OBJECTIVE: Both genetic and epigenetic factors play an important role in the pathogenesis of lupus. The aim of this study was to examine methyl-CpG-binding protein 2 gene (MECP2) polymorphisms in a large cohort of patients with lupus and control subjects, and to determine the functional consequences of the lupus-associated MECP2 haplotype. METHODS: We genotyped 18 single-nucleotide polymorphisms within MECP2, located on chromosome Xq28, in a large cohort of patients with lupus and control subjects of European descent. We studied the functional effects of the lupus-associated MECP2 haplotype by determining gene expression profiles in B cell lines in female lupus patients with and those without the lupus-associated MECP2 risk haplotype. RESULTS: We confirmed, replicated, and extended the genetic association between lupus and genetic markers within MECP2 in a large independent cohort of lupus patients and control subjects of European descent (odds ratio 1.35, P = 6.65 x 10(-11)). MECP2 is a dichotomous transcription regulator that either activates or represses gene expression. We identified 128 genes that are differentially expressed in lupus patients with the disease-associated MECP2 haplotype; most ( approximately 81%) were up-regulated. Genes that were up-regulated had significantly more CpG islands in their promoter regions compared with genes that were down-regulated. Gene ontology analysis using the differentially expressed genes revealed significant association with epigenetic regulatory mechanisms, suggesting that these genes are targets for MECP2 regulation in B cells. Furthermore, at least 13 of the 104 up-regulated genes are regulated by interferon. The disease-risk MECP2 haplotype was associated with increased expression of the MECP2 transcription coactivator CREB1 and decreased expression of the corepressor histone deacetylase 1. CONCLUSION: Polymorphism in the MECP2 locus is associated with lupus and, at least in part, contributes to the interferon signature observed in lupus patients.
OBJECTIVE: Both genetic and epigenetic factors play an important role in the pathogenesis of lupus. The aim of this study was to examine methyl-CpG-binding protein 2 gene (MECP2) polymorphisms in a large cohort of patients with lupus and control subjects, and to determine the functional consequences of the lupus-associated MECP2 haplotype. METHODS: We genotyped 18 single-nucleotide polymorphisms within MECP2, located on chromosome Xq28, in a large cohort of patients with lupus and control subjects of European descent. We studied the functional effects of the lupus-associated MECP2 haplotype by determining gene expression profiles in B cell lines in female lupuspatients with and those without the lupus-associated MECP2 risk haplotype. RESULTS: We confirmed, replicated, and extended the genetic association between lupus and genetic markers within MECP2 in a large independent cohort of lupuspatients and control subjects of European descent (odds ratio 1.35, P = 6.65 x 10(-11)). MECP2 is a dichotomous transcription regulator that either activates or represses gene expression. We identified 128 genes that are differentially expressed in lupuspatients with the disease-associated MECP2 haplotype; most ( approximately 81%) were up-regulated. Genes that were up-regulated had significantly more CpG islands in their promoter regions compared with genes that were down-regulated. Gene ontology analysis using the differentially expressed genes revealed significant association with epigenetic regulatory mechanisms, suggesting that these genes are targets for MECP2 regulation in B cells. Furthermore, at least 13 of the 104 up-regulated genes are regulated by interferon. The disease-risk MECP2 haplotype was associated with increased expression of the MECP2 transcription coactivator CREB1 and decreased expression of the corepressor histone deacetylase 1. CONCLUSION: Polymorphism in the MECP2 locus is associated with lupus and, at least in part, contributes to the interferon signature observed in lupuspatients.
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
Authors: P L Jones; G J Veenstra; P A Wade; D Vermaak; S U Kass; N Landsberger; J Strouboulis; A P Wolffe Journal: Nat Genet Date: 1998-06 Impact factor: 38.330
Authors: Wei-Dong Chen; Z James Han; Joel Skoletsky; Jeff Olson; Jerome Sah; Lois Myeroff; Petra Platzer; Shilong Lu; Dawn Dawson; Joseph Willis; Theresa P Pretlow; James Lutterbaugh; Lakshmi Kasturi; James K V Willson; J Sunil Rao; Anthony Shuber; Sanford D Markowitz Journal: J Natl Cancer Inst Date: 2005-08-03 Impact factor: 13.506
Authors: Amr H Sawalha; Lu Wang; Ajay Nadig; Emily C Somers; W Joseph McCune; Travis Hughes; Joan T Merrill; R Hal Scofield; Faith M Strickland; Bruce Richardson Journal: J Autoimmun Date: 2012-02-03 Impact factor: 7.094
Authors: Chaoran Li; Shan Jiang; Si-Qi Liu; Erik Lykken; Lin-tao Zhao; Jose Sevilla; Bo Zhu; Qi-Jing Li Journal: Proc Natl Acad Sci U S A Date: 2014-06-23 Impact factor: 11.205
Authors: Kristi A Koelsch; Ryan Webb; Matlock Jeffries; Mikhail G Dozmorov; Mark Barton Frank; Joel M Guthridge; Judith A James; Jonathan D Wren; Amr H Sawalha Journal: J Autoimmun Date: 2013-02-18 Impact factor: 7.094