Referee 2's review:

The authors reported that common SNP variants in the MECP2 gene in Xq28 confer risk of systemic lupus erythematosus, and they also provided functional evidence to suggest that MECP2 gene plays a role in regulating the expression of the methylation-sensitive gene CD70. The paper is well written but further data need to be presented in the genetic section and more experimental work that is closely related to the genetic data should be conducted.

Genetic data

• Genetic analysis and data presentation should be more structured and more complete. For female samples, for example, different genetic models (genotypic, allelic, trend, dominant and recessive) should be tested to gain more biological understanding of the risk factors. Odds ratios should always be listed for both alleles and genotypes in the tables.
• After single point analysis (above) is presented, haplotype testing may follow. Again, frequency and odds ratio should be presented in the table(s) alongside p values to examine whether there is indeed a haplotype effect (which can not be counted for by any single SNP effect). No haplotype testing data was presented for the European samples - why?
• Males in the European samples left unexplained - presumably due to lack of association? Even so, it is still desirable to provide a complete result set to the readers rather than keep them in dark as to what happened to the males, whether there was significant sex-difference for this risk factor, whether lack of association is purely due to insufficient number of male individuals, etc.
• Table 6 should provide a complete picture of the data used and results obtained, including the number of cases and controls, allele frequencies, odds ratios, and p values in Korean samples, in European samples and in the meta analysis.
• The authors should also check whether SNPs elsewhere in the chromosome have long range LD with SNPs under study to be certain about the target gene. It is also useful to check that no SNPs in the autosomes happen to be in high correlation with these SNPs. This should be fairly straightforward to do using the HapMap data.
• Population structure may not be a serious concern in this study. In addressing this problem, the authors used "a panel of 63 randomly chosen "null" SNPs" (presumably for both Korean and European populations) to conduct a genomic control and structure analysis. Both analyses need a large number of informative markers. But it is not clear why these 63 randomly chosen "null" SNPs were sufficient for the task.

Functional Work

The functional data presented is only remotely supportive that SNPs in MECP2 increase risk of SLE. The following would require a response:

• With the evidence pointing to intronic SNPs it suggested that they influence regulation of gene expression, either MECP2 itself or surrounding gene, as the mode of action for disease susceptibility. Therefore, investigation of the expression levels of MECP2 and IRAK1, and respective downstream targets would be more informative, and where expression levels are shown relative to genotype and/or haplotype.
• Mice carrying the MECP2 truncated protein were designed so that they develop Rett Syndrome, a multi-symptomatic neurological disease. It does not appear clear why such a mouse model was chosen when trying to address the pathological relevance of SNPs associated with SLE, given that SLE is an autoimmune disease. In addition, no information is given as to the age of the mice when peripheral blood was extracted for lymphocyte isolation and whether the mice had developed symptoms of Rett's
• The conclusion of MECP2 involvement in T lymphocyte function requires further evidence. It might be that the downregulation of CD70 in T cells is a downstream effect of onset of Rett's syndrome for which the mice are susceptible. Additionally, no evidence of MECP2 expression in T cells is provided either before or after stimulation.

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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.