Brief Report: Single-nucleotide polymorphisms in VKORC1 are risk factors for systemic lupus erythematosus in Asians.

Objective: The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. The present study was undertaken to investigate whether 33 established and novel single-nucleotide polymorphisms (SNPs) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis (DVT) in the general population are risk factors for SLE among Asian subjects.

Methods: Patients in the discovery cohort were enrolled in 1 of 2 North American SLE cohorts.

Correlation analyses of clinical and molecular findings identify candidate biological pathways in systemic juvenile idiopathic arthritis.

Background: Clinicians have long appreciated the distinct phenotype of systemic juvenile idiopathic arthritis (SJIA) compared to polyarticular juvenile idiopathic arthritis (POLY). We hypothesized that gene expression profiles of peripheral blood mononuclear cells (PBMC) from children with each disease would reveal distinct biological pathways when analyzed for significant associations with elevations in two markers of JIA activity, erythrocyte sedimentation rate (ESR) and number of affected joints (joint count, JC).

Methods: PBMC RNA from SJIA and POLY patients was profiled by kinetic PCR to analyze expression of 181 genes, selected for relevance to immune response pathways.

Genetic risk factors for thrombosis in systemic lupus erythematosus.

Objective: Thrombosis is a serious complication of systemic lupus erythematosus (SLE). We investigated whether genetic variants implicated in thrombosis pathways are associated with thrombosis among 2 ethnically diverse SLE cohorts.

Methods: Our discovery cohort consisted of 1698 patients with SLE enrolled in the University of California, San Francisco, Lupus Genetics Project and our replication cohort included 1361 patients with SLE enrolled in the PROFILE cohort.

A combined DPA1~DPB1 amino acid epitope is the primary unit of selection on the HLA-DP heterodimer.

Here, we present results for DPA1 and DPB1 four-digit allele-level typing in a large (n = 5,944) sample of unrelated European American stem cell donors previously characterized for other class I and class II loci. Examination of genetic data for both chains of the DP heterodimer in the largest cohort to date, at the amino acid epitope, allele, genotype, and haplotype level, allows new insights into the functional units of selection and association for the DP heterodimer. The data in this study suggest that for the DPA1-DPB1 heterodimer, the unit of selection is the combined amino acid epitope contributed by both the DPA1 and DPB1 genes, rather than the allele, and that patterns of LD are driven primarily by dimer stability and conformation of the P1 pocket.

Alternative activation in systemic juvenile idiopathic arthritis monocytes.

Systemic juvenile idiopathic arthritis (SJIA) is a chronic autoinflammatory condition. The association with macrophage activation syndrome, and the therapeutic efficacy of inhibiting monocyte-derived cytokines, has implicated these cells in SJIA pathogenesis. To characterize the activation state (classical/M1 vs.

Carriers of rare missense variants in IFIH1 are protected from psoriasis.

Testing of ∼25,000 putative functional single-nucleotide polymorphisms (SNPs) across the human genome in a genetic association study has identified three psoriasis genes, IL12B, IL23R, and IL13. We now report evidence for the association of psoriasis risk with missense SNPs in the interferon induced with helicase C domain 1 gene (IFIH1). The rare alleles of two independent SNPs were associated with decreased risk of psoriasis--rs35667974 (Ile923Val): odds ratio (OR) for minor allele carriers is 0.

Monocytes are resistant to apoptosis in systemic juvenile idiopathic arthritis.

We investigated whether circulating monocytes from patients with systemic juvenile idiopathic arthritis (SJIA) are resistant to apoptosis and which apoptotic pathway(s) may mediate this resistance. A microarray analysis of peripheral blood mononuclear cells (PBMC) of SJIA samples and RT-PCR analysis of isolated monocytes showed that monocytes from active SJIA patients express transcripts that imply resistance to apoptosis. SJIA monocytes incubated in low serum show reduced annexin binding and diminished FasL up-regulation compared to controls.

Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.

To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 x 10(-8)) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK.

Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk.

To discover new rheumatoid arthritis (RA) risk loci, we systematically examined 370 SNPs from 179 independent loci with P < 0.001 in a published meta-analysis of RA genome-wide association studies (GWAS) of 3,393 cases and 12,462 controls. We used Gene Relationships Across Implicated Loci (GRAIL), a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci.

Multiple Loci within the major histocompatibility complex confer risk of psoriasis.

Psoriasis is a common inflammatory skin disease characterized by thickened scaly red plaques. Previously we have performed a genome-wide association study (GWAS) on psoriasis with 1,359 cases and 1,400 controls, which were genotyped for 447,249 SNPs. The most significant finding was for SNP rs12191877, which is in tight linkage disequilibrium with HLA-Cw*0602, the consensus risk allele for psoriasis.

Association of a single-nucleotide polymorphism in CD40 with the rate of joint destruction in rheumatoid arthritis.

Objective: The severity of joint destruction in rheumatoid arthritis (RA) is highly variable from patient to patient and is influenced by genetic factors. Genome-wide association studies have enormously boosted the field of the genetics of RA susceptibility, but risk loci for RA severity remain poorly defined. A recent meta-analysis of genome-wide association studies identified 6 genetic regions for susceptibility to autoantibody-positive RA: CD40, KIF5A/PIP4K2C, CDK6, CCL21, PRKCQ, and MMEL1/TNFRSF14.

REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.

We conducted a genome-wide association study of rheumatoid arthritis in 2,418 cases and 4,504 controls from North America and identified an association at the REL locus, encoding c-Rel, on chromosome 2p13 (rs13031237, P = 6.01 x 10(-10)). Replication in independent case-control datasets comprising 2,604 cases and 2,882 controls confirmed this association, yielding an allelic OR = 1.

Unraveling the genetics of complex diseases: susceptibility genes for rheumatoid arthritis and psoriasis.

Talk of numerous genetic risk factors for rheumatoid arthritis (RA) and psoriasis has been percolating for years, but with the exception of the human leukocyte antigen (HLA) region, none have been definitively identified. Recently the results of multiple, well powered, genetic case-control studies have begun to appear providing convincing statistical evidence for at least ten non-HLA related risk genes or loci (C5/TRAF1, CD40, CTLA4, KIF5A/PIP4K2C, MMEL1/TNFRSF14, PADI4, PRKCQ, PTPN22, STAT4, and TNFAIP3/OLIG3) for RA and six (IL12B, IL13, IL23R, STAT2/IL23A, TNFAIP3, and TNIP1) for psoriasis. These initial, novel findings are beginning to shed light on the molecular pathways pertinent to the individual diseases and highlight the pleiotropic effects of several risk factors as well as the allelic heterogeneity underlying susceptibility to these and other autoimmune diseases.

Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.

Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls.

Further genetic evidence for three psoriasis-risk genes: ADAM33, CDKAL1, and PTPN22.

Predisposition to psoriasis is known to be affected by genetic variation in HLA-C, IL12B, and IL23R, and although other psoriasis-associated variants have been identified, incontrovertible statistical evidence for these markers has not yet been obtained. To help resolve this issue, we tested 15 single-nucleotide polymorphisms (SNPs) from 7 putative psoriasis-risk genes in 1,448 psoriasis patients and 1,385 control subjects; 3 SNPs, rs597980 in ADAM33, rs6908425 in CDKAL1 and rs3789604 in PTPN22, were significant with the same risk allele as in prior reports (one-sided P<0.05, false discovery rate<0.

Common variants at CD40 and other loci confer risk of rheumatoid arthritis.

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.

A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting both joints and extra-articular tissues. Although some genetic risk factors for RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not fully account for the observed heritability. To identify additional susceptibility loci, we carried out a multi-tiered, case-control association study, genotyping 25,966 putative functional SNPs in 475 white North American RA patients and 475 matched controls.

The 5q31 variants associated with psoriasis and Crohn's disease are distinct.

Predisposition to psoriasis is known to be affected by genetic variation in HLA-C, IL12B and IL23R, but other genetic risk factors also exist. We recently reported three psoriasis-associated single nucleotide polymorphisms (SNPs) in the 5q31 locus, a region of high linkage disequilibrium laden with inflammatory pathway genes. The aim of this study was to assess whether other variants in the 5q31 region are causal to these SNPs or make independent contributions to psoriasis risk by genotyping a comprehensive set of tagging SNPs in a 725 kb region bounded by IL3 and IL4 and testing for disease association.

Data for Genetic Analysis Workshop (GAW) 15 Problem 2, genetic causes of rheumatoid arthritis and associated traits.

For Genetic Analysis Workshop 15 Problem 2, we organized data from several ongoing studies designed to identify genetic and environmental risk factors for rheumatoid arthritis. Data were derived from the North American Rheumatoid Arthritis Consortium (NARAC), collaboration among Canadian researchers, the European Consortium on Rheumatoid Arthritis Families (ECRAF), and investigators from Manchester, England. All groups used a common standard for defining rheumatoid arthritis, but NARAC also further selected for a more severe phenotype in the probands.

The autoimmune disease-associated IL12B and IL23R polymorphisms in multiple sclerosis.

Recently published genetic studies in psoriasis, inflammatory bowel disease, and ankylosing spondylitis identified significant associations with IL12B and IL23R polymorphisms. An important role for the IL-12/IL-23 pathway in multiple sclerosis (MS) is supported by immunologic studies in patients and animal models. To determine whether IL12B/IL23R disease-associated polymorphisms play a role in susceptibility to MS, we genotyped 910 MS-nuclear families, totaling 3132 individuals.

A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting approximately 1% of the population. The disease results from the interplay between an individual's genetic background and unknown environmental triggers. Although human leukocyte antigens (HLAs) account for approximately 30% of the heritable risk, the identities of non-HLA genes explaining the remainder of the genetic component are largely unknown.

The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation.

Hematopoietic cell transplantation (HCT) from an HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele-matched unrelated donor is a well-recognized life-saving treatment modality for patients with hematologic disorders. The morbidity and mortality from clinically significant acute graft-versus-host disease (aGVHD) remains a limitation. The extent to which transplantation outcome may be improved with donor matching for HLA-DP is not well defined.

A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.

We performed a multitiered, case-control association study of psoriasis in three independent sample sets of white North American individuals (1,446 cases and 1,432 controls) with 25,215 genecentric single-nucleotide polymorphisms (SNPs) and found a highly significant association with an IL12B 3'-untranslated-region SNP (rs3212227), confirming the results of a small Japanese study. This SNP was significant in all three sample sets (odds ratio [OR](common) 0.64, combined P [Pcomb]=7.