Review for 10.1186/1471-230X-10-22 (2010)

Reviewer's report
Title:Prevalence of Genetic Polymorphisms in the Promoter Region of the
Alpha-1 Antitrypsin (SERPINA1) Gene in Chronic Liver Disease: a Case Control
Study
Version: 2Date:10 November 2009
Reviewer: Sally Chappell
Reviewer's report:
The aim of this study was to investigate the distribution of the -1973 promoter
polymorphism of SerpinA1 in patients with liver disease compared to healthy
controls. The results show that there is no difference in the allele frequency in the
patients compared to the controls for any of the aetiologies considered.
The work in this manuscript follows on from a published study which compared
alpha-1 antitrypsin deficient (AATD) individuals with liver disease against AATD
patients with lung disease. This previous work aimed to identify genetic variants
of alpha-1-antitrypsin that would identify which AATD individuals were at risk of
developing liver disease rather than COPD, and found a significant difference in
the allele frequency of SNP -1973.
Major Compulsory Revisions
1. The introduction in the current manuscript sets the scene well for the
consideration of AATD-induced liver disease, but the subjects included in this
study were not selected on the basis of AATD. There is little justification in the
current study for where alpha-1 antitrypsin may play a role in the various
aetiologies included in the liver disease group, and this is the main weakness of
the investigation. There is considerable heterogeneity in the liver disease group,
and there is little comment on how alpha-1 antitrypsin would be expected to play
a significant role in all of these causes. As a consequence of including such a
variety of conditions, the age at onset has a huge range –it is unsurprising
therefore that no significant effect was seen.
2. The power calculations were also carried out assuming one group of 297
patients, whereas in fact this is really a collection of much smaller sub-groups.
3. Inclusion criteria for the controls is lacking – how were these individuals
checked for the presence/absence of liver disease? Were they examined
clinically or was this on the basis of self-reporting?
4. What quality control measures were in place to check the genotyping results?
Were any samples done in duplicate? Were any sequenced, or analysed using
an alternative technique, to check the accuracy of the PCR method?
5. The authors state that the distribution of Z allele heterozygosity is similar
across all aetiologies, but do not give any further detail. Were statistical tests
done for all of these comparisons?
6. The distribution of -1973 alleles are likely to be different in MZ individuals
compared to wildtype MM individuals – this is unsurprising, and the altered allele
frequencies of -1973 in PiZ patients has already been documented (Ref 9 in the
current manuscript). It is possible that similar results would be seen for the S
allele, although why this should be different between the patients and control
groups is unclear. Potentially these results, and the conflict with the results in
References 13-15 as mentioned by the authors in the discussion (which are
much larger studies), are likely to be caused by the small sample numbers in the
current study.
Level of interest: An article of insufficient interest to warrant publication in a
scientific/medical journal
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests