ClinVar Genomic variation as it relates to human health

Bottini et al. (2004) found that an 1858C-T transition in the PTPN8 gene resulting in an arg620-to-trp (R620W) amino acid substitution was associated with insulin-dependent diabetes mellitus (IDDM; 222100). Begovich et al. (2004) found that the minor allele (T) was associated with susceptibility to rheumatoid arthritis (RA; 180300). In a study of 525 unrelated North American white individuals with systemic lupus erythematosus (SLE; 152700), Kyogoku et al. (2004) found an association between the R620W SNP and SLE, with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increased risk of SLE (odds ratio = 1.37), and 2 copies of the allele more than doubled this risk (OR = 4.37). Together with the evidence showing association of this SNP with type I diabetes and rheumatoid arthritis, the data provided compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity. To determine whether the R620W SNP in PTPN22 also plays a role in susceptibility to multiple sclerosis (126200), Begovich et al. (2005) genotyped 2 large, well-characterized, family-based data sets involving 748 MS-prone families. They found that the R620W polymorphism is not associated with multiple sclerosis. Criswell et al. (2005) described a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). In each of these families, at least 2 of the 9 'core' autoimmune diseases were present. They found that the R620W functional SNP in PTPN22 (rs2476601) conferred risk of 4 separate autoimmune phenotypes in these families: type I diabetes mellitus, RA, SLE, and Hashimoto thyroiditis (140300). Multiple sclerosis did not show association with the PTPN22 risk allele. These findings suggested a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggested that multiple sclerosis may have a pathogenesis that is distinct from that of RA, SLE, and type I diabetes mellitus. Qu et al. (2005) genotyped the R620W SNP in 588 nuclear families with at least 1 IDDM-affected child and 2 parents and in the 30 European CEPH family trios used in the International HapMap Project. Highly significant transmission disequilibrium was observed, with p = 1.7 x 10(-5), confirming the case-control study of Bottini et al. (2004). However, linkage disequilibrium structure studies revealed that R620W maps to a 293-kb LD block containing numerous polymorphisms, leading Qu et al. (2005) to suggest that other potentially functional polymorphisms may be responsible for the association with type I diabetes mellitus instead of, or in addition to, R620W. Vang et al. (2005) studied T cells from carriers of the 1858C-T SNP allele of the PTPN22 gene, which predisposes to type I diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease, and other autoimmune disorders. They found that T cells with the at-risk allele produced less interleukin-2 (IL2; 147680) upon T-cell antigen receptor (TCR) stimulation, and that the encoded phosphatase had higher catalytic activity and was a more potent negative regulator of T lymphocyte activation. Vang et al. (2005) concluded that the autoimmune-predisposing allele, 1858T, is a gain-of-function mutant. Kawasaki et al. (2006) genotyped 1,520 Japanese and 178 Korean individuals, including 732 patients with type I diabetes, 141 patients with autoimmune thyroid disease, and 825 healthy controls, for the 1858C-T SNP and found that all individuals had the wildtype homozygous C/C/ genotype. The absence of the 1858T allele in this Asian population was confirmed by 2 independent methods, PCR-RFLP and direct sequencing. Kallberg et al. (2007) compared the interaction between 2 major genetic risk factors of rheumatoid arthritis, the HLA-DRB1 shared epitope (SE) alleles (see 142857) and the PTPN22 R620W allele (600716.0001), in 3 large case-control studies, 1 Swedish, 1 North American, and 1 Dutch (in total, 1,977 cases and 2,405 controls). The Swedish study was also used to analyze interactions between smoking and the 2 genes. 'Interaction' was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium--i.e., deviation from independence of penetrance of 2 unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W were seen in all 3 studies regarding rheumatoid arthritis testing positive for antibodies to citrullinated proteins (anti-CCP). Testing for multiplicative interaction demonstrated an interaction between the 2 genes only when the 3 studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in the Swedish and North American studies, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. Huffmeier et al. (2006) excluded a major role of the R620W allele in German psoriasis patients but suggested that other susceptibility determinants within noncoding regions of PTPN22 or its proximity might exist acting independently of the major PSORS1 risk factor (see 177900). The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. The authors found that rs6679667, the marker within PTPN22 most associated with rheumatoid arthritis, was perfectly correlated with the previously described SNP 2476601, and that the effect size was consistent with previous estimates (Hinks et al., 2007). Using flow cytometry, Rieck et al. (2007) found that T cells from individuals homozygous for 1858T, all of whom were autoimmunity patients, had a profound deficit in responsiveness to antigen stimulation. CD4 (186940)-positive memory T cells from control subjects heterozygous for 1858T exhibited reduced responsiveness in terms of calcium mobilization, CD25 (IL2RA; 147730) expression, and IL10 (124092) production compared with cells from subjects homozygous for 1858C. The presence of 1858T in control subjects was associated with increased circulating memory T cells and fewer memory B cells, which had reduced responsiveness through the B-cell receptor, compared with 1858C homozygotes. Rieck et al. (2007) concluded that the PTPN22 1858T variant is associated with a dampened response of both the T- and B-cell antigen receptors, and that the 620W isoform has enhanced inhibitory function in lymphocytes. Skinningsrud et al. (2008) presented evidence suggesting an association between the 1858T allele and autoimmune Addison disease (240200). In a metaanalysis of 3 studies, including their own, comprising 563 European patients with the disorder, the authors found an odds ratio of 1.36 (p = 0.003) for carriers of the T allele. Barrett et al. (2009) reported the findings of a genomewide association study of type 1 diabetes, combined in a metaanalysis with 2 previously published studies (Wellcome Trust Case Control Consortium, 2007; Cooper et al., 2008). The total sample set included 7,514 cases and 9,045 reference samples. Using an analysis that combined comparisons over the 3 studies, they confirmed several previously reported associations, including rs2476601 at chromosome 1p13.2 (P = 8.5 x 10(-85)). Mahdi et al. (2009) tested the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated alpha-enolase, accounts for an important portion of the association between smoking, HLA-DRB1 shared epitope alleles, and PTPN22 association with rheumatoid arthritis susceptibility. In 1,497 individuals from 3 RA cohorts, antibodies to the immunodominant citrullinated alpha-enolase CEP-1 epitope were detected in 43 to 63% of the anti-CCP-positive individuals, and this subset was preferentially linked to HLA-DRB1*04. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22, and smoking showed the strongest associations with the anti-CEP-1-positive subset (odds ratio of 37, compared to an odds ratio of 2 for the corresponding anti-CEP1-negative, anti-CCP-positive subset). Mahdi et al. (2009) concluded that citrullinated alpha-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of rheumatoid arthritis. Arechiga et al. (2009) showed that B-cell signal transduction was impaired in individuals with the PTPN22 1858C-T SNP. This defect in signaling was characterized by a deficit in proliferation and a decrease in phosphorylation of key signaling proteins, such as SYK (600085), and could be reversed by PTPN22 inhibition. Arechiga et al. (2009) proposed that 1858C-T alters B-cell receptor signaling and that their findings implicate B cells in the mechanism by which the variant contributes to autoimmunity. In human T and B cells carrying the R620W mutation, Zhang et al. (2011) showed that calpain binding and cleavage were increased relative to wildtype, indicating that calpain-mediated degradation with consequently reduced expression in lymphocyte and dendritic cell hyperresponsiveness may represent a mechanism whereby the 620W mutation increases the risk for autoimmune disease. (less)

Bottini et al. (2004) found that an 1858C-T transition in the PTPN8 gene resulting in an arg620-to-trp (R620W) amino acid substitution was associated with insulin-dependent diabetes mellitus (IDDM; 222100). Begovich et al. (2004) found that the minor allele (T) was associated with susceptibility to rheumatoid arthritis (RA; 180300). In a study of 525 unrelated North American white individuals with systemic lupus erythematosus (SLE; 152700), Kyogoku et al. (2004) found an association between the R620W SNP and SLE, with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increased risk of SLE (odds ratio = 1.37), and 2 copies of the allele more than doubled this risk (OR = 4.37). Together with the evidence showing association of this SNP with type I diabetes and rheumatoid arthritis, the data provided compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity. To determine whether the R620W SNP in PTPN22 also plays a role in susceptibility to multiple sclerosis (126200), Begovich et al. (2005) genotyped 2 large, well-characterized, family-based data sets involving 748 MS-prone families. They found that the R620W polymorphism is not associated with multiple sclerosis. Criswell et al. (2005) described a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). In each of these families, at least 2 of the 9 'core' autoimmune diseases were present. They found that the R620W functional SNP in PTPN22 (rs2476601) conferred risk of 4 separate autoimmune phenotypes in these families: type I diabetes mellitus, RA, SLE, and Hashimoto thyroiditis (140300). Multiple sclerosis did not show association with the PTPN22 risk allele. These findings suggested a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggested that multiple sclerosis may have a pathogenesis that is distinct from that of RA, SLE, and type I diabetes mellitus. Qu et al. (2005) genotyped the R620W SNP in 588 nuclear families with at least 1 IDDM-affected child and 2 parents and in the 30 European CEPH family trios used in the International HapMap Project. Highly significant transmission disequilibrium was observed, with p = 1.7 x 10(-5), confirming the case-control study of Bottini et al. (2004). However, linkage disequilibrium structure studies revealed that R620W maps to a 293-kb LD block containing numerous polymorphisms, leading Qu et al. (2005) to suggest that other potentially functional polymorphisms may be responsible for the association with type I diabetes mellitus instead of, or in addition to, R620W. Vang et al. (2005) studied T cells from carriers of the 1858C-T SNP allele of the PTPN22 gene, which predisposes to type I diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease, and other autoimmune disorders. They found that T cells with the at-risk allele produced less interleukin-2 (IL2; 147680) upon T-cell antigen receptor (TCR) stimulation, and that the encoded phosphatase had higher catalytic activity and was a more potent negative regulator of T lymphocyte activation. Vang et al. (2005) concluded that the autoimmune-predisposing allele, 1858T, is a gain-of-function mutant. Kawasaki et al. (2006) genotyped 1,520 Japanese and 178 Korean individuals, including 732 patients with type I diabetes, 141 patients with autoimmune thyroid disease, and 825 healthy controls, for the 1858C-T SNP and found that all individuals had the wildtype homozygous C/C/ genotype. The absence of the 1858T allele in this Asian population was confirmed by 2 independent methods, PCR-RFLP and direct sequencing. Kallberg et al. (2007) compared the interaction between 2 major genetic risk factors of rheumatoid arthritis, the HLA-DRB1 shared epitope (SE) alleles (see 142857) and the PTPN22 R620W allele (600716.0001), in 3 large case-control studies, 1 Swedish, 1 North American, and 1 Dutch (in total, 1,977 cases and 2,405 controls). The Swedish study was also used to analyze interactions between smoking and the 2 genes. 'Interaction' was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium--i.e., deviation from independence of penetrance of 2 unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W were seen in all 3 studies regarding rheumatoid arthritis testing positive for antibodies to citrullinated proteins (anti-CCP). Testing for multiplicative interaction demonstrated an interaction between the 2 genes only when the 3 studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in the Swedish and North American studies, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. Huffmeier et al. (2006) excluded a major role of the R620W allele in German psoriasis patients but suggested that other susceptibility determinants within noncoding regions of PTPN22 or its proximity might exist acting independently of the major PSORS1 risk factor (see 177900). The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. The authors found that rs6679667, the marker within PTPN22 most associated with rheumatoid arthritis, was perfectly correlated with the previously described SNP 2476601, and that the effect size was consistent with previous estimates (Hinks et al., 2007). Using flow cytometry, Rieck et al. (2007) found that T cells from individuals homozygous for 1858T, all of whom were autoimmunity patients, had a profound deficit in responsiveness to antigen stimulation. CD4 (186940)-positive memory T cells from control subjects heterozygous for 1858T exhibited reduced responsiveness in terms of calcium mobilization, CD25 (IL2RA; 147730) expression, and IL10 (124092) production compared with cells from subjects homozygous for 1858C. The presence of 1858T in control subjects was associated with increased circulating memory T cells and fewer memory B cells, which had reduced responsiveness through the B-cell receptor, compared with 1858C homozygotes. Rieck et al. (2007) concluded that the PTPN22 1858T variant is associated with a dampened response of both the T- and B-cell antigen receptors, and that the 620W isoform has enhanced inhibitory function in lymphocytes. Skinningsrud et al. (2008) presented evidence suggesting an association between the 1858T allele and autoimmune Addison disease (240200). In a metaanalysis of 3 studies, including their own, comprising 563 European patients with the disorder, the authors found an odds ratio of 1.36 (p = 0.003) for carriers of the T allele. Barrett et al. (2009) reported the findings of a genomewide association study of type 1 diabetes, combined in a metaanalysis with 2 previously published studies (Wellcome Trust Case Control Consortium, 2007; Cooper et al., 2008). The total sample set included 7,514 cases and 9,045 reference samples. Using an analysis that combined comparisons over the 3 studies, they confirmed several previously reported associations, including rs2476601 at chromosome 1p13.2 (P = 8.5 x 10(-85)). Mahdi et al. (2009) tested the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated alpha-enolase, accounts for an important portion of the association between smoking, HLA-DRB1 shared epitope alleles, and PTPN22 association with rheumatoid arthritis susceptibility. In 1,497 individuals from 3 RA cohorts, antibodies to the immunodominant citrullinated alpha-enolase CEP-1 epitope were detected in 43 to 63% of the anti-CCP-positive individuals, and this subset was preferentially linked to HLA-DRB1*04. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22, and smoking showed the strongest associations with the anti-CEP-1-positive subset (odds ratio of 37, compared to an odds ratio of 2 for the corresponding anti-CEP1-negative, anti-CCP-positive subset). Mahdi et al. (2009) concluded that citrullinated alpha-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of rheumatoid arthritis. Arechiga et al. (2009) showed that B-cell signal transduction was impaired in individuals with the PTPN22 1858C-T SNP. This defect in signaling was characterized by a deficit in proliferation and a decrease in phosphorylation of key signaling proteins, such as SYK (600085), and could be reversed by PTPN22 inhibition. Arechiga et al. (2009) proposed that 1858C-T alters B-cell receptor signaling and that their findings implicate B cells in the mechanism by which the variant contributes to autoimmunity. In human T and B cells carrying the R620W mutation, Zhang et al. (2011) showed that calpain binding and cleavage were increased relative to wildtype, indicating that calpain-mediated degradation with consequently reduced expression in lymphocyte and dendritic cell hyperresponsiveness may represent a mechanism whereby the 620W mutation increases the risk for autoimmune disease. (less)

Bottini et al. (2004) found that an 1858C-T transition in the PTPN8 gene resulting in an arg620-to-trp (R620W) amino acid substitution was associated with insulin-dependent diabetes mellitus (IDDM; 222100). Begovich et al. (2004) found that the minor allele (T) was associated with susceptibility to rheumatoid arthritis (RA; 180300). In a study of 525 unrelated North American white individuals with systemic lupus erythematosus (SLE; 152700), Kyogoku et al. (2004) found an association between the R620W SNP and SLE, with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increased risk of SLE (odds ratio = 1.37), and 2 copies of the allele more than doubled this risk (OR = 4.37). Together with the evidence showing association of this SNP with type I diabetes and rheumatoid arthritis, the data provided compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity. To determine whether the R620W SNP in PTPN22 also plays a role in susceptibility to multiple sclerosis (126200), Begovich et al. (2005) genotyped 2 large, well-characterized, family-based data sets involving 748 MS-prone families. They found that the R620W polymorphism is not associated with multiple sclerosis. Criswell et al. (2005) described a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). In each of these families, at least 2 of the 9 'core' autoimmune diseases were present. They found that the R620W functional SNP in PTPN22 (rs2476601) conferred risk of 4 separate autoimmune phenotypes in these families: type I diabetes mellitus, RA, SLE, and Hashimoto thyroiditis (140300). Multiple sclerosis did not show association with the PTPN22 risk allele. These findings suggested a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggested that multiple sclerosis may have a pathogenesis that is distinct from that of RA, SLE, and type I diabetes mellitus. Qu et al. (2005) genotyped the R620W SNP in 588 nuclear families with at least 1 IDDM-affected child and 2 parents and in the 30 European CEPH family trios used in the International HapMap Project. Highly significant transmission disequilibrium was observed, with p = 1.7 x 10(-5), confirming the case-control study of Bottini et al. (2004). However, linkage disequilibrium structure studies revealed that R620W maps to a 293-kb LD block containing numerous polymorphisms, leading Qu et al. (2005) to suggest that other potentially functional polymorphisms may be responsible for the association with type I diabetes mellitus instead of, or in addition to, R620W. Vang et al. (2005) studied T cells from carriers of the 1858C-T SNP allele of the PTPN22 gene, which predisposes to type I diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease, and other autoimmune disorders. They found that T cells with the at-risk allele produced less interleukin-2 (IL2; 147680) upon T-cell antigen receptor (TCR) stimulation, and that the encoded phosphatase had higher catalytic activity and was a more potent negative regulator of T lymphocyte activation. Vang et al. (2005) concluded that the autoimmune-predisposing allele, 1858T, is a gain-of-function mutant. Kawasaki et al. (2006) genotyped 1,520 Japanese and 178 Korean individuals, including 732 patients with type I diabetes, 141 patients with autoimmune thyroid disease, and 825 healthy controls, for the 1858C-T SNP and found that all individuals had the wildtype homozygous C/C/ genotype. The absence of the 1858T allele in this Asian population was confirmed by 2 independent methods, PCR-RFLP and direct sequencing. Kallberg et al. (2007) compared the interaction between 2 major genetic risk factors of rheumatoid arthritis, the HLA-DRB1 shared epitope (SE) alleles (see 142857) and the PTPN22 R620W allele (600716.0001), in 3 large case-control studies, 1 Swedish, 1 North American, and 1 Dutch (in total, 1,977 cases and 2,405 controls). The Swedish study was also used to analyze interactions between smoking and the 2 genes. 'Interaction' was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium--i.e., deviation from independence of penetrance of 2 unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W were seen in all 3 studies regarding rheumatoid arthritis testing positive for antibodies to citrullinated proteins (anti-CCP). Testing for multiplicative interaction demonstrated an interaction between the 2 genes only when the 3 studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in the Swedish and North American studies, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. Huffmeier et al. (2006) excluded a major role of the R620W allele in German psoriasis patients but suggested that other susceptibility determinants within noncoding regions of PTPN22 or its proximity might exist acting independently of the major PSORS1 risk factor (see 177900). The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. The authors found that rs6679667, the marker within PTPN22 most associated with rheumatoid arthritis, was perfectly correlated with the previously described SNP 2476601, and that the effect size was consistent with previous estimates (Hinks et al., 2007). Using flow cytometry, Rieck et al. (2007) found that T cells from individuals homozygous for 1858T, all of whom were autoimmunity patients, had a profound deficit in responsiveness to antigen stimulation. CD4 (186940)-positive memory T cells from control subjects heterozygous for 1858T exhibited reduced responsiveness in terms of calcium mobilization, CD25 (IL2RA; 147730) expression, and IL10 (124092) production compared with cells from subjects homozygous for 1858C. The presence of 1858T in control subjects was associated with increased circulating memory T cells and fewer memory B cells, which had reduced responsiveness through the B-cell receptor, compared with 1858C homozygotes. Rieck et al. (2007) concluded that the PTPN22 1858T variant is associated with a dampened response of both the T- and B-cell antigen receptors, and that the 620W isoform has enhanced inhibitory function in lymphocytes. Skinningsrud et al. (2008) presented evidence suggesting an association between the 1858T allele and autoimmune Addison disease (240200). In a metaanalysis of 3 studies, including their own, comprising 563 European patients with the disorder, the authors found an odds ratio of 1.36 (p = 0.003) for carriers of the T allele. Barrett et al. (2009) reported the findings of a genomewide association study of type 1 diabetes, combined in a metaanalysis with 2 previously published studies (Wellcome Trust Case Control Consortium, 2007; Cooper et al., 2008). The total sample set included 7,514 cases and 9,045 reference samples. Using an analysis that combined comparisons over the 3 studies, they confirmed several previously reported associations, including rs2476601 at chromosome 1p13.2 (P = 8.5 x 10(-85)). Mahdi et al. (2009) tested the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated alpha-enolase, accounts for an important portion of the association between smoking, HLA-DRB1 shared epitope alleles, and PTPN22 association with rheumatoid arthritis susceptibility. In 1,497 individuals from 3 RA cohorts, antibodies to the immunodominant citrullinated alpha-enolase CEP-1 epitope were detected in 43 to 63% of the anti-CCP-positive individuals, and this subset was preferentially linked to HLA-DRB1*04. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22, and smoking showed the strongest associations with the anti-CEP-1-positive subset (odds ratio of 37, compared to an odds ratio of 2 for the corresponding anti-CEP1-negative, anti-CCP-positive subset). Mahdi et al. (2009) concluded that citrullinated alpha-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of rheumatoid arthritis. Arechiga et al. (2009) showed that B-cell signal transduction was impaired in individuals with the PTPN22 1858C-T SNP. This defect in signaling was characterized by a deficit in proliferation and a decrease in phosphorylation of key signaling proteins, such as SYK (600085), and could be reversed by PTPN22 inhibition. Arechiga et al. (2009) proposed that 1858C-T alters B-cell receptor signaling and that their findings implicate B cells in the mechanism by which the variant contributes to autoimmunity. In human T and B cells carrying the R620W mutation, Zhang et al. (2011) showed that calpain binding and cleavage were increased relative to wildtype, indicating that calpain-mediated degradation with consequently reduced expression in lymphocyte and dendritic cell hyperresponsiveness may represent a mechanism whereby the 620W mutation increases the risk for autoimmune disease. (less)

Bottini et al. (2004) found that an 1858C-T transition in the PTPN8 gene resulting in an arg620-to-trp (R620W) amino acid substitution was associated with insulin-dependent diabetes mellitus (IDDM; 222100). Begovich et al. (2004) found that the minor allele (T) was associated with susceptibility to rheumatoid arthritis (RA; 180300). In a study of 525 unrelated North American white individuals with systemic lupus erythematosus (SLE; 152700), Kyogoku et al. (2004) found an association between the R620W SNP and SLE, with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increased risk of SLE (odds ratio = 1.37), and 2 copies of the allele more than doubled this risk (OR = 4.37). Together with the evidence showing association of this SNP with type I diabetes and rheumatoid arthritis, the data provided compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity. To determine whether the R620W SNP in PTPN22 also plays a role in susceptibility to multiple sclerosis (126200), Begovich et al. (2005) genotyped 2 large, well-characterized, family-based data sets involving 748 MS-prone families. They found that the R620W polymorphism is not associated with multiple sclerosis. Criswell et al. (2005) described a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). In each of these families, at least 2 of the 9 'core' autoimmune diseases were present. They found that the R620W functional SNP in PTPN22 (rs2476601) conferred risk of 4 separate autoimmune phenotypes in these families: type I diabetes mellitus, RA, SLE, and Hashimoto thyroiditis (140300). Multiple sclerosis did not show association with the PTPN22 risk allele. These findings suggested a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggested that multiple sclerosis may have a pathogenesis that is distinct from that of RA, SLE, and type I diabetes mellitus. Qu et al. (2005) genotyped the R620W SNP in 588 nuclear families with at least 1 IDDM-affected child and 2 parents and in the 30 European CEPH family trios used in the International HapMap Project. Highly significant transmission disequilibrium was observed, with p = 1.7 x 10(-5), confirming the case-control study of Bottini et al. (2004). However, linkage disequilibrium structure studies revealed that R620W maps to a 293-kb LD block containing numerous polymorphisms, leading Qu et al. (2005) to suggest that other potentially functional polymorphisms may be responsible for the association with type I diabetes mellitus instead of, or in addition to, R620W. Vang et al. (2005) studied T cells from carriers of the 1858C-T SNP allele of the PTPN22 gene, which predisposes to type I diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease, and other autoimmune disorders. They found that T cells with the at-risk allele produced less interleukin-2 (IL2; 147680) upon T-cell antigen receptor (TCR) stimulation, and that the encoded phosphatase had higher catalytic activity and was a more potent negative regulator of T lymphocyte activation. Vang et al. (2005) concluded that the autoimmune-predisposing allele, 1858T, is a gain-of-function mutant. Kawasaki et al. (2006) genotyped 1,520 Japanese and 178 Korean individuals, including 732 patients with type I diabetes, 141 patients with autoimmune thyroid disease, and 825 healthy controls, for the 1858C-T SNP and found that all individuals had the wildtype homozygous C/C/ genotype. The absence of the 1858T allele in this Asian population was confirmed by 2 independent methods, PCR-RFLP and direct sequencing. Kallberg et al. (2007) compared the interaction between 2 major genetic risk factors of rheumatoid arthritis, the HLA-DRB1 shared epitope (SE) alleles (see 142857) and the PTPN22 R620W allele (600716.0001), in 3 large case-control studies, 1 Swedish, 1 North American, and 1 Dutch (in total, 1,977 cases and 2,405 controls). The Swedish study was also used to analyze interactions between smoking and the 2 genes. 'Interaction' was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium--i.e., deviation from independence of penetrance of 2 unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W were seen in all 3 studies regarding rheumatoid arthritis testing positive for antibodies to citrullinated proteins (anti-CCP). Testing for multiplicative interaction demonstrated an interaction between the 2 genes only when the 3 studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in the Swedish and North American studies, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. Huffmeier et al. (2006) excluded a major role of the R620W allele in German psoriasis patients but suggested that other susceptibility determinants within noncoding regions of PTPN22 or its proximity might exist acting independently of the major PSORS1 risk factor (see 177900). The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. The authors found that rs6679667, the marker within PTPN22 most associated with rheumatoid arthritis, was perfectly correlated with the previously described SNP 2476601, and that the effect size was consistent with previous estimates (Hinks et al., 2007). Using flow cytometry, Rieck et al. (2007) found that T cells from individuals homozygous for 1858T, all of whom were autoimmunity patients, had a profound deficit in responsiveness to antigen stimulation. CD4 (186940)-positive memory T cells from control subjects heterozygous for 1858T exhibited reduced responsiveness in terms of calcium mobilization, CD25 (IL2RA; 147730) expression, and IL10 (124092) production compared with cells from subjects homozygous for 1858C. The presence of 1858T in control subjects was associated with increased circulating memory T cells and fewer memory B cells, which had reduced responsiveness through the B-cell receptor, compared with 1858C homozygotes. Rieck et al. (2007) concluded that the PTPN22 1858T variant is associated with a dampened response of both the T- and B-cell antigen receptors, and that the 620W isoform has enhanced inhibitory function in lymphocytes. Skinningsrud et al. (2008) presented evidence suggesting an association between the 1858T allele and autoimmune Addison disease (240200). In a metaanalysis of 3 studies, including their own, comprising 563 European patients with the disorder, the authors found an odds ratio of 1.36 (p = 0.003) for carriers of the T allele. Barrett et al. (2009) reported the findings of a genomewide association study of type 1 diabetes, combined in a metaanalysis with 2 previously published studies (Wellcome Trust Case Control Consortium, 2007; Cooper et al., 2008). The total sample set included 7,514 cases and 9,045 reference samples. Using an analysis that combined comparisons over the 3 studies, they confirmed several previously reported associations, including rs2476601 at chromosome 1p13.2 (P = 8.5 x 10(-85)). Mahdi et al. (2009) tested the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated alpha-enolase, accounts for an important portion of the association between smoking, HLA-DRB1 shared epitope alleles, and PTPN22 association with rheumatoid arthritis susceptibility. In 1,497 individuals from 3 RA cohorts, antibodies to the immunodominant citrullinated alpha-enolase CEP-1 epitope were detected in 43 to 63% of the anti-CCP-positive individuals, and this subset was preferentially linked to HLA-DRB1*04. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22, and smoking showed the strongest associations with the anti-CEP-1-positive subset (odds ratio of 37, compared to an odds ratio of 2 for the corresponding anti-CEP1-negative, anti-CCP-positive subset). Mahdi et al. (2009) concluded that citrullinated alpha-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of rheumatoid arthritis. Arechiga et al. (2009) showed that B-cell signal transduction was impaired in individuals with the PTPN22 1858C-T SNP. This defect in signaling was characterized by a deficit in proliferation and a decrease in phosphorylation of key signaling proteins, such as SYK (600085), and could be reversed by PTPN22 inhibition. Arechiga et al. (2009) proposed that 1858C-T alters B-cell receptor signaling and that their findings implicate B cells in the mechanism by which the variant contributes to autoimmunity. In human T and B cells carrying the R620W mutation, Zhang et al. (2011) showed that calpain binding and cleavage were increased relative to wildtype, indicating that calpain-mediated degradation with consequently reduced expression in lymphocyte and dendritic cell hyperresponsiveness may represent a mechanism whereby the 620W mutation increases the risk for autoimmune disease. (less)

Bottini et al. (2004) found that an 1858C-T transition in the PTPN8 gene resulting in an arg620-to-trp (R620W) amino acid substitution was associated with insulin-dependent diabetes mellitus (IDDM; 222100). Begovich et al. (2004) found that the minor allele (T) was associated with susceptibility to rheumatoid arthritis (RA; 180300). In a study of 525 unrelated North American white individuals with systemic lupus erythematosus (SLE; 152700), Kyogoku et al. (2004) found an association between the R620W SNP and SLE, with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increased risk of SLE (odds ratio = 1.37), and 2 copies of the allele more than doubled this risk (OR = 4.37). Together with the evidence showing association of this SNP with type I diabetes and rheumatoid arthritis, the data provided compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity. To determine whether the R620W SNP in PTPN22 also plays a role in susceptibility to multiple sclerosis (126200), Begovich et al. (2005) genotyped 2 large, well-characterized, family-based data sets involving 748 MS-prone families. They found that the R620W polymorphism is not associated with multiple sclerosis. Criswell et al. (2005) described a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). In each of these families, at least 2 of the 9 'core' autoimmune diseases were present. They found that the R620W functional SNP in PTPN22 (rs2476601) conferred risk of 4 separate autoimmune phenotypes in these families: type I diabetes mellitus, RA, SLE, and Hashimoto thyroiditis (140300). Multiple sclerosis did not show association with the PTPN22 risk allele. These findings suggested a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggested that multiple sclerosis may have a pathogenesis that is distinct from that of RA, SLE, and type I diabetes mellitus. Qu et al. (2005) genotyped the R620W SNP in 588 nuclear families with at least 1 IDDM-affected child and 2 parents and in the 30 European CEPH family trios used in the International HapMap Project. Highly significant transmission disequilibrium was observed, with p = 1.7 x 10(-5), confirming the case-control study of Bottini et al. (2004). However, linkage disequilibrium structure studies revealed that R620W maps to a 293-kb LD block containing numerous polymorphisms, leading Qu et al. (2005) to suggest that other potentially functional polymorphisms may be responsible for the association with type I diabetes mellitus instead of, or in addition to, R620W. Vang et al. (2005) studied T cells from carriers of the 1858C-T SNP allele of the PTPN22 gene, which predisposes to type I diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease, and other autoimmune disorders. They found that T cells with the at-risk allele produced less interleukin-2 (IL2; 147680) upon T-cell antigen receptor (TCR) stimulation, and that the encoded phosphatase had higher catalytic activity and was a more potent negative regulator of T lymphocyte activation. Vang et al. (2005) concluded that the autoimmune-predisposing allele, 1858T, is a gain-of-function mutant. Kawasaki et al. (2006) genotyped 1,520 Japanese and 178 Korean individuals, including 732 patients with type I diabetes, 141 patients with autoimmune thyroid disease, and 825 healthy controls, for the 1858C-T SNP and found that all individuals had the wildtype homozygous C/C/ genotype. The absence of the 1858T allele in this Asian population was confirmed by 2 independent methods, PCR-RFLP and direct sequencing. Kallberg et al. (2007) compared the interaction between 2 major genetic risk factors of rheumatoid arthritis, the HLA-DRB1 shared epitope (SE) alleles (see 142857) and the PTPN22 R620W allele (600716.0001), in 3 large case-control studies, 1 Swedish, 1 North American, and 1 Dutch (in total, 1,977 cases and 2,405 controls). The Swedish study was also used to analyze interactions between smoking and the 2 genes. 'Interaction' was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium--i.e., deviation from independence of penetrance of 2 unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W were seen in all 3 studies regarding rheumatoid arthritis testing positive for antibodies to citrullinated proteins (anti-CCP). Testing for multiplicative interaction demonstrated an interaction between the 2 genes only when the 3 studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in the Swedish and North American studies, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. Huffmeier et al. (2006) excluded a major role of the R620W allele in German psoriasis patients but suggested that other susceptibility determinants within noncoding regions of PTPN22 or its proximity might exist acting independently of the major PSORS1 risk factor (see 177900). The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. The authors found that rs6679667, the marker within PTPN22 most associated with rheumatoid arthritis, was perfectly correlated with the previously described SNP 2476601, and that the effect size was consistent with previous estimates (Hinks et al., 2007). Using flow cytometry, Rieck et al. (2007) found that T cells from individuals homozygous for 1858T, all of whom were autoimmunity patients, had a profound deficit in responsiveness to antigen stimulation. CD4 (186940)-positive memory T cells from control subjects heterozygous for 1858T exhibited reduced responsiveness in terms of calcium mobilization, CD25 (IL2RA; 147730) expression, and IL10 (124092) production compared with cells from subjects homozygous for 1858C. The presence of 1858T in control subjects was associated with increased circulating memory T cells and fewer memory B cells, which had reduced responsiveness through the B-cell receptor, compared with 1858C homozygotes. Rieck et al. (2007) concluded that the PTPN22 1858T variant is associated with a dampened response of both the T- and B-cell antigen receptors, and that the 620W isoform has enhanced inhibitory function in lymphocytes. Skinningsrud et al. (2008) presented evidence suggesting an association between the 1858T allele and autoimmune Addison disease (240200). In a metaanalysis of 3 studies, including their own, comprising 563 European patients with the disorder, the authors found an odds ratio of 1.36 (p = 0.003) for carriers of the T allele. Barrett et al. (2009) reported the findings of a genomewide association study of type 1 diabetes, combined in a metaanalysis with 2 previously published studies (Wellcome Trust Case Control Consortium, 2007; Cooper et al., 2008). The total sample set included 7,514 cases and 9,045 reference samples. Using an analysis that combined comparisons over the 3 studies, they confirmed several previously reported associations, including rs2476601 at chromosome 1p13.2 (P = 8.5 x 10(-85)). Mahdi et al. (2009) tested the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated alpha-enolase, accounts for an important portion of the association between smoking, HLA-DRB1 shared epitope alleles, and PTPN22 association with rheumatoid arthritis susceptibility. In 1,497 individuals from 3 RA cohorts, antibodies to the immunodominant citrullinated alpha-enolase CEP-1 epitope were detected in 43 to 63% of the anti-CCP-positive individuals, and this subset was preferentially linked to HLA-DRB1*04. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22, and smoking showed the strongest associations with the anti-CEP-1-positive subset (odds ratio of 37, compared to an odds ratio of 2 for the corresponding anti-CEP1-negative, anti-CCP-positive subset). Mahdi et al. (2009) concluded that citrullinated alpha-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of rheumatoid arthritis. Arechiga et al. (2009) showed that B-cell signal transduction was impaired in individuals with the PTPN22 1858C-T SNP. This defect in signaling was characterized by a deficit in proliferation and a decrease in phosphorylation of key signaling proteins, such as SYK (600085), and could be reversed by PTPN22 inhibition. Arechiga et al. (2009) proposed that 1858C-T alters B-cell receptor signaling and that their findings implicate B cells in the mechanism by which the variant contributes to autoimmunity. In human T and B cells carrying the R620W mutation, Zhang et al. (2011) showed that calpain binding and cleavage were increased relative to wildtype, indicating that calpain-mediated degradation with consequently reduced expression in lymphocyte and dendritic cell hyperresponsiveness may represent a mechanism whereby the 620W mutation increases the risk for autoimmune disease. (less)