Cytogenetic location: 6q23 Genomic coordinates (GRCh38) : 6:130,000,001-138,300,000
For a phenotypic description and a discussion of genetic heterogeneity of systemic lupus erythematosus (SLE), see 152700.
Graham et al. (2008) carried out a genomewide association scan in 431 unrelated SLE cases and 2,155 controls and a replication study in 740 independent trios and found association between SLE and rs5029939, a variant in the TNFAIP3 gene (191163) on chromosome 6q23 (metaanalysis P = 2.89 x 10(-12), OR = 2.29). Graham et al. (2008) also found evidence of 2 independent signals near TNFAIP3 associated with SLE, including one, rs6920220, previously associated with rheumatoid arthritis (180300). In addition to TNFAIP3, associations with HLA and IRF5 (612251) were confirmed in this study.
Musone et al. (2008) performed a genomewide association study in 1,239 SLE cases and 1,629 controls of European ancestry and identified 3 independently associated SNPs in the TNFAIP3 region: rs13192841, which generated an OR of 1.4, 95% CI = 1.2-1.6, P = 5.4 x 10(-8); rs2230926, OR = 2.0, 95% CI = 1.4-3.0, P = 3.0 x 10(-4); and rs6922466, OR = 1.3, 95% CI = 1.1-1.4, P = 1.0 x 10(-4).
To identify risk loci for SLE susceptibility, Gateva et al. (2009) selected SNPs from 2,466 regions that showed nominal evidence of association with SLE (P less than 0.05) in a genomewide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. Gateva et al. (2009) showed an association with the TNFAIP3 gene at rs5029937 (combined P value = 5.3 x 10(-13), odds ratio = 1.71, 95% confidence interval = 1.51-1.95).
Lodolce et al. (2010) noted that there are 2 nonsynonymous coding polymorphisms in the deubiquitinating (DUB) domain of TNFAIP3: phe127 to cys (F127C ; rs2230926), which is in high linkage disequilibrium with SLE risk variants in people of European descent, and ala125 to val (A125V; rs5029941). They performed a case-control study with 217 African-American SLE patients using these coding variants, along with 6 tagging SNPs in TNFAIP3, and identified a novel African-derived risk haplotype. Although F127C was associated with SLE risk in this African American population, the most significant SLE-associated risk variant was an African-derived tagging SNP, rs5029953 (p = 0.008; odds ratio = 1.6). The rare minor allele of A125V was associated with protection from SLE in African Americans (p = 0.05; odds ratio = 0.38) and with susceptibility to inflammatory bowel disease (IBD; 266600) (p = 0.027; odds ratio = 3.73). Enzymatic functional analysis showed that A125V was associated with diminished TNFAIP3 deubiquitinating activity, and computer modeling suggested that A125V altered the 3-dimensional structure of the DUB domain to a greater extent than F127C.
Adrianto et al. (2011) used fine mapping and genomic resequencing in ethnically diverse populations with SLE to fully characterize the TNFAIP3 risk haplotype and identified a TT-A polymorphic dinucleotide (deletion T followed by a T-to-A transversion) associated with SLE in subjects of European (p = 1.58 x 10(-8), odds ratio = 1.70) and Korean (p = 8.33 x 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-kappa-B subunits (see 164011) with reduced avidity. Further, compared with the nonrisk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. Adrianto et al. (2011) concluded that their results established this TT-A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.
Adrianto, I., Wen, F., Templeton, A., Wiley, G., King, J. B., Lessard, C. J., Bates, J. S., Hu, Y., Kelly, J. A., Kaufman, K. M., Guthridge, J. M., Alarcon-Riquelme, M. E., and 35 others. Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nature Genet. 43: 253-258, 2011. [PubMed: 21336280, images, related citations] [Full Text]
Gateva, V., Sandling, J. K., Hom, G., Taylor, K. E., Chung, S. A., Sun, X., Ortmann, W., Kosoy, R., Ferreira, R. C., Nordmark, G., Gunnarsson, I., Svenungsson, E., and 24 others. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nature Genet. 41: 1228-1233, 2009. [PubMed: 19838195, images, related citations] [Full Text]
Graham, R. R., Cotsapas, C., Davies, L., Hackett, R., Lessard, C. J., Leon, J. M., Burtt, N. P., Guiducci, C., Parkin, M., Gates, C., Plenge, R. M., Behrens, T. W., and 10 others. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nature Genet. 40: 1059-1061, 2008. [PubMed: 19165918, related citations] [Full Text]
Lodolce, J. P., Kolodziej, L. E., Rhee, L., Kariuki, S. N., Franek, B. S., McGreal, N. M., Logsdon, M. F., Bartulis, S. J., Perera, M. A., Ellis, N. A., Adams, E. J., Hanauer, S. B., Jolly, M., Niewold, T. B., Boone, D. L. African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity. J. Immun. 184: 7001-7009, 2010. [PubMed: 20483768, images, related citations] [Full Text]
Musone, S. L., Taylor, K. E., Lu, T. T., Nititham, J., Ferreira, R. C., Ortmann, W., Shifrin, N., Petri, M. A., Kamboh, M. I., Manzi, S., Seldin, M. F., Gregersen, P. K., Behrens, T. W., Ma, A., Kwok, P.-Y., Criswell, L. A. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nature Genet. 40: 1062-1064, 2008. [PubMed: 19165919, related citations] [Full Text]
DO: 9074;
Cytogenetic location: 6q23 Genomic coordinates (GRCh38) : 6:130,000,001-138,300,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q23 | {Systemic lupus erythematosus, susceptibility to, 13} | 612378 | 2 |
For a phenotypic description and a discussion of genetic heterogeneity of systemic lupus erythematosus (SLE), see 152700.
Graham et al. (2008) carried out a genomewide association scan in 431 unrelated SLE cases and 2,155 controls and a replication study in 740 independent trios and found association between SLE and rs5029939, a variant in the TNFAIP3 gene (191163) on chromosome 6q23 (metaanalysis P = 2.89 x 10(-12), OR = 2.29). Graham et al. (2008) also found evidence of 2 independent signals near TNFAIP3 associated with SLE, including one, rs6920220, previously associated with rheumatoid arthritis (180300). In addition to TNFAIP3, associations with HLA and IRF5 (612251) were confirmed in this study.
Musone et al. (2008) performed a genomewide association study in 1,239 SLE cases and 1,629 controls of European ancestry and identified 3 independently associated SNPs in the TNFAIP3 region: rs13192841, which generated an OR of 1.4, 95% CI = 1.2-1.6, P = 5.4 x 10(-8); rs2230926, OR = 2.0, 95% CI = 1.4-3.0, P = 3.0 x 10(-4); and rs6922466, OR = 1.3, 95% CI = 1.1-1.4, P = 1.0 x 10(-4).
To identify risk loci for SLE susceptibility, Gateva et al. (2009) selected SNPs from 2,466 regions that showed nominal evidence of association with SLE (P less than 0.05) in a genomewide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. Gateva et al. (2009) showed an association with the TNFAIP3 gene at rs5029937 (combined P value = 5.3 x 10(-13), odds ratio = 1.71, 95% confidence interval = 1.51-1.95).
Lodolce et al. (2010) noted that there are 2 nonsynonymous coding polymorphisms in the deubiquitinating (DUB) domain of TNFAIP3: phe127 to cys (F127C ; rs2230926), which is in high linkage disequilibrium with SLE risk variants in people of European descent, and ala125 to val (A125V; rs5029941). They performed a case-control study with 217 African-American SLE patients using these coding variants, along with 6 tagging SNPs in TNFAIP3, and identified a novel African-derived risk haplotype. Although F127C was associated with SLE risk in this African American population, the most significant SLE-associated risk variant was an African-derived tagging SNP, rs5029953 (p = 0.008; odds ratio = 1.6). The rare minor allele of A125V was associated with protection from SLE in African Americans (p = 0.05; odds ratio = 0.38) and with susceptibility to inflammatory bowel disease (IBD; 266600) (p = 0.027; odds ratio = 3.73). Enzymatic functional analysis showed that A125V was associated with diminished TNFAIP3 deubiquitinating activity, and computer modeling suggested that A125V altered the 3-dimensional structure of the DUB domain to a greater extent than F127C.
Adrianto et al. (2011) used fine mapping and genomic resequencing in ethnically diverse populations with SLE to fully characterize the TNFAIP3 risk haplotype and identified a TT-A polymorphic dinucleotide (deletion T followed by a T-to-A transversion) associated with SLE in subjects of European (p = 1.58 x 10(-8), odds ratio = 1.70) and Korean (p = 8.33 x 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-kappa-B subunits (see 164011) with reduced avidity. Further, compared with the nonrisk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. Adrianto et al. (2011) concluded that their results established this TT-A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.
Adrianto, I., Wen, F., Templeton, A., Wiley, G., King, J. B., Lessard, C. J., Bates, J. S., Hu, Y., Kelly, J. A., Kaufman, K. M., Guthridge, J. M., Alarcon-Riquelme, M. E., and 35 others. Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nature Genet. 43: 253-258, 2011. [PubMed: 21336280] [Full Text: https://doi.org/10.1038/ng.766]
Gateva, V., Sandling, J. K., Hom, G., Taylor, K. E., Chung, S. A., Sun, X., Ortmann, W., Kosoy, R., Ferreira, R. C., Nordmark, G., Gunnarsson, I., Svenungsson, E., and 24 others. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nature Genet. 41: 1228-1233, 2009. [PubMed: 19838195] [Full Text: https://doi.org/10.1038/ng.468]
Graham, R. R., Cotsapas, C., Davies, L., Hackett, R., Lessard, C. J., Leon, J. M., Burtt, N. P., Guiducci, C., Parkin, M., Gates, C., Plenge, R. M., Behrens, T. W., and 10 others. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nature Genet. 40: 1059-1061, 2008. [PubMed: 19165918] [Full Text: https://doi.org/10.1038/ng.200]
Lodolce, J. P., Kolodziej, L. E., Rhee, L., Kariuki, S. N., Franek, B. S., McGreal, N. M., Logsdon, M. F., Bartulis, S. J., Perera, M. A., Ellis, N. A., Adams, E. J., Hanauer, S. B., Jolly, M., Niewold, T. B., Boone, D. L. African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity. J. Immun. 184: 7001-7009, 2010. [PubMed: 20483768] [Full Text: https://doi.org/10.4049/jimmunol.1000324]
Musone, S. L., Taylor, K. E., Lu, T. T., Nititham, J., Ferreira, R. C., Ortmann, W., Shifrin, N., Petri, M. A., Kamboh, M. I., Manzi, S., Seldin, M. F., Gregersen, P. K., Behrens, T. W., Ma, A., Kwok, P.-Y., Criswell, L. A. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nature Genet. 40: 1062-1064, 2008. [PubMed: 19165919] [Full Text: https://doi.org/10.1038/ng.202]
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