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1.  A genetic study on C5-TRAF1 and progression of joint damage in rheumatoid arthritis 
Introduction
The severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts.
Methods
In total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients.
Results
No associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA. Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population (P-value meta-analysis = 5.85 × 10−7); the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1. The P-value for rs7021880 in meta-analysis was 6.35 × 10−8. Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5.
Conclusion
Variants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression. Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0514-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-014-0514-0
PMCID: PMC4318544  PMID: 25566937
2.  Relationship between air pollution and positivity of RA-related autoantibodies in individuals without established RA: a report on SERA 
Annals of the rheumatic diseases  2013;72(12):10.1136/annrheumdis-2012-202949.
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.
doi:10.1136/annrheumdis-2012-202949
PMCID: PMC3818364  PMID: 23572338
3.  Genome-wide Association Study of Dermatomyositis Reveals Genetic Overlap with other Autoimmune Disorders 
Arthritis and rheumatism  2013;65(12):3239-3247.
Objective
To identify new genetic associations with juvenile and adult dermatomyositis (DM).
Methods
We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1178) and controls (n = 4724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM.
Results
Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5x10−8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that three SNPs linked with three genes were associated with DM, with a false discovery rate (FDR) < 0.05. These genes were phospholipase C like 1 (PLCL1, rs6738825, FDR=0.00089), B lymphoid tyrosine kinase (BLK, rs2736340, FDR=0.00031), and chemokine (C-C motif) ligand 21 (CCL21, rs951005, FDR=0.0076). None of these genes was previously reported to be associated with DM.
Conclusion
Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.
doi:10.1002/art.38137
PMCID: PMC3934004  PMID: 23983088
dermatomyositis; adult; juvenile; shared autoimmunity genes
4.  Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci 
Nature genetics  2010;42(6):508-514.
To identify novel genetic risk factors for rheumatoid arthritis (RA), we conducted a genome-wide association study (GWAS) meta-analysis of 5,539 autoantibody positive RA cases and 20,169 controls of European descent, followed by replication in an independent set of 6,768 RA cases and 8,806 controls. Of 34 SNPs selected for replication, 7 novel RA risk alleles were identified at genome-wide significance (P<5×10−8) in analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5, and PXK. We also refined the risk alleles at two established RA risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed RA risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P<0.05, many of which are validated autoimmune risk alleles, suggesting that most represent bona fide RA risk alleles.
doi:10.1038/ng.582
PMCID: PMC4243840  PMID: 20453842
5.  Risk for Myasthenia Gravis maps to 151Pro→ Ala change in TNIP1 and to HLA-B*08 
Annals of neurology  2012;72(6):927-935.
Objective
The objective of this study is to comprehensively define the genetic basis of Early Onset Myasthenia Gravis.
Methods
We have carried out a two-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 HLA region.
Results
We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 × 10−92, 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.
doi:10.1002/ana.23691
PMCID: PMC3535539  PMID: 23055271
6.  Genome-wide association analysis of anti-TNF drug response in rheumatoid arthritis patients 
Annals of the rheumatic diseases  2012;72(8):1375-1381.
Background
Treatment strategies blocking tumor 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 prior to treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patient with RA using a genome-wide association approach.
Methods
We conducted a multi-stage, genome-wide association study with a primary analysis of 2,557,253 single nucleotide polymorphisms (SNPs) in 882 RA patients 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 a p<10−3 were selected for replication in 1,821 RA patients from three independent cohorts. Pathway analysis including all SNPs with a p-value < 10−3 was performed using Ingenuity.
Results
Seven hundred seventy two markers demonstrated evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p-value in the overall meta-analysis compared to the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four studied cohorts. 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.
Conclusion
Using a multi-stage strategy, we have identified 8 genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections.
doi:10.1136/annrheumdis-2012-202405
PMCID: PMC4169706  PMID: 23233654
anti-TNF; gene polymorphism; pharmacogenetics; rheumatoid arthritis; genome-wide association study
7.  Common Variants near the Melanocortin 4 Receptor Gene are Associated with Severe Antipsychotic Drug-induced Weight Gain 
Archives of general psychiatry  2012;69(9):904-912.
Context
Second-generation antipsychotics (SGAs) are increasingly used in the treatment of many psychotic and non-psychotic disorders. Unfortunately, SGAs are often associated with substantial weight gain, with no means to predict which patients are at greatest risk.
Objective
To detect alleles of single nucleotide polymorphisms (SNPs) associated with antipsychotic drug-induced weight gain.
Design
Pharmacogenetic association study
Setting
Discovery cohort was collected at a U.S. general psychiatric hospital. Three additional cohorts were collected from psychiatric hospitals in the U.S. and Germany, and from a European antipsychotic drug trial.
Participants
The discovery cohort was comprised of 139 pediatric patients undergoing first exposure to SGA treatment. An additional three cohorts were comprised of 73, 40 and 92 subjects.
Intervention
Patients in the discovery cohort were treated with SGAs for twelve weeks. Additional cohorts were treated for six and twelve weeks.
Main outcome measure
We conducted a genome-wide association study (GWAS) assessing weight gain associated with twelve weeks of SGA treatment in patients undergoing first exposure to antipsychotic treatment. We next genotyped three independent cohorts of subjects assessed for antipsychotic drug-induced weight gain.
Results
GWAS yielded twenty SNPs at a single locus exceeding a statistical threshold of p < 10−5. This locus, near the melanocortin 4 receptor (MC4R) gene, overlaps a region previously identified by large-scale GWAS of obesity in the general population. Effects were recessive, with minor allele homozygotes gaining extreme amounts of weight over the 12-week trial. These results were replicated in three additional cohorts with SNP rs489693 demonstrating consistent recessive effects; meta analysis revealed a genome-wide significant effect (p=5.59×10−12). Moreover, we observed consistent effects on related metabolic indices, including triglycerides, leptin, insulin, and HOMA-IR in our discovery cohort.
Conclusion
These data implicate the MC4R locus in extreme SGA-induced weight gain and related metabolic disturbances. A priori identification of high-risk subjects could lead to alternative treatment strategies in this population.
doi:10.1001/archgenpsychiatry.2012.191
PMCID: PMC4166499  PMID: 22566560
8.  The Influence of Polygenic Risk Scores on Heritability of Anti-CCP Level in RA 
Genes and immunity  2014;15(2):107-114.
Objective
To study genetic factors that influence quantitative anti-cyclic citrullinated peptide (anti-CCP) antibody levels in RA patients.
Methods
We carried out a genome wide association study (GWAS) meta-analysis using 1,975 anti-CCP+ RA patients from 3 large cohorts, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), North American Rheumatoid Arthritis Consortium (NARAC), and the Epidemiological Investigation of RA (EIRA). We also carried out a genome-wide complex trait analysis (GCTA) to estimate the heritability of anti-CCP levels.
Results
GWAS-meta analysis showed that anti-CCP levels were most strongly associated with the human leukocyte antigen (HLA) region with a p-value of 2×10−11 for rs1980493. There were 112 SNPs in this region that exceeded the genome-wide significance threshold of 5×10−8, and all were in linkage disequilibrium (LD) with the HLA- DRB1*03 allele with LD r2 in the range of 0.25-0.88. Suggestive novel associations outside of the HLA region were also observed for rs8063248 (near the GP2 gene) with a p-value of 3×10−7. None of the known RA risk alleles (~52 loci) were associated with anti-CCP level. Heritability analysis estimated that 44% of anti-CCP variation was attributable to genetic factors captured by GWAS variants.
Conclusions
Anti-CCP level is a heritable trait. HLA-DR3 and GP2 are associated with lower anti-CCP levels.
doi:10.1038/gene.2013.68
PMCID: PMC3948067  PMID: 24385024
RA; GWAS; anti-CCP; heritability
9.  Anti-Cyclic Citrullinated Peptide Assays Differ in Subjects at Elevated Risk for Rheumatoid Arthritis and Subjects with Established Disease 
Arthritis and rheumatism  2013;65(9):2243-2252.
Objective
To compare commonly-available tests for antibodies to citrullinated protein antigens (ACPAs) for diagnostic accuracy and assay agreement in established rheumatoid arthritis (RA) and subjects at elevated risk for RA.
Methods
ELISA testing for anti-cyclic citrullinated peptide (anti-CCP) antibodies was performed using CCP2 (Axis-Shield) and CCP3.1 (IgA/IgG INOVA) in the following subjects: 1) probands with established RA (N=340) from the Studies of the Etiology of RA (SERA), 2) first degree relatives (FDRs) without RA (family members of SERA RA probands; N=681), 3) Department of Defense Serum Repository (DoDSR) RA cases with pre-diagnosis samples (N=83; 47/83 also had post-diagnosis samples), and 4) blood-donor and DoDSR controls (N=283).
Results
In established RA, CCP2 was more specific (99.2% vs. 93.1%, p<0.01), but less sensitive (58.7% vs. 67.4%, p=0.01) than CCP3.1, with specificity of CCP3.1 increasing to 97.2% if levels ≥3 times the standard cut-off level were considered. In all subjects, at standard cut-off levels, CCP3.1 positivity was more prevalent. In DoDSR cases, CCP2 was more specific than CCP3.1 for a future diagnosis of RA, and higher CCP levels trended towards greater specificity for disease onset within 2 years. At standard cut-off levels, assay agreement was good in established RA (kappa=0.76), but poor in FDRs without inflammatory arthritis (kappa=0.25).
Conclusion
Anti-CCP assays differ to an extent that may be meaningful in diagnosing RA in patients with inflammatory arthritis, and in evaluating the natural history of RA development in subjects at-risk for future RA. Mechanisms underlying these differences in test performance need further investigation.
doi:10.1002/art.38017
PMCID: PMC3776020  PMID: 23686569
Rheumatoid arthritis; autoantibodies; CCP; ACPA; preclinical
10.  Genetics of rheumatoid arthritis contributes to biology and drug discovery 
Okada, Yukinori | Wu, Di | Trynka, Gosia | Raj, Towfique | Terao, Chikashi | Ikari, Katsunori | Kochi, Yuta | Ohmura, Koichiro | Suzuki, Akari | Yoshida, Shinji | Graham, Robert R. | Manoharan, Arun | Ortmann, Ward | Bhangale, Tushar | Denny, Joshua C. | Carroll, Robert J. | Eyler, Anne E. | Greenberg, Jeffrey D. | Kremer, Joel M. | Pappas, Dimitrios A. | Jiang, Lei | Yin, Jian | Ye, Lingying | Su, Ding-Feng | Yang, Jian | Xie, Gang | Keystone, Ed | Westra, Harm-Jan | Esko, Tõnu | Metspalu, Andres | Zhou, Xuezhong | Gupta, Namrata | Mirel, Daniel | Stahl, Eli A. | Diogo, Dorothée | Cui, Jing | Liao, Katherine | Guo, Michael H. | Myouzen, Keiko | Kawaguchi, Takahisa | Coenen, Marieke J.H. | van Riel, Piet L.C.M. | van de Laar, Mart A.F.J. | Guchelaar, Henk-Jan | Huizinga, Tom W.J. | Dieudé, Philippe | Mariette, Xavier | Bridges, S. Louis | Zhernakova, Alexandra | Toes, Rene E.M. | Tak, Paul P. | Miceli-Richard, Corinne | Bang, So-Young | Lee, Hye-Soon | Martin, Javier | Gonzalez-Gay, Miguel A. | Rodriguez-Rodriguez, Luis | Rantapää-Dahlqvist, Solbritt | Ärlestig, Lisbeth | Choi, Hyon K. | Kamatani, Yoichiro | Galan, Pilar | Lathrop, Mark | Eyre, Steve | Bowes, John | Barton, Anne | de Vries, Niek | Moreland, Larry W. | Criswell, Lindsey A. | Karlson, Elizabeth W. | Taniguchi, Atsuo | Yamada, Ryo | Kubo, Michiaki | Liu, Jun S. | Bae, Sang-Cheol | Worthington, Jane | Padyukov, Leonid | Klareskog, Lars | Gregersen, Peter K. | Raychaudhuri, Soumya | Stranger, Barbara E. | De Jager, Philip L. | Franke, Lude | Visscher, Peter M. | Brown, Matthew A. | Yamanaka, Hisashi | Mimori, Tsuneyo | Takahashi, Atsushi | Xu, Huji | Behrens, Timothy W. | Siminovitch, Katherine A. | Momohara, Shigeki | Matsuda, Fumihiko | Yamamoto, Kazuhiko | Plenge, Robert M.
Nature  2013;506(7488):376-381.
A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs). We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012–4. We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7–9 – as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes – to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
doi:10.1038/nature12873
PMCID: PMC3944098  PMID: 24390342
11.  Immunochip Identifies Novel, and Replicates Known, Genetic Risk Loci for Rheumatoid Arthritis in Black South Africans 
Molecular Medicine  2014;20(1):341-349.
The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n = 263) were compared with healthy controls (n = 374). Genotyping was performed using the Immunochip, and four-digit high-resolution human leukocyte antigen (HLA) typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA-DRB1 and HLA-DQA1 loci. After conditioning on HLA-DRB1 alleles, the effect in the rest of the extended major histocompatibility (MHC) diminished. Non-HLA single nucleotide polymorphisms (SNPs) in the intergenic regions LOC389203|RBPJ, LOC100131131|IL1R1, KIAA1919|REV3L, LOC643749|TRAF3IP2, and SNPs in the intron and untranslated regions (UTR) of IRF1 and the intronic region of ICOS and KIAA1542 showed association with RA (p < 5 × 10−5). Of the SNPs previously associated with RA in Caucasians, one SNP, rs874040, locating to the intergenic region LOC389203|RBPJ was replicated in this study. None of the variants in the PTPN22 gene was significantly associated. The seropositive subgroups showed similar results to the overall cohort. The effects observed across the HLA region are most likely due to HLA-DRB1, and secondary effects in the extended MHC cannot be detected. Seven non-HLA loci are associated with RA in black South Africans. Similar to Caucasians, the intergenic region between LOC38920 and RBPJ is associated with RA in this population. The strong association of the R620W variant of the PTPN22 gene with RA in Caucasians was not replicated since this variant was monomorphic in our study, but other SNP variants of the PTPN22 gene were also not associated with RA in black South Africans, suggesting that this locus does not play a major role in RA in this population.
doi:10.2119/molmed.2014.00097
PMCID: PMC4153842  PMID: 25014791
12.  Relatives Without Rheumatoid Arthritis Show Reactivity to Anti-Citrullinated Protein/Peptide Antibodies Which are Associated with Arthritis-Related Traits: Studies of the Etiology of Rheumatoid Arthritis 
Arthritis and rheumatism  2013;65(8):1995-2004.
Objective
Examine anti-citrullinated protein/peptide antibodies (ACPA) reactivity and determine associations between ACPA and other rheumatoid arthritis (RA)-related autoantibodies and clinically-assessed swollen or tender joints in first-degree relatives (FDRs) without 1987 and 2010 American College of Rheumatology classified RA.
Methods
A bead-based assay measured 16 separate ACPA in sera from 111 FDRs (Ab+) who were positive on at least one visit for any of 5 RA-related autoantibodies (RF, anti-CCP2, and RF isotypes), and 99 FDRs (Ab−) who were never autoantibody positive. Cut-offs for positivity for each ACPA were determined using receiver operating characteristic curves of data from 200 RA cases and 98 blood-bank controls, wherein positivity for ≥ 9 ACPA had 92% specificity and 62% sensitivity for RA. In FDRs, we assessed ACPA reactivity and examined associations between ACPA (number positive and positivity for ≥ 9 ACPA) and RA-related characteristics.
Results
Four of 7 anti-CCP2 positive and 8% of anti-CCP2 negative FDRs were positive for ≥ 9 ACPA. After adjusting for age, gender, ethnicity and pack-years of smoking, increasing number of ACPA was directly associated with having ≥ 1 tender joint on exam (OR=1.18, 95% CI 1.04–1.34), with the greatest risk seen in FDRs positive for ≥ 9 ACPA (OR=5.00, 95% CI 1.37–18.18).
Conclusions
RA-free FDRs demonstrate reactivity to multiple ACPA, even in those negative for rheumatoid factor and anti-CCP2, and increasing ACPA may be associated with signs of joint inflammation. Prospective evaluation of the relationship between these findings and progression of classifiable RA is warranted.
doi:10.1002/art.38022
PMCID: PMC3729718  PMID: 23754702
pre-clinical RA; autoantibodies; ACPA; rheumatoid arthritis
14.  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) 
Annals of the rheumatic diseases  2012;72(6):901-907.
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.
doi:10.1136/annrheumdis-2012-201505
PMCID: PMC3726193  PMID: 22915618
15.  European Population Substructure Correlates with Systemic Lupus Erythematosus Endophenotypes in North Americans of European Descent 
Genes and immunity  2009;11(6):515-521.
Previous work has demonstrated that northern and southern European ancestries are associated with specific systemic lupus erythematosus (SLE) manifestations. Here, 1855 SLE cases of European descent were genotyped for 4965 single nucleotide polymorphisms and principal components analysis of genotype information was used to define population substructure. The first principal component (PC1) distinguished northern from southern European ancestry, PC2 differentiated eastern from western European ancestry, and PC3 delineated Ashkenazi Jewish ancestry. Compared to northern European ancestry, southern European ancestry was associated with autoantibody production (OR=1.40, 95% CI 1.07-1.83) and renal involvement (OR 1.41, 95% CI 1.06-1.87), and was protective for discoid rash (OR=0.51, 95% CI 0.32-0.82) and photosensitivity (OR=0.74, 95% CI 0.56-0.97). Both serositis (OR=1.46, 95% CI 1.12-1.89) and autoantibody production (OR=1.38, 95% CI 1.06-1.80) were associated with Western compared to Eastern European ancestry. Ashkenazi Jewish ancestry was protective against neurologic manifestations of SLE (OR=0.62, 95% CI 0.40-0.94). Homogeneous clusters of cases defined by multiple PCs demonstrated stronger phenotypic associations. Genetic ancestry may contribute to the development of SLE endophenotypes and should be accounted for in genetic studies of disease characteristics.
doi:10.1038/gene.2009.80
PMCID: PMC3951966  PMID: 19847193
Systemic lupus erythematosus; epidemiology; population substructure; genetics
16.  Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene 
PLoS ONE  2014;9(2):e87645.
Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10−6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.
doi:10.1371/journal.pone.0087645
PMCID: PMC3919745  PMID: 24520335
17.  Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder 
Nature Communications  2013;4:2739.
Schizophrenia and bipolar disorder are major psychiatric disorders with high heritability and overlapping genetic variance. Here we perform a genome-wide association study in an ethnically homogeneous cohort of 904 schizophrenia cases and 1,640 controls drawn from the Ashkenazi Jewish population. We identify a novel genome-wide significant risk locus at chromosome 4q26, demonstrating the potential advantages of this founder population for gene discovery. The top single-nucleotide polymorphism (SNP; rs11098403) demonstrates consistent effects across 11 replication and extension cohorts, totalling 23, 191 samples across multiple ethnicities, regardless of diagnosis (schizophrenia or bipolar disorder), resulting in Pmeta=9.49 × 10−12 (odds ratio (OR)=1.13, 95% confidence interval (CI): 1.08–1.17) across both disorders and Pmeta=2.67 × 10−8 (OR=1.15, 95% CI: 1.08–1.21) for schizophrenia alone. In addition, this intergenic SNP significantly predicts postmortem cerebellar gene expression of NDST3, which encodes an enzyme critical to heparan sulphate metabolism. Heparan sulphate binding is critical to neurite outgrowth, axon formation and synaptic processes thought to be aberrant in these disorders.
Schizophrenia and bipolar disorder are important psychiatric disorders with overlapping genetic components. Here, the authors identify and replicate a genome-wide significant risk locus for the two disorders, and suggest a role for NDST3 in severe psychiatric disease.
doi:10.1038/ncomms3739
PMCID: PMC3905728  PMID: 24253340
18.  Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus 
Nature genetics  2008;40(9):1062-1064.
The TNFAIP3 (tumor necrosis factor alpha–induced protein 3) gene encodes a ubiquitin editing enzyme, A20, that restricts NF-κB–dependent signaling and prevents inflammation. We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry. These findings provide critical links between A20 and the etiology of SLE.
doi:10.1038/ng.202
PMCID: PMC3897246  PMID: 19165919
19.  Genome-Wide Association Study Reveals Novel Genetic Determinants of DNA Repair Capacity in Lung Cancer 
Cancer research  2012;73(1):256-264.
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.
doi:10.1158/0008-5472.CAN-12-1915
PMCID: PMC3537906  PMID: 23108145
DNA repair capacity; genetic susceptibility; genome-wide association; molecular epidemiology
20.  Gene expression patterns in peripheral blood cells associated with radiographic severity in African Americans with early rheumatoid arthritis 
Rheumatology international  2012;33(1):129-137.
Gene expression profiling may be used to stratify patients by disease severity to test the hypothesis that variable disease outcome has a genetic component. In order to define unique expression signatures in African American rheumatoid arthritis (RA) patients with severe erosive disease, we undertook a gene expression study using samples of RNA from peripheral blood mononuclear cells (PBMCs). RNA from baseline PBMC samples of 96 African American RA patients with early RA (<2 years disease duration) was hybridized to cDNA probes of the Illumina Human HT-V3 expression array. Expression analyses were performed using the ca. 25,000 cDNA probes, and then expression levels were compared to the total number of erosions in radiographs of the hands and feet at baseline and 36 months. Using a false discovery rate cutoff of Q = 0.30, 1,138 genes at baseline and 680 genes at 36 months significantly correlated with total erosions. No evidence of a signal differentiating disease progression, or change in erosion scores between baseline and 36 months, was found. Further analyses demonstrated that the differential gene expression signature was localized to the patients with the most erosive disease (>10 erosions). Ingenuity Pathway Analysis demonstrated that genes with fold change greater than 1.5 implicated immune pathways such as CTLA signaling in cytotoxic T lymphocytes. These results demonstrate that CLEAR patients with early RA having the most severe erosive disease, as compared to more mild cases (<10 erosions), may be characterized by a set of differentially expressed genes that represent biological pathways with relevance to autoimmune disease.
doi:10.1007/s00296-011-2355-3
PMCID: PMC3769702  PMID: 22238028
Genome-wide gene expression; Sharp/van der Heijde; Pathway analysis; CLEAR; ABCoN
21.  Extended haplotype association study in Crohn’s disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3 
Genes and immunity  2013;14(5):310-316.
The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn’s disease compared to non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to Crohn’s disease etiology in this population, most notably at NOD2, in which three causal, uncommon, and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes which showed significantly greater association to Crohn’s disease in the Ashkenazi Jewish population compared to a non-Jewish population (145 haplotypes and no haplotypes with P-value < 10−3, respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established Crohn’s disease loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-κB signaling. The BRD7 signal showed conditional dependence with only the downstream rare Crohn’s disease-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association.
doi:10.1038/gene.2013.19
PMCID: PMC3785105  PMID: 23615072
haplotype association; Ashkenazi Jewish; Crohn’s disease; NF-κB signaling; synthetic association
22.  Quantifying Missing Heritability at Known GWAS Loci 
PLoS Genetics  2013;9(12):e1003993.
Recent work has shown that much of the missing heritability of complex traits can be resolved by estimates of heritability explained by all genotyped SNPs. However, it is currently unknown how much heritability is missing due to poor tagging or additional causal variants at known GWAS loci. Here, we use variance components to quantify the heritability explained by all SNPs at known GWAS loci in nine diseases from WTCCC1 and WTCCC2. After accounting for expectation, we observed all SNPs at known GWAS loci to explain more heritability than GWAS-associated SNPs on average (). For some diseases, this increase was individually significant: for Multiple Sclerosis (MS) () and for Crohn's Disease (CD) (); all analyses of autoimmune diseases excluded the well-studied MHC region. Additionally, we found that GWAS loci from other related traits also explained significant heritability. The union of all autoimmune disease loci explained more MS heritability than known MS SNPs () and more CD heritability than known CD SNPs (), with an analogous increase for all autoimmune diseases analyzed. We also observed significant increases in an analysis of Rheumatoid Arthritis (RA) samples typed on ImmunoChip, with more heritability from all SNPs at GWAS loci () and more heritability from all autoimmune disease loci () compared to known RA SNPs (including those identified in this cohort). Our methods adjust for LD between SNPs, which can bias standard estimates of heritability from SNPs even if all causal variants are typed. By comparing adjusted estimates, we hypothesize that the genome-wide distribution of causal variants is enriched for low-frequency alleles, but that causal variants at known GWAS loci are skewed towards common alleles. These findings have important ramifications for fine-mapping study design and our understanding of complex disease architecture.
Author Summary
Heritable diseases have an unknown underlying “genetic architecture” that defines the distribution of effect-sizes for disease-causing mutations. Understanding this genetic architecture is an important first step in designing disease-mapping studies, and many theories have been developed on the nature of this distribution. Here, we evaluate the hypothesis that additional heritable variation lies at previously known associated loci but is not fully explained by the single most associated marker. We develop methods based on variance-components analysis to quantify this type of “local” heritability, demonstrating that standard strategies can be falsely inflated or deflated due to correlation between neighboring markers and propose a robust adjustment. In analysis of nine common diseases we find a significant average increase of local heritability, consistent with multiple common causal variants at an average locus. Intriguingly, for autoimmune diseases we also observe significant local heritability in loci not associated with the specific disease but with other autoimmune diseases, implying a highly correlated underlying disease architecture. These findings have important implications to the design of future studies and our general understanding of common disease.
doi:10.1371/journal.pgen.1003993
PMCID: PMC3873246  PMID: 24385918
23.  European Genetic Ancestry is Associated with a Decreased Risk of Lupus Nephritis 
Arthritis and rheumatism  2012;64(10):10.1002/art.34567.
Objective
African Americans, East Asians, and Hispanics with systemic lupus erythematosus (SLE) are more likely to develop renal disease than SLE patients of European descent. We investigated whether European genetic ancestry protects against the development of lupus nephritis and explored genetic and socioeconomic factors that might explain this effect.
Methods
This was a cross-sectional study of 1906 adults with SLE. 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. We used logistic regression to test the association between European ancestry and renal disease. Analyses adjusted for continental ancestries, socioeconomic status, and candidate genes.
Results
Participants (n=1906) had on average 62.4% European, 15.8% African, 11.5% East Asian, 6.5% Amerindian, and 3.8% South Asian ancestry. Among participants, 34% (n=656) had renal disease. A 10% increase in European ancestry was associated with a 15% reduction in the odds of having renal disease after adjustment for disease duration and sex (OR 0.85, 95% CI 0.82-0.87, p=1.9 × 10−30). Adjusting for other genetic ancestries, measures of socioeconomic status, or SNPs in genes most associated with renal disease (IRF5 (rs4728142), BLK (rs2736340), STAT4 (rs3024912), ITGAM (rs9937837) and HLA-DRB1*0301 and DRB1*1501, p<0.05) did not substantively alter this relationship.
Conclusion
European ancestry is protective against the development of renal disease in SLE, an effect independent of other genetic ancestries, common risk alleles, and socioeconomic status.
doi:10.1002/art.34567
PMCID: PMC3865923  PMID: 23023776
24.  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 
Human Molecular Genetics  2012;21(23):5209-5221.
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.
doi:10.1093/hmg/dds359
PMCID: PMC3490520  PMID: 22936693
25.  Is synaesthesia more common in autism? 
Molecular Autism  2013;4:40.
Background
Synaesthesia is a neurodevelopmental condition in which a sensation in one modality triggers a perception in a second modality. Autism (shorthand for Autism Spectrum Conditions) is a neurodevelopmental condition involving social-communication disability alongside resistance to change and unusually narrow interests or activities. Whilst on the surface they appear distinct, they have been suggested to share common atypical neural connectivity.
Methods
In the present study, we carried out the first prevalence study of synaesthesia in autism to formally test whether these conditions are independent. After exclusions, 164 adults with autism and 97 controls completed a synaesthesia questionnaire, Autism Spectrum Quotient, and Test of Genuineness-Revised (ToG-R) online.
Results
The rate of synaesthesia in adults with autism was 18.9% (31 out of 164), almost three times greater than in controls (7.22%, 7 out of 97, P <0.05). ToG-R proved unsuitable for synaesthetes with autism.
Conclusions
The significant increase in synaesthesia prevalence in autism suggests that the two conditions may share some common underlying mechanisms. Future research is needed to develop more feasible validation methods of synaesthesia in autism.
doi:10.1186/2040-2392-4-40
PMCID: PMC3834557  PMID: 24252644

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