ted R Mikuls, James R O'Dell, Richard M Keating, Peter K Gregersen, William H Robinson, V Michael Holers, Jill M Norris
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  ABSTRACT: OBJECTIVE: We investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with systemic inflammation in a prospective cohort of first-degree relatives (FDRs) of RA probands, a population without RA but at increased risk for its future development. METHODS: We studied 44 autoantibody positive FDRs, of whom 29 were rheumatoid factor (RF) positive, 25 were positive for the high risk autoantibody profile (HRP), that is, positive for anti-cyclic citrullinated peptide and/or for at least two RF IgM, IgG or IgA isotypes, and nine FDRs who were positive for both; and 62 FDRs who were never autoantibody positive. Twenty-five cytokines/chemokines were measured using a bead-based assay in serum. As a comprehensive measure of inflammation, we calculated a Cytokine Score by summing all cytokine/chemokine levels, weighted by their regression coefficients for RA-autoantibody association. We compared C-reactive protein, individual cytokines/chemokines and Cytokine Score to the outcomes: positivity for RF and for the HRP using logistic regression. RESULTS: Adjusting for age, sex, ethnicity and ever smoking, the Cytokine Score and levels of IL-6 and IL-9 were associated with both RF and HRP. IL-2, granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon (IFN)-γ were associated with HRP only. Associations between the Cytokine Score and RF and HRP positivity were replicated in an independent military personnel cohort. CONCLUSIONS: In first-degree relatives of patients with RA, RA-related autoimmunity is associated with inflammation, as evidenced by associations with multiple cytokines and chemokines.
  Annals of the rheumatic diseases 08/2012; · 8.11 Impact Factor
• Article: Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08.

  Peter K Gregersen, Roman Kosoy, Annette T Lee, Janine Lamb, Jon Sussman, David McKee, Kim R Simpfendorfer, Ritva Pirskanen-Matell, Frederik Piehl, Qiang Pan-Hammarstrom, [......], Chantal Tallaksen, Hanne F Harbo, Benedicte A Lie, Soumya Raychaudhuri, Paul I W de Bakker, Arthur Melms, Henri-Jean Garchon, Nicholas Willcox, Lennart Hammarstrom, Michael F Seldin
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  ABSTRACT: OBJECTIVE: The objective of this study is to comprehensively define the genetic basis of early onset myasthenia gravis (EOMG). METHODS: We have carried out a 2-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region. RESULTS: We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 × 10(-92) ; odds ratio [OR], 6.25). By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 × 10(-113) ; OR, 6.41). In addition to the expected association with PTPN22 (rs2476601; OR, 1.71; p = 8.2 × 10(-10) ), an imputed coding variant (rs2233290) at position 151 (Pro→Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR, 1.91; p = 3.2 × 10(-10) ). INTERPRETATION: The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-κB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that CD8(+) T cells may play a key role in disease initiation or pathogenesis. ANN NEUROL 2012;
  Annals of Neurology 07/2012; · 11.09 Impact Factor
• Article: Porphyromonas gingivalis and disease-related autoantibodies in individuals at increased risk for future rheumatoid arthritis.

  Ted R Mikuls, Geoffrey M Thiele, Kevin D Deane, Jeffrey B Payne, James R O'Dell, Fang Yu, Harlan Sayles, Michael H Weisman, Peter K Gregersen, Jane H Buckner, Richard M Keating, Lezlie A Derber, William H Robinson, V Michael Holers, Jill M Norris
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  ABSTRACT: PURPOSE: To examine the relationship of Porphyromonas gingivalis (Pg) with the presence of autoantibodies in individuals at risk for rheumatoid arthritis (RA). METHODS: Participants included: 1) a cohort enriched with HLA-DR4 and 2) those at risk for RA by virtue of having a first-degree relative with RA. None satisfied 1987 ACR RA classification criteria. Autoantibodies measured included anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF; nephelometry, IgA, IgM, IgG). Individuals were considered autoantibody positive (n = 113) with ≥ 1 positive autoantibody with individuals further categorized as 'high-risk' (n = 38; positive ACPA or ≥ 2 RF assays). Autoantibody negative individuals served as comparators (n = 171). Antibody to Pg, P. intermedia (Pi), and F. nucleatum (Fn) were measured. Associations of bacterial antibodies with group status were examined using logistic regression. RESULTS: Anti-Pg concentrations were higher in high-risk (p = 0.011) and autoantibody positive group (p = 0.010) than in the autoantibody negative group. There were no group differences in anti-Pi or anti-Fn concentrations. After multivariable adjustment, anti-Pg concentrations (but not anti-Pi or anti-Fn) were significantly associated with autoantibody positive and high-risk status (p < 0.05). CONCLUSION: Immunity to Pg, but not Pi or Fn, is significantly associated with the presence of RA-related autoantibodies in individuals at risk for RA. These results support the hypothesis that infection with Pg may play a central role in the early loss of tolerance to self-antigens in RA pathogenesis.
  Arthritis & Rheumatism 06/2012; · 7.87 Impact Factor
• Article: The autoimmunity-associated BLK haplotype exhibits cis-regulatory effects on mRNA and protein expression that are prominently observed in B cells early in development.

  Kim R Simpfendorfer, Lina M Olsson, Nataly Manjarrez Orduño, Houman Khalili, Alyssa M Simeone, Matthew S Katz, Annette T Lee, Betty Diamond, Peter K Gregersen
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  ABSTRACT: The gene B lymphocyte kinase (BLK) is associated with rheumatoid arthritis, systemic lupus erythematosus and several other autoimmune disorders. The disease risk haplotype is known to be associated with reduced expression of BLK mRNA transcript in human B cell lines; however, little is known about cis-regulation of BLK message or protein levels in native cell types. Here, we show that in primary human B lymphocytes, cis-regulatory effects of disease-associated single nucleotide polymorphisms in BLK are restricted to naïve and transitional B cells. Cis-regulatory effects are not observed in adult B cells in later stages of differentiation. Allelic expression bias was also identified in primary human T cells from adult peripheral and umbilical cord blood (UCB), thymus and tonsil, although mRNA levels were reduced compared with B cells. Allelic regulation of Blk expression at the protein level was confirmed in UCB B cell subsets by intracellular staining and flow cytometry. Blk protein expression in CD4(+) and CD8(+) T cells was documented by western blot analysis; however, differences in protein expression levels by BLK genotype were not observed in any T cell subset. Blk allele expression differences at the protein level are thus restricted to early B cells, indicating that the involvement of Blk in the risk for autoimmune disease likely acts during the very early stages of B cell development.
  Human Molecular Genetics 06/2012; 21(17):3918-25. · 7.64 Impact Factor