Rheumatoid Arthritis: Lee A

Liu C, Batliwalla F, Li W, Lee A, Roubenoff R, Beckman E, Khalili H, Damle A, Kern M, Furie R, Dupuis J, Plenge RM, Coenen MJ, Behrens TW, Carulli JP, Gregersen PK. · Biogen Idec Inc., Cambridge, Massachusetts, USA. · Mol Med. · Pubmed #18615156 links to  free full text

Abstract: The prediction of response (or non-response) to anti-TNF treatment for rheumatoid arthritis (RA) is a pressing clinical problem. We conducted a genome-wide association study using the Illumina HapMap300 SNP chip on 89 RA patients prospectively followed after beginning anti-TNF therapy as part of Autoimmune Biomarkers Collaborative Network (ABCoN [Autoimmune Bio-markers Collaborative Network]) patient cohort. Response to therapy was determined by the change in Disease Activity Score (DAS28) observed after 14 wks. We used a two-part analysis that treated the change in DAS28 as a continuous trait and then incorporated it into a dichotomous trait of "good responder" and "nonresponder" by European League Against Rheumatism (EULAR) criteria. We corrected for multiple tests by permutation, and adjusted for potential population stratification using EIGENSTRAT. Multiple single nucleotide polymorphism (SNP) markers showed significant associations near or within loci including: the v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene on chromosome 20; the type I interferon gene IFNk on chromosome 9; and in a locus on chromosome 7 that includes the paraoxonase I (PON1) gene. An SNP in the IL10 promoter (rs1800896) that was previously reported as associated with anti-TNF response was weakly associated with response in this cohort. Replications of these results in independent and larger data sets clearly are required. We provide a reference list of candidate SNPs (P < 0.01) that can be investigated in future pharmacogenomic studies.

Riise ØR, Lee A, Cvancarova M, Handeland KS, Wathne KO, Nakstad B, Gaustad P, Flatø B. · Department of Rheumatology, Rikshospitalet Medical Centre N-0027, Oslo, Norway. · Rheumatology (Oxford). · Pubmed #18420659 No free full text.

Abstract: OBJECTIVES: To assess the frequency of Streptococcus pyogenes in children with early arthritis, compare the characteristics in patients with post-streptococcal ReA (PSReA) with those in patients with other types of arthritis, and describe the occurrence of carditis in PSRA. PATIENTS: In a population-based Norwegian study, the physicians were asked to refer all children with suspected arthritis. The arthritis patients were followed up at 6 weeks, 6 months and 18 months. The presence of S. pyogenes was based on throat smear or antibodies. Echocardiography was performed in the patients with ARF or PSRA. RESULTS: Thirty-two (18%) of the 173 children with arthritis tested positive for S. pyogenes. The percentage of positive tests rose steadily with age and peaked at ages 8-11 (35%). Six weeks after admission arthritis was present in 33% of the PSRA patients, which was less frequent than in the juvenile idiopathic arthritis (JIA) patients (P < 0.001), but more frequent than in the transient arthritis patients (P = 0.012). Hip arthritis was more frequent and knee/ankle arthritis, ANA and HLA-B27 were less frequent in PSRA than in JIA (P < 0.001, P = 0.009 and P = 0.029, respectively). The PSRA patients were older than those with transient arthritis (P = 0.007). One child with ARF had carditis. CONCLUSIONS: Streptococcus pyogenes was present in 18% of children with arthritis. The patient characteristics, clinical presentation and early disease course in PSRA was different from that of JIA and transient arthritis.

Tian C, Plenge RM, Ransom M, Lee A, Villoslada P, Selmi C, Klareskog L, Pulver AE, Qi L, Gregersen PK, Seldin MF. · Rowe Program in Human Genetics, University of California Davis, Davis, California, United States of America. · PLoS Genet. · Pubmed #18208329 links to  free full text

Abstract: European population genetic substructure was examined in a diverse set of >1,000 individuals of European descent, each genotyped with >300 K SNPs. Both STRUCTURE and principal component analyses (PCA) showed the largest division/principal component (PC) differentiated northern from southern European ancestry. A second PC further separated Italian, Spanish, and Greek individuals from those of Ashkenazi Jewish ancestry as well as distinguishing among northern European populations. In separate analyses of northern European participants other substructure relationships were discerned showing a west to east gradient. Application of this substructure information was critical in examining a real dataset in whole genome association (WGA) analyses for rheumatoid arthritis in European Americans to reduce false positive signals. In addition, two sets of European substructure ancestry informative markers (ESAIMs) were identified that provide substantial substructure information. The results provide further insight into European population genetic substructure and show that this information can be used for improving error rates in association testing of candidate genes and in replication studies of WGA scans.

Tian C, Hinds DA, Shigeta R, Adler SG, Lee A, Pahl MV, Silva G, Belmont JW, Hanson RL, Knowler WC, Gregersen PK, Ballinger DG, Seldin MF. · Rowe Program in Human Genetics, Department of Biochemistry, University of California Davis, Davis, CA 95616, USA. · Am J Hum Genet. · Pubmed #17557415 links to  free full text

Abstract: For admixture mapping studies in Mexican Americans (MAM), we define a genomewide single-nucleotide-polymorphism (SNP) panel that can distinguish between chromosomal segments of Amerindian (AMI) or European (EUR) ancestry. These studies used genotypes for >400,000 SNPs, defined in EUR and both Pima and Mayan AMI, to define a set of ancestry-informative markers (AIMs). The use of two AMI populations was necessary to remove a subset of SNPs that distinguished genotypes of only one AMI subgroup from EUR genotypes. The AIMs set contained 8,144 SNPs separated by a minimum of 50 kb with only three intermarker intervals >1 Mb and had EUR/AMI FST values >0.30 (mean FST = 0.48) and Mayan/Pima FST values <0.05 (mean FST < 0.01). Analysis of a subset of these SNP AIMs suggested that this panel may also distinguish ancestry between EUR and other disparate AMI groups, including Quechuan from South America. We show, using realistic simulation parameters that are based on our analyses of MAM genotyping results, that this panel of SNP AIMs provides good power for detecting disease-associated chromosomal segments for genes with modest ethnicity risk ratios. A reduced set of 5,287 SNP AIMs captured almost the same admixture mapping information, but smaller SNP sets showed substantial drop-off in admixture mapping information and power. The results will enable studies of type 2 diabetes, rheumatoid arthritis, and other diseases among which epidemiological studies suggest differences in the distribution of ancestry-associated susceptibility.

Lee HS, Irigoyen P, Kern M, Lee A, Batliwalla F, Khalili H, Wolfe F, Lum RF, Massarotti E, Weisman M, Bombardier C, Karlson EW, Criswell LA, Vlietinck R, Gregersen PK. · Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA. · Arthritis Rheum. · Pubmed #17530703 links to  free full text

Abstract: OBJECTIVE: Recently, Swedish members of the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) provided evidence that smoking may trigger RA-specific immune reactions to citrullinated protein in carriers of HLA-DR shared epitope alleles. In an effort to confirm this interaction between smoking and shared epitope alleles, we performed a case-only analysis of 3 North American RA cohorts. METHODS: A total of 2,476 white patients with RA were studied, 1,105 from the North American Rheumatoid Arthritis Consortium (NARAC) family collection, 753 from the National Inception Cohort of Rheumatoid Arthritis Patients (Inception Cohort), and 618 from the Study of New Onset Rheumatoid Arthritis (SONORA). All patients were HLA-DRB1 typed, and tested for anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor. Information about smoking history was obtained by questionnaire. RESULTS: A significant association was found between smoking and the presence of anti-CCP in the NARAC and the Inception Cohort, but not in the SONORA. The shared epitope alleles consistently correlated with anti-CCP in all 3 populations. Using multiple logistic regression analyses, shared epitope alleles were still the most significant risk factor for anti-CCP positivity. Weak evidence of gene-environment interaction between smoking and shared epitope alleles for anti-CCP formation was found only in the NARAC. CONCLUSION: Unlike the EIRA data, we could not confirm a major gene-environment interaction for anti-CCP formation between shared epitope alleles and smoking in 3 North American RA cohorts. Our data indicate a need for further studies to address the full range of environmental factors other than smoking that may be associated with citrullination and RA.

Lee A, Kasama R, Evangelisto A, Elfenbein B, Falasca G. · Division of Rheumatology, the Department of Clinical Medicine, Cooper University Hospital, UMDNJ-Robert Wood Johnson Medical School at Camden, Camden, New Jersey 08103, USA. · J Clin Rheumatol. · Pubmed #17023811 No free full text.

Abstract: Etanercept is a recombinant dimeric fusion protein consisting of a tumor necrosis factor-alpha receptor ligand-binding region linked to the Fc portion of human IgG. It is approved for use in the treatment of rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriasis, and psoriatic arthritis. Since 1998, there have been reports of vasculitic adverse events, including necrotizing vasculitis and leukocytoclastic vasculitis. In addition, the adverse events reporting system of the U.S. Food and Drug Administration has recorded 35 cases of leukocytoclastic vasculitis, 20 after etanercept therapy and 15 after infliximab. Most cases of cutaneous vasculitis describe development of symptoms within 3 months of etanercept use. In only one case report was direct immunofluorescence performed on tissue and no specific immunoreactivity found. We describe the first case of Henoch-Schönlein purpura with acute renal failure associated with increase in etanercept dose after 11 months of use for treatment of psoriasis. Discontinuation of the drug and treatment with a course of systemic steroids led to the complete resolution of the vasculitis and improvement of renal function. Vasculitis occurring even during chronic use of antitumor necrosis factor agents must be considered as possibly related to the therapy.

Lee HS, Li W, Lee A, Rodine P, Graham RR, Ortmann WA, Batliwalla F, Lee KW, Bae SC, Behrens TW, Gregersen PK. · Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA. · Genes Immun. · Pubmed #16855621 No free full text.

Abstract: The current methods for molecular typing of HLA-DR alleles incur a substantial financial burden when performing large population studies. In the current study, we aimed to provide much less expensive typing approach with high predictability for DRB1 genotype. We have used a panel of three microsatellite markers in the class II region (D6S2666, D6S2665 and D6S2446) for genotyping and haplotype reconstruction in a total of 1687 Caucasian (1313 RA patients and 374 controls) and 1364 Korean individuals (744 RA patients and 620 controls), all of whom were previously genotyped for DRB1. We found that a total of 88.4 and 87.4% of all observed three-marker haplotypes could determine the DR type with a positive predictive value >0.8 with high sensitivity and specificity. There was a high degree of haplotype conservation when comparing Caucasian and Asian populations. Interestingly, we found that the majority of DRB1*09 and DRB1*10 alleles share a common three-marker haplotype in both Caucasian and Asian populations. This is unexpected, since these two alleles are found on very different haplotype families. In addition, these two alleles are both associated with rheumatoid arthritis, making the elucidation of these haplotype relationships potentially important for understanding disease susceptibility.

Amos CI, Chen WV, Lee A, Li W, Kern M, Lundsten R, Batliwalla F, Wener M, Remmers E, Kastner DA, Criswell LA, Seldin MF, Gregersen PK. · Department of Epidemiology, University of Texas, MD Anderson Cancer Center, Houston, USA. · Genes Immun. · Pubmed #16691188 No free full text.

Abstract: We have completed a genome wide linkage scan using >5700 informative single-nucleotide polymorphism (SNP) markers (Illumina IV SNP linkage panel) in 642 Caucasian families containing affected sibling pairs with rheumatoid arthritis (RA), ascertained by the North American Rheumatoid Arthritis Consortium. The results show striking new evidence of linkage at chromosomes 2q33 and 11p12 with logarithm of odds (LOD) scores of 3.52 and 3.09, respectively. In addition to a strong and broad linkage interval surrounding the major histocompatibility complex (LOD>16), regions with LOD>2.5 were observed on chromosomes 5 and 10. Additional linkage evidence (LOD scores between 1.46 and 2.35) was also observed on chromosomes 4, 7, 12, 16 and 18. This new evidence for multiple regions of genetic linkage is partly explained by the significantly increased information content of the Illumina IV SNP linkage panel (75.6%) compared with a standard microsatellite linkage panel utilized previously (mean 52.6%). Stratified analyses according to whether or not the sibling pair members showed elevated anticyclic citrullinated peptide titers indicates significant variation in evidence for linkage among strata on chromosomes 4, 5, 6 and 7. Overall, these new linkage data should reinvigorate efforts to utilize positional information to identify susceptibility genes for RA.

Addo A, Le J, Li W, Aksentijevich I, Balow J, Lee A, Gregersen PK, Kastner DL, Remmers EF. · Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892-0908, USA. · Scand J Rheumatol. · Pubmed #16134725 No free full text.

Abstract: OBJECTIVES: The CARD15/NOD2 gene product plays an important role in host response to bacterial lipopolysaccharides and bacterial muramyl dipeptide via activation of NF-kappaB in monocytes. Mutations in CARD15 are associated with Crohn's disease (CD), a chronic inflammatory bowel disease. In this study we sought to determine whether CD-associated mutations or any common variants of this gene might contribute to susceptibility to another chronic inflammatory disease, rheumatoid arthritis (RA). METHODS: We genotyped 376 Caucasian RA cases and 376 ethnically matched healthy controls for three CD-associated CARD15 mutations. We also genotyped these 752 individuals for 12 common CARD15 single nucleotide polymorphisms (SNPs), determined the linkage disequilibrium structure of the gene, and compared the frequencies of the common CARD15 haplotypes in the RA cases and controls. RESULTS: None of the CD-associated mutations or the CARD15 SNPs was associated with susceptibility to RA. We also found no significant difference in the frequencies of any of the common haplotypes of the CARD15 gene in RA patients and controls. Our haplotype analysis was consistent with earlier observations that all three CD-associated variants independently arose on the same ancestral haplotype. CONCLUSIONS: These data suggest that CARD15 variants are not associated with RA susceptibility.

Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, Chang M, Ramos P, Baechler EC, Batliwalla FM, Novitzke J, Williams AH, Gillett C, Rodine P, Graham RR, Ardlie KG, Gaffney PM, Moser KL, Petri M, Begovich AB, Gregersen PK, Behrens TW. · Department of Medicine, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA. · Am J Hum Genet. · Pubmed #15273934 links to  free full text

Abstract: We genotyped 525 independent North American white individuals with systemic lupus erythematosus (SLE) for the PTPN22 R620W polymorphism and compared the results with data generated from 1,961 white control individuals. The R620W SNP was associated with SLE (genotypic P=.00009), with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increases risk of SLE (odds ratio [OR]=1.37; 95% confidence interval [CI] 1.07-1.75), and two copies of the allele more than double this risk (OR=4.37; 95% CI 1.98-9.65). Together with recent evidence showing association of this SNP with type 1 diabetes and rheumatoid arthritis, these data provide compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity.

Jawaheer D, Li W, Graham RR, Chen W, Damle A, Xiao X, Monteiro J, Khalili H, Lee A, Lundsten R, Begovich A, Bugawan T, Erlich H, Elder JT, Criswell LA, Seldin MF, Amos CI, Behrens TW, Gregersen PK. · Center for Genomics and Human Genetics, North Shore-Long Island Jewish Research Institute, Manhasset, NY, 11030, USA. · Am J Hum Genet. · Pubmed #12181776 links to  free full text

Abstract: Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 "shared epitope" in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus.