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 P
comb=7.85×10
−10). A Monte Carlo simulation to address multiple testing suggests that this association is not a type I error. The coding regions of
IL12B were resequenced in 96 individuals with psoriasis, and 30 additional
IL12B-region SNPs were genotyped. Haplotypes were estimated, and genotype-conditioned analyses identified a second risk allele (
rs6887695) located ∼60 kb upstream of the
IL12B coding region that exhibited association with psoriasis after adjustment for
rs3212227. Together, these two SNPs mark a common
IL12B risk haplotype (OR
common 1.40,
P
comb=8.11×10
−9) and a less frequent protective haplotype (OR
common 0.58,
P
comb=5.65×10
−12), which were statistically significant in all three studies. Since
IL12B encodes the common IL-12p40 subunit of IL-12 and IL-23, we individually genotyped 17 SNPs in the genes encoding the other chains of these cytokines (
IL12A and
IL23A) and their receptors (
IL12RB1, IL12RB2, and
IL23R). Haplotype analyses identified two
IL23R missense SNPs that together mark a common psoriasis-associated haplotype in all three studies (OR
common 1.44,
P
comb=3.13×10
−6). Individuals homozygous for both the
IL12B and the
IL23R predisposing haplotypes have an increased risk of disease (OR
common 1.66,
P
comb=1.33×10
−8). These data, and the previous observation that administration of an antibody specific for the IL-12p40 subunit to patients with psoriasis is highly efficacious, suggest that these genes play a fundamental role in psoriasis pathogenesis.
PTPN22: Setting thresholds for autoimmunity Gregersen, Peter K.; Lee, Hye-Soon; Batliwalla, Franak ...
Seminars in Immunology,
08/2006, Volume:
18, Issue:
4
Journal Article
Peer reviewed
The 620W allelic variant of the intracellular tyrosine phosphatase, PTPN22, is associated with a number of different autoimmune disorders, and this provides direct evidence for common mechanisms ...underlying many of these diseases. The associated allele appears to influence thresholds for T cell receptor signaling, and a variety of disease models involving both central and peripheral tolerance can be proposed. However, given the fact that PTPN22 is expressed in a variety of immunologically relevant cell types, the precise mechanisms for these associations remain unclear. In general, the PTPN22 620W allele appears to play a role in autoimmune disorders that have a prominent humoral component, suggesting that further investigation of PTPN22 activity in B cells will be useful. From a genetic perspective, the data highlights the genetic heterogeneity underlying autoimmunity in different ethnic groups.
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. The risks of aGVHD, relapse, and mortality associated with HLA-DPB1 allele mismatching were determined in 5929 patients who received a myeloablative HCT from an HLA-A–, HLA-B–, HLA-C–, HLA-DRB1–, and HLA-DQB1–matched or –mismatched donor. There was a statistically significantly higher risk of both grades 2 to 4 aGVHD (odds ratio OR = 1.33; P < .001) and grades 3 to 4 aGVHD (OR = 1.26; P < .001) after HCT from an HLA-DPB1–mismatched donor compared with a matched donor. The increased risk of aGVHD was accompanied by a statistically significantly decrease in disease relapse (hazard ratio HR = 0.82; P = .01). HLA-DPB1 functions as a classical transplantation antigen. The increased risk of GVHD associated with HLA-DPB1 mismatching is accompanied by a lower risk of relapse. Knowledge of the DPB1 matching status prior to transplantation will aid in more precise risk stratification for the individual patient.
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. Based on functional data in mice, we hypothesized that the immune-related genes complement component 5 (C5) and/or TNF receptor-associated factor 1 (TRAF1), located on Chromosome 9q33-34, would represent relevant candidate genes for RA. We therefore aimed to investigate whether this locus would play a role in RA.
We performed a multitiered case-control study using 40 single-nucleotide polymorphisms (SNPs) from the TRAF1 and C5 (TRAF1/C5) region in a set of 290 RA patients and 254 unaffected participants (controls) of Dutch origin. Stepwise replication of significant SNPs was performed in three independent sample sets from the Netherlands (ncases/controls = 454/270), Sweden (ncases/controls = 1,500/1,000) and US (ncases/controls = 475/475). We observed a significant association (p < 0.05) of SNPs located in a haplotype block that encompasses a 65 kb region including the 3' end of C5 as well as TRAF1. A sliding window analysis revealed an association peak at an intergenic region located approximately 10 kb from both C5 and TRAF1. This peak, defined by SNP14/rs10818488, was confirmed in a total of 2,719 RA patients and 1,999 controls (odds ratiocommon = 1.28, 95% confidence interval 1.17-1.39, pcombined = 1.40 x 10(-8)) with a population-attributable risk of 6.1%. The A (minor susceptibility) allele of this SNP also significantly correlates with increased disease progression as determined by radiographic damage over time in RA patients (p = 0.008).
Using a candidate-gene approach we have identified a novel genetic risk factor for RA. Our findings indicate that a polymorphism in the TRAF1/C5 region increases the susceptibility to and severity of RA, possibly by influencing the structure, function, and/or expression levels of TRAF1 and/or C5.
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. However, it is not known whether there are other psoriasis loci within the MHC in addition to HLA-C. In the present study, we searched for additional susceptibility loci within the human leukocyte antigen (HLA) region through in-depth analyses of the GWAS data; then, we followed up our findings in an independent Han Chinese 1,139 psoriasis cases and 1,132 controls. Using the phased CEPH dataset as a reference, we imputed the HLA-Cw*0602 in all samples with high accuracy. The association of the imputed HLA-Cw*0602 dosage with disease was much stronger than that of the most significantly associated SNP, rs12191877. Adjusting for HLA-Cw*0602, there were two remaining association signals: one demonstrated by rs2073048 (p = 2 x 10(-6), OR = 0.66), located within c6orf10, a potential downstream effecter of TNF-alpha, and one indicated by rs13437088 (p = 9 x 10(-6), OR = 1.3), located 30 kb centromeric of HLA-B and 16 kb telomeric of MICA. When HLA-Cw*0602, rs2073048, and rs13437088 were all included in a logistic regression model, each of them was significantly associated with disease (p = 3 x 10(-47), 6 x 10(-8), and 3 x 10(-7), respectively). Both putative loci were also significantly associated in the Han Chinese samples after controlling for the imputed HLA-Cw*0602. A detailed analysis of HLA-B in both populations demonstrated that HLA-B*57 was associated with an increased risk of psoriasis and HLA-B*40 a decreased risk, independently of HLA-Cw*0602 and the C6orf10 locus, suggesting the potential pathogenic involvement of HLA-B. These results demonstrate that there are at least two additional loci within the MHC conferring risk of psoriasis.
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. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 × 10−8). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-α and regulate NF-κB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.
Abstract 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.
Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting ∼1% of the adult population worldwide, with an estimated heritability of 60%. To identify genes involved in RA ...susceptibility, we investigated the association between putative functional single-nucleotide polymorphisms (SNPs) and RA among white individuals by use of a case-control study design; a second sample was tested for replication. Here we report the association of RA susceptibility with the minor allele of a missense SNP in
PTPN22 (discovery-study allelic
P=6.6×10
−4; replication-study allelic
P=5.6×10
−8), which encodes a hematopoietic-specific protein tyrosine phosphatase also known as “Lyp.” We show that the risk allele, which is present in ∼17% of white individuals from the general population and in ∼28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with Csk, potentially altering these proteins' normal function as negative regulators of T-cell activation. The minor allele of this SNP recently was implicated in type 1 diabetes, suggesting that the variant phosphatase may increase overall reactivity of the immune system and may heighten an individual carrier’s risk for autoimmune disease.
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 × 10^sup -10^). Replication in independent case-control datasets comprising 2,604 cases and 2,882 controls confirmed this association, yielding an allelic OR = 1.25 (P = 3.08 × 10^sup -14^) for marker rs13031237 and an allelic OR = 1.21 (P = 2.60 × 10^sup -11^) for marker rs13017599 in the combined dataset. The combined dataset also provides definitive support for associations at both CTLA4 (rs231735; OR = 0.85; P = 6.25 × 10^sup -9^) and BLK (rs2736340; OR = 1.19; P = 5.69 × 10^sup -9^). c-Rel is an NF-κB family member with distinct functional properties in hematopoietic cells, and its association with rheumatoid arthritis suggests disease pathways that involve other recently identified rheumatoid arthritis susceptibility genes including CD40, TRAF1, TNFAIP3 and PRKCQ. PUBLICATION ABSTRACT
Autoimmune disorders constitute a diverse group of phenotypes with overlapping features and a tendency toward familial aggregation. It is likely that common underlying genes are involved in these ...disorders. Until very recently, no specific alleles—aside from a few common human leukocyte antigen class II genes—had been identified that clearly associate with multiple different autoimmune diseases. In this study, we describe a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). At least two of nine “core” autoimmune diseases are present in each of these families. These core diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis (MS), autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease), juvenile RA, inflammatory bowel disease (Crohn disease or ulcerative colitis), psoriasis, and primary Sjögren syndrome. We report that a recently described functional single-nucleotide polymorphism (
rs2476601, encoding R620W) in the intracellular tyrosine phosphatase (PTPN22) confers risk of four separate autoimmune phenotypes in these families: T1D, RA, SLE, and Hashimoto thyroiditis. MS did not show association with the PTPN22 risk allele. These findings suggest a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggest that MS may have a pathogenesis that is distinct from RA, SLE, and T1D. DNA and clinical data for the MADGC families are available to the scientific community; these data will provide a valuable resource for the dissection of the complex genetic factors that underlie the various autoimmune phenotypes.
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