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ABSTRACT: The aim of this study was to explore the role of vitamin D in rheumatoid arthritis (RA) pathogenesis by investigating the enrichment of vitamin D response elements (VDREs) in confirmed RA susceptibility loci and testing variants associated with vitamin D levels for association with RA. Bioinformatically, VDRE genomic positions were overlaid with non-HLA (human leukocyte antigen)-confirmed RA susceptibility regions. The number of VDREs at RA loci was compared to a randomly selected set of genomic loci to calculate an average relative risk (RR). Single-nucleotide polymorphisms (SNPs) in the DHCR7/NADSYN1 (nicotinamide adenine dinucleotide synthase 1) and CYP2R1 loci, previously associated with circulating vitamin D levels, were tested in UK RA cases (n=3870) and controls (n=8430). Significant enrichment of VDREs was seen at RA loci (P=9.23 × 10(-8)) when regions were defined either by gene (RR 5.50) or position (RR 5.86). SNPs in the DHCR7/NADSYN1 locus showed evidence of positive association with RA, rs4944076 (P=0.008, odds ratio (OR) 1.14, 95% confidence interval (CI) 1.03-1.24). The significant enrichment of VDREs at RA-associated loci and the modest association of variants in loci-controlling levels of circulating vitamin D supports the hypothesis that vitamin D has a role in the development of RA.Genes and Immunity advance online publication, 2 May 2013; doi:10.1038/gene.2013.23.
Genes and immunity 05/2013; · 4.22 Impact Factor
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F R Ali,
A Barton,
R L I Smith,
J Bowes,
E Flynn,
M Mangino,
V Bataille,
J P Foerster, J Worthington,
C E M Griffiths,
R B Warren
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ABSTRACT: Phenotypically diverse autoimmune conditions share common genetic susceptibility loci and underlying molecular pathways. We therefore investigated 18 single nucleotide polymorphisms, previously confirmed as being associated with rheumatoid arthritis (RA), in a UK cohort of 623 patients with early-onset psoriasis (presenting before age 40y) comparing with 2662 control subjects. Our findings confirm the association of early-onset psoriasis with REL (rs13031237, p=0.0027). The minor allele of REL had opposing effects upon susceptibility to disease in psoriasis and RA patients. Similar exploration of additional autoimmune loci and fine-mapping of such regions may provide further insight into the genetics and molecular pathophysiology of psoriasis.
British Journal of Dermatology 10/2012; · 3.67 Impact Factor
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J-E Martin,
F D Carmona,
J C A Broen,
C P Simeón,
M C Vonk,
P Carreira,
R Ríos-Fernández,
G Espinosa,
E Vicente-Rabaneda,
C Tolosa, [......],
Ø Palm,
M M Chee,
J M van Laar,
C Denton,
A Herrick, J Worthington,
B P C Koeleman,
T R D J Radstake,
C Fonseca,
J Martín
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ABSTRACT: Regulatory T cells (T(regs)) are crucial in the maintenance of the immune tolerance and seem to have an important role in systemic sclerosis (SSc). The interleukin 2 receptor α (IL2RA) is an important T(reg) marker, and polymorphisms of IL2RA gene are associated with a number of autoimmune diseases. Therefore, we aimed to investigate for the first time the association of the IL2RA locus in SSc. For this purpose, a total of 3023 SSc patients and 2735 matched healthy controls, from six European Caucasian cohorts, were genotyped for the IL2RA gene variants rs11594656, rs2104286 and rs12722495 using the TaqMan allelic discrimination technology. The overall meta-analysis reached statistical significance when the three polymorphisms were tested for association with SSc, the limited subtype (lcSSc) and anti-centromere auto-antibodies (ACAs). However, no significant P-values were obtained when the ACA-positive patients were removed from the SSc and lcSSc groups, suggesting that these associations rely on ACA positivity. The strongest association signal with ACA production was detected for rs2104286 (P(FDR)=2.07 × 10(-4), odds ratio=1.30 (1.14-1.47)). The associations of rs11594656 and rs12722495 were lost after conditioning to rs2104286, and allelic combination tests did not evidence a combined effect, indicating that rs2104286 best described the association between IL2RA and ACA presence in SSc.
Genes and immunity 02/2012; 13(2):191-6. · 4.22 Impact Factor
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J C A Broen,
L Bossini-Castillo,
L van Bon,
M C Vonk,
H Knaapen,
L Beretta,
B Rueda,
R Hesselstrand,
A Herrick, J Worthington, [......],
G Riemekasten,
H P Kiener,
R Scorza,
C P Simeón,
N Ortego-Centeno,
M A Gonzalez-Gay,
P Airò,
M J H Coenen,
J Martín,
T R D J Radstake
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ABSTRACT: To investigate whether polymorphisms in Toll-like receptor (TLR) genes, previously reported to be associated with immune-mediated diseases, are involved in systemic sclerosis (SSc).
We genotyped 14 polymorphisms in the genes for TLRs 2, 4, 7, 8, and 9 in a discovery cohort comprising 452 SSc patients and 537 controls and a replication cohort consisting of 1,170 SSc patients and 925 controls. In addition, we analyzed 15-year followup data on 964 patients to assess the potential association of TLR variants with the development of disease complications. We analyzed the functional impact of the associated polymorphism on monocyte-derived dendritic cells.
In the discovery cohort, we observed that a rare functional polymorphism in TLR2 (Pro631His) was associated with antitopoisomerase (antitopo) positivity (odds ratio 2.24 [95% confidence interval 1.24-4.04], P=0.003). This observation was validated in the replication cohort (odds ratio 2.73 [95% confidence interval 1.85-4.04], P=0.0001). In addition, in the replication cohort the TLR2 variant was associated with the diffuse subtype of the disease (P=0.02) and with the development of pulmonary arterial hypertension (PAH) (Cox proportional hazards ratio 5.61 [95% confidence interval 1.53-20.58], P=0.003 by log rank test). Functional analysis revealed that monocyte-derived dendritic cells carrying the Pro63His variant produced increased levels of inflammatory mediators (tumor necrosis factor α and interleukin-6) upon TLR-2-mediated stimulation (both P<0.0001).
Among patients with SSc, the rare TLR2 Pro631His variant is robustly associated with antitopoisomerase positivity, the diffuse form of the disease, and the development of PAH. In addition, this variant influences TLR-2-mediated cell responses. Further research is needed to elucidate the precise role of TLR-2 in the pathogenesis of SSc.
Arthritis & Rheumatism 09/2011; 64(1):264-71. · 7.87 Impact Factor
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ABSTRACT: Previously-proposed rheumatoid arthritis (RA) HLA-DRB1 susceptibility and protective models were compared, based on amino acids at positions 67-74 and autoantibody combinations. 3 657 RA patients and 1 357 controls were studied using logistic regression, with secondary stratification by anti-citrullinated peptide antibodies(ACPA) and rheumatoid factor(RF). Susceptibility models were based on previously defined HLA-DRB1 shared epitope(SE) subgroups. (70)DERAA(74), D(70) and I(67) protective models were compared, adjusting for HLA-DRB1 SE. A hierarchy of risk was observed within the HLA-DRB1 SE, particularly for ACPA-positive and RF-positive RA: HLA-DRB1(*)0401∼(*)0404>(*)0101∼(*)1001 ((*)0404>(*)0101: P=0.0003). HLA-DRB1(*)0401/(*)0404 compound heterozygosity conferred a risk similar to (*)0401 homozygosity (P=0.70). Protective effects of D(70) and I(67) were similar. Predictions of the D(70) model fitted the data better than those of the I(67) model. The protective effect of D(70) showed a gene-dose effect (OR 0.82, 95% CI 0.73-0.92, P=5.8 × 10(-4)), but was only seen in RA patients positive for RF or ACPA. HLA-DRB1 SE alleles were also associated with ACPA-negative, RF-positive RA (OR 1.42 (1.15-1.76), P=0.0012). In conclusion, HLA-DRB1 SE alleles show heterogeneity in RA susceptibility; their major effect appears to be mediated by ACPA positivity, but a significant association of HLA-DRB1 SE with RF-positive, ACPA-negative RA was also observed. D(70) specifically protected against antibody-positive RA.
Genes and immunity 09/2011; 13(2):120-8. · 4.22 Impact Factor
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ABSTRACT: With the exception of the major histocompatibility complex (MHC) and STAT4, no other rheumatoid arthritis (RA) linkage peak has been successfully fine-mapped to date. This apparent failure to identify association under peaks of linkage could be ascribed to the examination of common variation, when linkage is likely to be driven by rare variants. The purpose of this study was to investigate the overlap between genome-wide rare variant RA association signals observed in the Wellcome Trust Case Control Consortium (WTCCC) study and 11 replicating RA linkage peaks, defined as regions with evidence for linkage in >1 study.
The WTCCC data set contained 40,482 variants with minor allele frequency of ≤0.05 in 1,860 RA patients and 2,938 controls. Genotypes of all rare variants within a given gene region were collapsed into a single locus and a global P value was calculated per gene.
The distribution of rare variant signals (association P≤10(-5)) was found to differ significantly between regions with and without linkage evidence (P=2×10(-17) by Fisher's exact test). No significant difference was observed after data from the MHC region were removed or when the effect of the HLA-DRB1 locus was accounted for.
The results suggest that rare variant association signals are significantly overrepresented under linkage peaks in RA, but the effect is driven by the MHC. This is the first study to examine the overlap between linkage peaks and rare variant association signals genome-wide in a complex disease.
Arthritis & Rheumatism 03/2011; 63(6):1522-6. · 7.87 Impact Factor
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L M Diaz-Gallo,
P Gourh,
J Broen,
C Simeon,
V Fonollosa,
N Ortego-Centeno,
S Agarwal,
M C Vonk,
M Coenen,
G Riemekasten, [......],
G Espinosa,
I Castellvi,
T Witte,
F de Keyser,
M Vanthuyne,
M D Mayes,
T R D J Radstake,
F C Arnett,
J Martin,
B Rueda
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ABSTRACT: Two functional single nucleotide polymorphisms (SNP) in the PTPN22 gene (rs24746601 and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W SNP in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes.
3422 SSc patients (2020 with limited cutaneous SSc and 1208 with diffuse cutaneous SSc) and 3638 healthy controls of Caucasian ancestry from an initial case--control set of Spain and seven additional independent replication cohorts were included in our study. Both rs33996649 and rs2476601 PTPN22 polymorphisms were genotyped by TaqMan allelic discrimination assay. A meta-analysis was performed to test the overall effect of these PTPN22 polymorphisms in SSc.
The meta-analysis revealed evidence of association of the rs2476601 T allele with SSc susceptibility (p(FDRcorrected)=0.03 pooled, OR 1.15, 95% CI 1.03 to 1.28). In addition, the rs2476601 T allele was significantly associated with anticentromere-positive status (p(FDRcorrected)=0.02 pooled, OR 1.22, 95% CI 1.05 to 1.42). Although the rs33996649 A allele was significantly associated with SSc in the Spanish population (p(FDRcorrected)=0.04, OR 0.58, 95% CI 0.36 to 0.92), this association was not confirmed in the meta-analysis (p=0.36 pooled, OR 0.89, 95% CI 0.72 to 1.1).
The study suggests that the PTPN22 R620W polymorphism influences SSc genetic susceptibility but the novel R263Q genetic variant does not. These data strengthen evidence that the R620W mutation is a common risk factor in autoimmune diseases.
Annals of the rheumatic diseases 03/2011; 70(3):454-62. · 8.11 Impact Factor
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ABSTRACT: A common allele at the TAGAP gene locus demonstrates a suggestive, but not conclusive association with risk of rheumatoid arthritis (RA). To fine map the locus, we conducted comprehensive imputation of CEU HapMap single-nucleotide polymorphisms (SNPs) in a genome-wide association study (GWAS) of 5,500 RA cases and 22,621 controls (all of European ancestry). After controlling for population stratification with principal components analysis, the strongest signal of association was to an imputed SNP, rs212389 (P=3.9 × 10(-8), odds ratio=0.87). This SNP remained highly significant upon conditioning on the previous RA risk variant (rs394581, P=2.2 × 10(-5)) or on a SNP previously associated with celiac disease and type I diabetes (rs1738074, P=1.7 × 10(-4)). Our study has refined the TAGAP signal of association to a single haplotype in RA, and in doing so provides conclusive statistical evidence that the TAGAP locus is associated with RA risk. Our study also underscores the utility of comprehensive imputation in large GWAS data sets to fine map disease risk alleles.
Genes and immunity 03/2011; 12(4):314-8. · 4.22 Impact Factor
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ABSTRACT: Many autoimmune diseases share common susceptibility loci suggesting similar underlying cellular mechanisms involved in disease expression.
The purpose of this investigation was to study 21 genetic variants in 14 genes that are confirmed autoimmune loci in a cohort of patients with early-onset psoriasis.
Patients with early-onset psoriasis (n = 750) and controls (n = 3531) were genotyped using the Sequenom(®) MassArray™ iPLEX Gold platform.
We found strong evidence of association with two variants in the IL2/IL21 (rs6822844, genotypic P = 3·3 × 10(-4) ; rs2069778, genotypic P = 7·86 × 10(-4)) region.
The findings, although requiring replication, suggest that IL2/IL21 may play a key role in the pathogenesis of psoriasis as well as in other diverse autoimmune diseases.
British Journal of Dermatology 03/2011; 164(3):660-4. · 3.67 Impact Factor
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ABSTRACT: The aim of this study was to investigate the complex association pattern of the extended major histocompatibility complex (xMHC) region with rheumatoid arthritis (RA) susceptibility to identify effects independent of HLA-DRB1. A total of 1804 RA cases and 1474 controls were included. High-resolution HLA-DRB1 typing was performed. Subjects were genotyped for 1546 single-nucleotide polymorphisms (SNPs) using Affymetrix GeneChip 500 K (Santa Clara, CA, USA) as part of the Wellcome Trust Case Control Consortium Study. Statistical analysis was carried out using PLINK. To avoid confounding by RA-associated HLA-DRB1 alleles, we analyzed xMHC SNPs using a data set with pairwise matching of cases and controls on DRB1 genotypes. A total of 594 case-control pairs with identical DRB1 genotypes were identified. After this adjustment, 104 SNPs remained significantly associated with RA (P<0.05), suggesting that additional RA loci independent of HLA-DRB1 can be found in the xMHC region. Of these, four loci showed the strongest associations with RA (P<0.005): ZNF391, the olfactory receptor (OR) gene cluster, C6orf26-RDBP and HLA-DPB1-COL11A2. An additional locus mapping to the BTN (butyrophilin) cluster showed independent association with RA in anti-cyclic citrullinated peptide-positive patients exclusively. We have validated the previously described independent association of the HLA-DPB1-COL11A2 locus with RA. In addition, association with three novel independent RA loci in the xMHC region (ZNF391, OR2H1 and C6orf26-RDBP) has been detected.
Genes and immunity 02/2011; 12(3):169-75. · 4.22 Impact Factor
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ABSTRACT: Whole-genome association studies in rheumatoid arthritis have identified single-nucleotide polymorphisms (SNPs) predisposing to disease with moderate risk. We aimed to investigate the role of these markers in predicting methotrexate (MTX) response, measured by continuation on MTX monotherapy in patients with recent onset inflammatory polyarthritis (IP). In all, 19 SNPs were genotyped in 736 patients treated with MTX following registration, or not more than 3 months before registration, to the Norfolk Arthritis Register. The association of SNPs with MTX continuation by year 1 and by year 2 was investigated using Cox proportional hazard regression models. A SNP within the OLIG3/TNFAIP3 locus (rs6920220) was associated with being less likely to maintain MTX monotherapy at year 1, hazards ratio (HR) 1.73 (1.18, 2.52) and year 2, HR 1.49 (1.11, 2.00); correlating with an increased in adverse events. Weak evidence for an effect at the PTPN22 locus was also observed. These findings require replication in other large datasets.
The Pharmacogenomics Journal 10/2010; 12(2):128-33. · 4.54 Impact Factor
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ABSTRACT: The CC chemokine receptor 5 (CCR5) has been shown to be important in the recruitment of T-helper cells to the synovium, where they accumulate, drive the inflammatory process and the consequent synovitis and joint destruction. A 32 base-pair insertion/deletion variant (CCR5Δ32) within the gene leads to a frame shift and a nonfunctional receptor. CCR5Δ32 has been investigated for its association with juvenile idiopathic arthritis (JIA), with conflicting results. The aim of this study was to investigate whether CCR5Δ32 is associated with JIA in an UK population. CCR5Δ32 was genotyped in JIA cases (n=1054) and healthy controls (n=3129) and genotype and allele frequencies were compared. A meta-analysis of our study combined with previously published studies was performed. CCR5Δ32 was significantly associated with protection from developing JIA, in this UK data set (Ptrend=0.006, odds ratio (OR) 0.79 95% confidence interval (95% CI): 0.66–0.94). The meta-analysis of all published case–control association studies confirmed the protective association with JIA (P=0.001 OR 0.82 95% CI: 0.73–0.93). CCR5Δ32 is a functional variant determining the number of receptors on the surface of T cells, and it is hypothesized that the level of CCR5 expression could influence the migration of proinflammatory T cells into the synovium and thus susceptibility to JIA.Keywords: CCR5; juvenile idiopathic arthritis; chemokine
Genes and Immunity 05/2010; 11(7):584-589. · 3.87 Impact Factor
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ABSTRACT: The CC chemokine receptor 5 (CCR5) has been shown to be important in the recruitment of T-helper cells to the synovium, where they accumulate, drive the inflammatory process and the consequent synovitis and joint destruction. A 32 base-pair insertion/deletion variant (CCR5Δ32) within the gene leads to a frame shift and a nonfunctional receptor. CCR5Δ32 has been investigated for its association with juvenile idiopathic arthritis (JIA), with conflicting results. The aim of this study was to investigate whether CCR5Δ32 is associated with JIA in an UK population. CCR5Δ32 was genotyped in JIA cases (n=1054) and healthy controls (n=3129) and genotype and allele frequencies were compared. A meta-analysis of our study combined with previously published studies was performed. CCR5Δ32 was significantly associated with protection from developing JIA, in this UK data set (P(trend)=0.006, odds ratio (OR) 0.79 95% confidence interval (95% CI): 0.66-0.94). The meta-analysis of all published case-control association studies confirmed the protective association with JIA (P=0.001 OR 0.82 95% CI: 0.73-0.93). CCR5Δ32 is a functional variant determining the number of receptors on the surface of T cells, and it is hypothesized that the level of CCR5 expression could influence the migration of proinflammatory T cells into the synovium and thus susceptibility to JIA.
Genes and immunity 05/2010; 11(7):584-9. · 4.22 Impact Factor
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ABSTRACT: Recent genetic studies have led to identification of numerous loci that are associated with susceptibility to autoimmune diseases. The strategy of using information from these studies has facilitated the identification of novel juvenile idiopathic arthritis (JIA) susceptibility loci, specifically, PTPN22 and IL2RA. Several novel autoimmune susceptibility loci have recently been identified, and we hypothesise that single-nucleotide polymorphisms (SNPs) within these genes may also be JIA susceptibility loci. Five SNPs within the genes AFF3, IL2/IL21, IL7R, CTLA4 and CD226, previously associated with multiple autoimmune diseases were genotyped, in a large data set of Caucasian JIA patients and controls, and tested for association with JIA. We identified two susceptibility loci for JIA, AFF3 and the IL2/IL21 region and additional weak evidence supporting an association with the CTLA4 and IL7R genes, which warrant further investigation. All results require validation in independent JIA data sets. Further characterisation of the specific causal variants will be required before functional studies can be performed.
Genes and immunity 03/2010; 11(2):194-8. · 4.22 Impact Factor
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JCA Broen,
P Gourh,
M Vonk,
L Beretta,
F Niederer,
B Rueda,
Geurts-van Bon L,
C Brouwer,
R Hesselstrand,
A Herrick, [......],
P Carreira,
N Ortego-Centeno,
M Gonzalez-Gay,
P Airò,
MJH Coenen,
M Mayes,
D Kyburz,
F Arnett,
J Martin,
TRDJ Radstake
Journal of Translational Medicine. 01/2010;
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JCA Broen,
P Dieude,
M Vonk,
L Beretta,
B Rueda,
A Herrick, J Worthington,
N Hunzelmann,
G Riemekasten,
H Kiener, [......],
V Fonollosa,
P Carreira,
N Ortego-Centeno,
M Gonzalez-Gay,
P Airò,
MJH Coenen,
A Aliprantis,
J Martin,
Y Allanore,
TRDJ Radstake
Journal of Translational Medicine. 01/2010;
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L Bossini-Castillo,
JCA Broen,
C Simeon,
L Beretta,
M Vonk,
N Ortego-Centeno,
G Espinosa,
P Carreira,
M Camps,
N Navarrete, [......],
P Airó,
R Scorza,
van Laar J,
N Hunzelmann,
A Kreuter,
A Herrick, J Worthington,
TRDJ Radstake,
J Martín,
B Rueda
Journal of Translational Medicine. 01/2010;
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O. Gorlova,
J Martin,
B Rueda,
BPC Koeleman,
J. Ying,
M Teruel,
L Diaz-Gallo,
J Broen,
M Vonk,
C Simeon, [......],
L Beretta,
C Fonseca,
C Denton,
P Gregersen,
S Agarwal,
S Assassi,
F Tan,
F Arnett,
TRDJ Radstake,
M Mayes
Journal of Translational Medicine. 01/2010;
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D Plant,
A Barton,
W Thomson,
X Ke,
S Eyre,
A Hinks,
J Bowes,
L J Gibbons,
A G Wilson,
I Marinou,
A W Morgan,
S Steer,
L J Hocking,
D M Reid,
P Wordsworth,
P Harrison, J Worthington
Annals of the rheumatic diseases 09/2009; 68(8):1373-5. · 8.11 Impact Factor
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ABSTRACT: Psoriasis is an immune-mediated skin disorder, which is inherited as a complex trait. Genome-wide linkage and association studies have identified a major disease susceptibility locus on chromosome 6p21, as well as a number of genetic determinants of smaller effect. Our group has also documented a significant association between psoriasis and CDKAL1, a gene previously implicated in the pathogenesis of Crohn's disease (CD) and type II diabetes (TIID). With this study, we validate this association, through the analysis of CDKAL1 single nucleotide polymorphism (SNP) rs6908425 in an independently ascertained psoriasis dataset (replication sample: 1323 cases vs 1368 controls, P=0.00012, odds ratio (OR): 1.28; combined sample: 2579 cases vs 4306 controls, P=4 x 10(-6), OR: 1.26). We also show that the association with psoriasis and CD is completely independent from that with TIID. Finally, we report the results of expression studies demonstrating that CDKAL1 transcripts are virtually absent from skin keratinocytes, but are abundantly expressed in immune cells, especially in CD4+ and CD19+ lymphocytes. It is to be noted that our data indicate that CDKAL1 becomes markedly downregulated when immune cells are activated with proliferating signals. Taken together, our results document the presence of allelic heterogeneity at the CDKAL1 locus and suggest that CDKAL1 alleles may confer susceptibility to clinically distinct disorders through differential effects on disease-specific cell types.
Genes and immunity 08/2009; 10(7):654-8. · 4.22 Impact Factor
