MECP2 – Systemic Lupus Erythematosus

Multiple genome‐wide and candidate‐gene studies have implicated the X-linked methyl-CpG binding protein gene MECP2 in systemic lupus erythematosus (SLE) susceptibility across diverse populations. A European replication study of 1,579 SLE cases and 1,726 controls identified a SNP in MECP2 with an odds ratio of 1.26 in women (P=0.00085) ([PMID:19442287]). Fine mapping of the Xq28 region in 15,783 multi-ancestral case-control subjects found a risk haplotype that, while driven by IRAK1 variant rs1059702, was also associated with lower MECP2 mRNA levels in SLE patients and healthy controls (P=0.0012) ([PMID:22904263]). In an Iranian cohort (492 patients, 392 controls), rs1734787 and rs1734791 in MECP2 were significantly associated with SLE risk (P=0.028 each) ([PMID:26156810]). A Chinese meta-analysis (5,373 cases, 9,166 controls) replicated the Xq28 association (rs1059702, OR=0.71, P=2.4×10⁻¹⁸) and highlighted independent signals in adjacent X-linked genes ([PMID:25149475]). A subphenotype study of 1,444 European SLE patients linked the MECP2 locus to earlier age of onset in men ([PMID:23049788]).

Functional follow-up remains limited to expression analyses: the homozygous risk genotype at rs1059702 correlates with reduced MECP2 transcript levels, suggesting allele-specific downregulation of a transcriptional repressor in immune cells ([PMID:22904263]). No Mendelian segregation or rare coding variants have been reported. Additional mechanistic and cellular studies are needed to clarify how MECP2 dysregulation contributes to autoimmunity. Key Take-home: MECP2 variants at Xq28 are modest polygenic risk factors for SLE and may inform risk stratification but are not diagnostic markers for monogenic disease.

References

• PLoS One • 2012 • Further evidence of subphenotype association with systemic lupus erythematosus susceptibility loci: a European cases only study. PMID:23049788
• Arthritis Research & Therapy • 2009 • Replication of recently identified systemic lupus erythematosus genetic associations: a case-control study. PMID:19442287
• Annals of the Rheumatic Diseases • 2013 • Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups. PMID:22904263
• Inflammation • 2015 • Methyl-CpG-Binding Protein 2 (MECP2) Polymorphism in Iranian Patients with Systemic Lupus Erythematosus. PMID:26156810
• Human Molecular Genetics • 2015 • Meta-analysis of GWAS on two Chinese populations followed by replication identifies novel genetic variants on the X chromosome associated with systemic lupus erythematosus. PMID:25149475

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