[show abstract][hide abstract] ABSTRACT: Behçet's disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behçet's disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behçet's disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 x 10(-8)). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 x 10(-18), odds ratio = 1.45, 95% CI 1.34-1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 x 10(-9), OR = 1.28, 95% CI 1.18-1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production.
[show abstract][hide abstract] ABSTRACT: Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone.
We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN.
We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly.
We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)
New England Journal of Medicine 07/2009; 360(23):2426-37. · 51.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent studies have identified a number of novel rheumatoid arthritis (RA) susceptibility loci in Caucasian populations. The aim of this study was to determine whether the genetic variants at 4q27, 6q23, CCL21, TRAF1/C5, and CD40 identified in Caucasians are also associated with RA in a Korean case-control collection. We also comprehensively evaluated the genetic variation within PTPN22, a well-established autoimmune disease-associated gene.
We designed an experiment to thoroughly evaluate the PTPN22 linkage disequilibrium region, using tag single-nucleotide polymorphisms (SNPs) and disease-associated SNPs at 5 RA-associated loci recently identified in Caucasians, in 1,128 Korean patients with RA and 1,022 ethnically matched control subjects. We also resequenced the PTPN22 gene to seek novel coding variants that might be contributing to disease in this population.
None of the susceptibility loci identified in Caucasian patients with RA contributed significantly to disease in Koreans. Although tag SNPs covering the PTPN22 linkage disequilibrium block were polymorphic, they did not reveal any disease association, and resequencing did not identify any new common coding region variants in this population. The 6q23 and 4q27 SNPs assayed were nonpolymorphic in this population, and the TRAF1/C5, CD40, and CCL21 SNPs did not show any evidence for association with RA in this population of Korean patients.
The genetic risk factors for RA are different in Caucasian and Korean patients. Although patients of different ethnic groups share the HLA region as a major genetic risk locus, most other genes shown to be significantly associated with disease in Caucasians appear not to play a role in Korean patients with RA.
[show abstract][hide abstract] ABSTRACT: The single-nucleotide polymorphism (SNP) rs11761231 on chromosome 7q has been reported to be sexually dimorphic marker for rheumatoid arthritis (RA) susceptibility in a British population. We sought to replicate this finding and to better characterize susceptibility alleles in the region in a North American population.
DNA from 2 North American collections of RA patients and controls (1,605 cases and 2,640 controls) was genotyped for rs11761231 and 16 additional chromosome 7q tag SNPs using Sequenom iPlex assays. Association tests were performed for each collection and also separately, contrasting male cases with male controls and female cases with female controls. Principal components analysis (EigenStrat) was used to determine association with RA before and after adjusting for population stratification in the subset of the samples for which there were whole-genome SNP data (772 cases and 1,213 controls).
We failed to replicate an association of the 7q region with RA. Initially, rs11761231 showed evidence for association with RA in the North American Rheumatoid Arthritis Consortium (NARAC) collection (P=0.0073), and rs11765576 showed association with RA in both the NARAC (P=0.038) and RA replication (P = 0.0013) collections. These markers also exhibited sex differentiation. However, in the whole-genome subset, neither SNP showed significant association with RA after correction for population stratification.
While 2 SNPs on chromosome 7q appeared to be associated with RA in a North American cohort, the significance of this finding did not withstand correction for population substructure. Our results emphasize the need to carefully account for population structure to avoid false-positive disease associations.
[show abstract][hide abstract] ABSTRACT: To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall).
[show abstract][hide abstract] ABSTRACT: Recent advances in genetics and technology have led to breakthroughs in understanding the genes that predispose individuals to autoimmune diseases. A common haplotype of the signal transducer and activator of transcription 4 (STAT4) gene has been shown to be associated with susceptibility to rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome. STAT4 is a transcription factor that transduces interleukin-12, interleukin-23, and type 1 interferon cytokine signals in T cells and monocytes, leading to T-helper type 1 and T-helper type 17 differentiation, monocyte activation, and interferon-gamma production. Although the evidence for this association is very strong and well replicated, the exact mechanism by which polymorphisms in this gene lead to disease remains unknown. In concert with the identification of other disease-associated loci, elucidating how the variant form of STAT4 modulates immune function should lead to an improved understanding of the pathophysiology of autoimmunity.
Current Allergy and Asthma Reports 10/2008; 8(5):398-403. · 2.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: Single nucleotide polymorphisms in the STAT4 gene have recently been shown to be associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Primary Sjögren's syndrome (pSS) is a related autoimmune disease thought to have a pathogenesis similar to these diseases. To test the hypothesis that the variant haplotype of STAT4 seen in RA and SLE is also associated with pSS, we genotyped rs7574865, the most strongly disease-associated SNP in the variant STAT4 haplotype, in 124 Caucasian pSS subjects and compared them to 1143 Caucasian controls. The disease-associated T allele was more common in chromosomes of the pSS patients (29.6%) than in controls (22.3%), leading to a P-value for association of 0.01. These results implicate polymorphisms in the STAT4 gene in the pathogenesis of pSS.
Genes and immunity 05/2008; 9(3):267-70. · 4.22 Impact Factor