Referee 1's Review:

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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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This manuscript explores potential genetic defects in IL-12R function with susceptibility to SARS infection and severity of symptoms in infected subjects. The premise of the work is novel and worthy of study, and once validated the findings would represent an advance in our understanding of the interaction between the immune system and infectious disease susceptibility. Overall, the manuscript was well-documented and well-written, and appropriate statistical corrections were applied. There are some major and minor points that require clarification and have been listed below:

Major points
The authors do not account for the subjects who did not have one of the three defined genotypes for each of the SNPs analyzed. For the +C1664T SNP, different percentages of the cohort were not accounted for as CC, CT, or TT based on SARS infection state. Of the SARS, Control A, and Control B groups, 11 (9.6%), 9 (6.4%), and 5 (3.2%) of each of the respective groups were not included in the defined genotypes. Was there another SNP that accounted for the increased fraction of subjects without the defined genotypes in the SARS patient group (9.6% vs. 3.2% in normal controls)? If so, what was the effect of the unmeasured SNP on IL-12R function?

The authors stated that 115 confirmed SARS cases were included in the study. What was the denominator of overall SARS cases, and how were these 115 cases selected from the total number? The study could be biased if subjects with certain IL-12R B1 genetic polymorphisms were more likely to die or alternatively if they were more likely to have mildly symptomatic disease not requiring hospitalization and were not captured in the study.

It was not always clear how percentages were calculated in the manuscript. For example, in the first paragraph of the results section 39 of the 115 SARS patients were classified as severe, but this was listed as 68.7%.

Minor point
It would be helpful in the discussion section to put the possible defects in IL-12R activity in context with the inflammatory state found in SARS patients, particularly elevated plasma IL-12 levels (Clin Exp Immunol. 2004 Apr;136(1):95-103). One could hypothesize that decreased IL-12R activity might predispose to infection but protect from severe disease manifestations, but the data presented on pages 9-10 appear to suggest that IL-12R activity is also required for protection from severe disease.