Patrick M Gaffney

Publications (59)575.58 Total impact

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

  Paula S Ramos, James C Oates, Diane L Kamen, Adrienne H Williams, Patrick M Gaffney, Jennifer A Kelly, Kenneth M Kaufman, Robert P Kimberly, Timothy B Niewold, Chaim O Jacob, [......], Barry I Freedman, R Hal Scofield, Anne M Stevens, Timothy J Vyse, Lindsey A Criswell, Kathy L Moser, Marta E Alarcón-Riquelme, Carl D Langefeld, John B Harley, Gary S Gilkeson
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  ABSTRACT: 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. We analyzed variation in reactive intermediate genes for association with SLE in 2 populations with African ancestry. METHODS: A total of 244 single-nucleotide polymorphisms (SNP) from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls). Single-marker, haplotype, and 2-locus interaction tests were computed for these populations. RESULTS: The glutathione reductase gene GSR (rs2253409; p = 0.0014, OR 1.26, 95% CI 1.09-1.44) was the most significant single SNP association in AA. In the Gullah, the NADH dehydrogenase NDUFS4 (rs381575; p = 0.0065, OR 2.10, 95% CI 1.23-3.59) and NO synthase gene NOS1 (rs561712; p = 0.0072, OR 0.62, 95% CI 0.44-0.88) were most strongly associated with SLE. When both populations were analyzed together, GSR remained the most significant effect (rs2253409; p = 0.00072, OR 1.26, 95% CI 1.10-1.44). Haplotype and 2-locus interaction analyses also uncovered different loci in each population. 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.
  The Journal of Rheumatology 05/2013; · 3.69 Impact Factor
• Article: Admixture Mapping in Lupus Identifies Multiple Functional Variants within IFIH1 Associated with Apoptosis, Inflammation, and Autoantibody Production.

  Julio E Molineros, Amit K Maiti, Celi Sun, Loren L Looger, Shizhong Han, Xana Kim-Howard, Stuart Glenn, Adam Adler, Jennifer A Kelly, Timothy B Niewold, [......], Kathy L Moser, R Hal Scofield, Marta E Alarcón-Riquelme, Scott M Williams, Joan T Merrill, Judith A James, Kenneth M Kaufman, Robert P Kimberly, John B Harley, Swapan K Nath
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  ABSTRACT: Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD = 6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ∼1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.
  PLoS Genetics 02/2013; 9(2):e1003222. · 8.69 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: 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: A female autoimmunity gene exists: DDX3X.

  Skyler P Dillon, Biji T Kurien, Jacen S Maier-Moore, Graham B Wiley, Patrick M Gaffney, R Hal Scofield
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  ABSTRACT: Approximately 4-7% of all women currently have an autoimmune disease, but only 1-3% of men do. Additionally, autoimmunity is a leading cause of death for young women, but not for men. Why this female bias exists is not known. Here, a thought experiment reveals that the female bias in autoimmune diseases is, at least in part, due to a woman's naturally higher dose of the X-linked gene DDX3X. Exome sequencing of all genes on the X chromosome in 74 lupus patients was consistent with the thought experiment, as no obvious mutations were found on X for lupus; a female-biased autoimmune disease. Furthermore, the thought experiment also predicted the existence of a new gene regulatory mechanism. We encourage researchers to investigate the extent to which DDX3X contributes to the many differences between male and female immune responses and pursue the utility in this knowledge.
  Medical Hypotheses 08/2012; · 1.39 Impact Factor
• Article: Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups.

  Kenneth M Kaufman, Jian Zhao, Jennifer A Kelly, Travis Hughes, Adam Adler, Elena Sanchez, Joshua O Ojwang, Carl D Langefeld, Julie T Ziegler, Adrienne H Williams, [......], Timothy B Niewold, Timothy James Vyse, Sang-Cheol Bae, Marta E Alarcón-Riquelme, Chaim O Jacob, Kathy Moser Sivils, Patrick M Gaffney, John B Harley, Amr H Sawalha, Betty P Tsao
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  ABSTRACT: 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 ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups. 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, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p(meta )= 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). CONCLUSIONS: These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.
  Annals of the rheumatic diseases 08/2012; · 8.11 Impact Factor
• Article: RBPJ mutations identified in two families affected by Adams-Oliver syndrome.

  Susan J Hassed, Graham B Wiley, Shaofeng Wang, Ji-Yun Lee, Shibo Li, Weihong Xu, Zhizhuang J Zhao, John J Mulvihill, James Robertson, James Warner, Patrick M Gaffney
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  ABSTRACT: Through exome resequencing, we identified two unique mutations in recombination signal binding protein for immunoglobulin kappa J (RBPJ) in two independent families affected by Adams-Oliver syndrome (AOS), a rare multiple-malformation disorder consisting primarily of aplasia cutis congenita of the vertex scalp and transverse terminal limb defects. These identified mutations link RBPJ, the primary transcriptional regulator for the Notch pathway, with AOS, a human genetic disorder. Functional assays confirmed impaired DNA binding of mutated RBPJ, placing it among other notch-pathway proteins altered in human genetic syndromes.
  The American Journal of Human Genetics 08/2012; 91(2):391-5. · 10.60 Impact Factor
• Article: Two independent functional risk haplotypes in TNIP1 are associated with systemic lupus erythematosus.

  Indra Adrianto, Shaofeng Wang, Graham B Wiley, Christopher J Lessard, Jennifer A Kelly, Adam J Adler, Stuart B Glenn, Adrienne H Williams, Julie T Ziegler, Mary E Comeau, [......], R Hal Scofield, Anne M Stevens, Betty P Tsao, Timothy J Vyse, Carl D Langefeld, John B Harley, Edward K Wakeland, Kathy L Moser, Courtney G Montgomery, Patrick M Gaffney
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  ABSTRACT: 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.
  Arthritis & Rheumatism 07/2012; · 7.87 Impact Factor
• Source

  Available from: Changwon Kang

  Article: Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries.

  Kwangwoo Kim, Elizabeth E Brown, Chan-Bum Choi, Marta E Alarcón-Riquelme, Jennifer A Kelly, Stuart B Glenn, Joshua O Ojwang, Adam Adler, Hye-Soon Lee, Susan A Boackle, [......], Mary Comeau, John D Reveille, Judith A James, R Hal Scofield, Carl D Langefeld, Kenneth M Kaufman, John B Harley, Changwon Kang, Robert P Kimberly, Sang-Cheol Bae
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  ABSTRACT: OBJECTIVE: Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin α(M) (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 (OR(meta)=1.16, 95% CI 1.11 to 1.22; p=4.88×10(-10) and OR(meta)=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.
  Annals of the rheumatic diseases 04/2012; 71(11):1809-1814. · 8.11 Impact Factor
• Source

  Available from: Edward K Wakeland

  Article: Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study.

  Christopher J Lessard, Indra Adrianto, John A Ice, Graham B Wiley, Jennifer A Kelly, Stuart B Glenn, Adam J Adler, He Li, Astrid Rasmussen, Adrienne H Williams, [......], Timothy J Vyse, Chack-Yung Yu, Joel M Guthridge, Kenneth M Kaufman, John B Harley, Edward K Wakeland, Carl D Langefeld, Patrick M Gaffney, Courtney G Montgomery, Kathy L Moser
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  ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p(meta-Euro) = 2.08 × 10(-10)), transmembrane protein 39A (TMEM39A; rs1132200; p(meta-all) = 8.62 × 10(-9)), and 17q21 (rs1453560; p(meta-all) = 3.48 × 10(-10)) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10(-8) < p(meta-Euro) < 9.99 × 10(-5)) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation.
  The American Journal of Human Genetics 04/2012; 90(4):648-60. · 10.60 Impact Factor
• Article: Contributions of mass spectrometry-based proteomics to defining cellular mechanisms and diagnostic markers for systemic lupus erythematosus.

  Erik A Korte, Patrick M Gaffney, David W Powell
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  ABSTRACT: Systematic lupus erythematosus (SLE) is a complex disease for which molecular diagnostics are limited and pathogenesis is not clearly understood. Important information is provided in this regard by identification and characterization of more specific molecular and cellular targets in SLE immune cells and target tissue and markers of early-onset and effective response to treatment of SLE complications. In recent years, advances in proteomic technologies and applications have facilitated such discoveries. Here we provide a review of insights into SLE pathogenesis, diagnosis and treatment that have been provided by mass spectrometry-based proteomic approaches.
  Arthritis research & therapy 02/2012; 14(1):204. · 4.27 Impact Factor
• Article: The genomics of autoimmune disease in the era of genome-wide association studies and beyond.

  Christopher J Lessard, John A Ice, Indra Adrianto, Graham B Wiley, Jennifer A Kelly, Patrick M Gaffney, Courtney G Montgomery, Kathy L Moser
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  ABSTRACT: Recent advances in the field of genetics have dramatically changed our understanding of autoimmune disease. Candidate gene and, more recently, genome-wide association (GWA) studies have led to an explosion in the number of loci and pathways known to contribute to autoimmune phenotypes. Since the 1970s, researchers have known that several alleles in the MHC region play a role in the pathogenesis of many autoimmune diseases. More recent work has identified numerous risk loci involving both the innate and adaptive immune responses. However, much remains to be learned about the heritability of autoimmune conditions. Most regions found through GWA scans have yet to isolate the association to the causal allele(s) responsible for conferring disease risk. A role for rare variants (allele frequencies of <1%) has begun to emerge. Future research will use next-generation sequencing (NGS) technology to comprehensively evaluate the human genome for risk variants. Whole-transcriptome sequencing is now possible, which will provide much more detailed gene expression data. The dramatic drop in the cost and time required to sequence the entire human genome will ultimately make it possible for this technology to be used as a clinical diagnostic tool.
  Autoimmunity reviews 02/2012; 11(4):267-75. · 6.37 Impact Factor
• Source

  Available from: Changwon Kang

  Article: Evaluation of TRAF6 in a large multiancestral lupus cohort.

  Bahram Namjou, Chan-Bum Choi, Isaac T W Harley, Marta E Alarcón-Riquelme, Jennifer A Kelly, Stuart B Glenn, Joshua O Ojwang, Adam Adler, Kwangwoo Kim, Caroline J Gallant, [......], Adrienne H Williams, Mary E Comeau, John D Reveille, Changwon Kang, Judith A James, R Hal Scofield, Carl D Langefeld, Kenneth M Kaufman, John B Harley, Sang-Cheol Bae
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  ABSTRACT: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development. Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Evidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 × 10(-5) and P = 4.73 × 10(-5) , respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r(2) = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 × 10(-4) , OR 0.89 [95% CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 × 10(-6) , OR 0.57 [95% CI 0.45-0.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model. Our data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.
  Arthritis & Rheumatism 01/2012; 64(6):1960-9. · 7.87 Impact Factor
• Article: Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK.

  Casimiro Castillejo-López, Angélica M Delgado-Vega, Jerome Wojcik, Sergey V Kozyrev, Elangovan Thavathiru, Ying-Yu Wu, Elena Sánchez, David Pöllmann, Juan R López-Egido, Serena Fineschi, [......], Johan Frostegård, Bernardo A Pons-Estel, Sandra D'Alfonso, Torsten Witte, José Luis Callejas, John B Harley, Patrick M Gaffney, Javier Martin, Joel M Guthridge, Marta E Alarcón-Riquelme
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  ABSTRACT: Altered signalling in B cells is a predominant feature of systemic lupus erythematosus (SLE). The genes BANK1 and BLK were recently described as associated with SLE. BANK1 codes for a B-cell-specific cytoplasmic protein involved in B-cell receptor signalling and BLK codes for an Src tyrosine kinase with important roles in B-cell development. To characterise the role of BANK1 and BLK in SLE, a genetic interaction analysis was performed hypothesising that genetic interactions could reveal functional pathways relevant to disease pathogenesis. The GPAT16 method was used to analyse the gene-gene interactions of BANK1 and BLK. Confocal microscopy was used to investigate co-localisation, and immunoprecipitation was used to verify the physical interaction of BANK1 and BLK. Epistatic interactions between BANK1 and BLK polymorphisms associated with SLE were observed in a discovery set of 279 patients and 515 controls from northern Europe. A meta-analysis with 4399 European individuals confirmed the genetic interactions between BANK1 and BLK. As BANK1 was identified as a binding partner of the Src tyrosine kinase LYN, the possibility that BANK1 and BLK could also show a protein-protein interaction was tested. The co-immunoprecipitation and co-localisation of BLK and BANK1 were demonstrated. In a Daudi cell line and primary naive B cells endogenous binding was enhanced upon B-cell receptor stimulation using anti-IgM antibodies. This study shows a genetic interaction between BANK1 and BLK, and demonstrates that these molecules interact physically. The results have important consequences for the understanding of SLE and other autoimmune diseases and identify a potential new signalling pathway.
  Annals of the rheumatic diseases 01/2012; 71(1):136-42. · 8.11 Impact Factor
• Source

  Available from: PubMed Central

  Article: Effects of IRF5 lupus risk haplotype on pathways predicted to influence B cell functions.

  Joel M Guthridge, Daniel N Clark, Amanda Templeton, Nicolas Dominguez, Rufei Lu, Gabriel S Vidal, Jennifer A Kelly, Kenneth M Kauffman, John B Harley, Patrick M Gaffney, Judith A James, Brian D Poole
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  ABSTRACT: Both genetic and environmental interactions affect systemic lupus erythematosus (SLE) development and pathogenesis. One known genetic factor associated with lupus is a haplotype of the interferon regulatory factor 5 (IRF5) gene. Analysis of global gene expression microarray data using gene set enrichment analysis identified multiple interferon- and inflammation-related gene sets significantly overrepresented in cells with the risk haplotype. Pathway analysis using expressed genes from the significant gene sets impacted by the IRF5 risk haplotype confirmed significant correlation with the interferon pathway, Toll-like receptor pathway, and the B-cell receptor pathway. SLE patients with the IRF5 risk haplotype have a heightened interferon signature, even in an unstimulated state (P = 0.011), while patients with the IRF5 protective haplotype have a B cell interferon signature similar to that of controls. These results identify multiple genes in functionally significant pathways which are affected by IRF5 genotype. They also establish the IRF5 risk haplotype as a key determinant of not only the interferon response, but also other B-cell pathways involved in SLE.
  Journal of Biomedicine and Biotechnology 01/2012; 2012:594056. · 2.44 Impact Factor
• Article: Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase.

  Chaim O Jacob, Miriam Eisenstein, Mary C Dinauer, Wenyu Ming, Qiang Liu, Sutha John, Francesco P Quismorio, Andreas Reiff, Barry L Myones, Kenneth M Kaufman, [......], Earl Silverman, Robert P Kimberly, Timothy J Vyse, Patrick M Gaffney, Kathy L Moser, Marisa Klein-Gitelman, Linda Wagner-Weiner, Carl D Langefeld, Don L Armstrong, Raphael Zidovetzki
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  ABSTRACT: Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 with the guanine nucleotide exchange factor Vav1. The model predicts that NCF2/H389 residue interacts with Vav1 residues E509, N510, E556, and G559 in the ZF domain of Vav1. Furthermore, replacing H389 with Q results in 1.5 kcal/mol weaker binding. To examine the effect of the NCF2 H389Q mutation on NADPH oxidase function, site-specific mutations at the 389 position in NCF2 were tested. Results show that an H389Q mutation causes a twofold decrease in reactive oxygen species production induced by the activation of the Vav-dependent Fcγ receptor-elicited NADPH oxidase activity. Our study completes the chain of evidence from genetic association to specific molecular function.
  Proceedings of the National Academy of Sciences 12/2011; 109(2):E59-67. · 9.68 Impact Factor
• Article: Sex chromosome aneuploidies among men with systemic lupus erythematosus.

  Skyler P Dillon, Biji T Kurien, Shibo Li, Gail R Bruner, Kenneth M Kaufman, John B Harley, Patrick M Gaffney, Daniel J Wallace, Michael H Weisman, R Hal Scofield
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  ABSTRACT: About 90% of patients with systemic lupus erythematosus (SLE) are female. We hypothesize that the number of X chromosomes, not sex, is a determinate of risk of SLE. Number of X chromosomes was determined by single nucleotide typing and then confirmed by karyotype or fluorescent in situ hybridization in a large group of men with SLE. Presence of an sry gene was assessed by RT-PCR. We calculated 96% confidence intervals using the Adjusted Wald method, and used Bayes' theorem to estimate the prevalence of SLE among 47,XXY and 46,XX men. Among 316 men with SLE, 7 had 47,XXY and 1 had 46,XX. The rate of Klinefelter's syndrome (47,XXY) was statistically different from that found in control men and from the known prevalence in the population. The 46,XX man had an sry gene, which encodes the testes determining factor, on an X chromosome as a result of an abnormal crossover during meiosis. In the case of 46,XX, 1 of 316 was statistically different from the known population prevalence of 1 in 20,000 live male births. A previously reported 46,XX man with SLE had a different molecular mechanism in which there were no common gene copy number abnormalities with our patient. Thus, men with SLE are enriched for conditions with additional X chromosomes. Especially since 46,XX men are generally normal males, except for infertility, these data suggest the number of X chromosomes, not phenotypic sex, is responsible for the sex-bias of SLE.
  Journal of Autoimmunity 12/2011; 38(2-3):J129-34. · 7.37 Impact Factor
• Source

  Available from: Marta E Alarcón-Riquelme

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

  Paula S Ramos, Lindsey A Criswell, Kathy L Moser, Mary E Comeau, Adrienne H Williams, Nicholas M Pajewski, Sharon A Chung, Robert R Graham, Raphael Zidovetzki, Jennifer A Kelly, Kenneth M Kaufman, Chaim O Jacob, Timothy J Vyse, Betty P Tsao, Robert P Kimberly, Patrick M Gaffney, Marta E Alarcón-Riquelme, John B Harley, Carl D Langefeld
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  ABSTRACT: In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non-Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, P = 2.02×10(-06)) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohn's disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non-MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases.
  PLoS Genetics 12/2011; 7(12):e1002406. · 8.69 Impact Factor
• Article: Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus.

  Travis Hughes, Adam Adler, Joan T Merrill, Jennifer A Kelly, Kenneth M Kaufman, Adrienne Williams, Carl D Langefeld, Gary S Gilkeson, Elena Sanchez, Javier Martin, [......], Patrick M Gaffney, Kathy L Moser, Timothy J Vyse, Marta E Alarcón-Riquelme, Judith A James, Betty P Tsao, R Hal Scofield, John B Harley, Bruce C Richardson, Amr H Sawalha
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  ABSTRACT: 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. 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 non-parametric 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. A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10-8) 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. 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.
  Annals of the rheumatic diseases 11/2011; 71(5):694-9. · 8.11 Impact Factor