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Referee comments: Referee 1

Posted by PLOS_ONE_Group on 07 Mar 2008 at 18:30 GMT

Referee 1's review:

This paper reports a gene MECP2 associated with systemic lupus erythematosus (SLE) for the first time on chromosome X. Generally, the claim is well supported by the experimental data. Researchers who are devoted to unraveling pathogenesis of SLE would be interested in this paper. Therefore, this manuscript is definitely welcome and can provide insight into the dissection of etiology of SLE. Most of parts of this manuscript are well written and easy to read. However, some issues need be addressed before it can be considered for publication. Below, some points are listed below and need to address.

1. Please describe how the snps were selected? Are they Tag snps for the region?
2. In the 9th line of Page 5, please provide relevant reference. In addition, it looks that the reason to choose MECP2 as the candidate gene is sufficient but not necessary. Readers may wonder why the authors did not choose other genes which are critical in the transcriptional suppression of methylation sensitive genes, like MBD1, MBD2, and MBD4.
3. In the first paragraph of the result section (Page5 and 6), p-values should be adjusted for multiple-testing by some methods like permutation and please detail the final result of the step-wise conditional analysis in a table.
4. MECP2 is a gene on X chromosome. But the European-derived cohort contains both males and females. The allelic association and HWE tests for SNPs on X chromosome are different between SNPs on X chromosome and those on autosomes. Dose the result in Table 5 consider this issue? If it is, please point out this.
5. In the last paragraph of the result section (Page 7), did authors check the expression of other methylationsensitive genes? If not, why did you only check CD70?
6. Please label the x axis in Fig 2(a)?
7. In the last line of page 7, what is a "powerful association"?
8. In the first paragraph of the Discussion section and Table 6, a simple combination of the two cohorts is not safe. The two cohorts are from different populations and each has different frequency of the risk allele and OR. A combination without testing heterogeneity runs the risk of combination. The combined odds ratio and the potential heterogeneity across populations need to be assessed by the Mantel-Haenszel procedure or Meta-analysis.
9. Any dosage effect of risk alleles has been observed because the high risk allele frequency in Korean population? Dose homozygous genotypes of the risk alleles have more severe phenotype than heterozygous individual? I suspect that this could partially explain why the female to male ratio is high and author need to include this interesting information.
10. Since IRAK1 gene is also a strong candidate gene and high LD with MECP2, authors need cautiously claim that MECP2 is the gene associated SLE before excluding the association of IRAK1 in the region.

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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.

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