Two critical references including biopsy data demonstrated
that most dogs in a pedigree have a mild kidney defect, most dogs with
one or two copies of a Cox-2 allelic variant only have a mild kidney
defect and have a normal lifespan with no signs of kidney disease. This
is documented in the 10-year biopsy study by Bovee reference:
Bovee, K.C. "Renal Dysplasia in Shih Tzu Dogs." Proceedings of the 28th
World Congress of the World Small Animal Veterinary Association, 2003
and the biopsy study of Whiteley (Lhasa apso): Whiteley, Mary H.,
Jerold S. Bell, and Debby A. Rothman. "Novel allelic variants in the
canine cyclooxgenase-2 (Cox-2) promoter are associated with renal
dysplasia in dogs." PLoS One 6.2 (2011): e16684.
| CONCLUSIONS FROM THE BIOPSY STUDIES
The
majority of dogs have a mild kidney defect and appear to be healthy
throughout their lives. Biopsy data is necessary to determine the
status of a dog in regard to renal dysplasia. The DNA test is used to
eliminate the mutant RD alleles to prevent clinical cases in future
generations. Bovee states
that :”Wedge renal biopsy is required to detect affected dogs. Since
the majority of affected dogs go undetected and can pass the defect on,
control is extremely difficult.” He also suggested that the percentage
of dogs with an RD defect could be as high as 85% in the Shih tzu breed
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MANUSCRIPT THAT DOES NOT SUPPORT THE BIOPSY DATA
In 2015, Safra et al., published a paper entitled "DNA sequence
variants in the five prime untranslated region of the cyclooxygenase-2
gene are commonly found in healthy dogs and gray wolves." PLoS One 10.8
(2015): e0133127. This publication was published a full year after the
publication regarding hypermethylation of the Cox-2 promoter in
clinical cases of renal dysplasia, although there was no reference to
this paper in the initial version of this paper (Whiteley, Mary H.
"Allelic variation in the canine Cox-2 promoter causes hypermethylation
of the canine Cox-2 promoter in clinical cases of renal dysplasia."
Clinical Epigenetics 6.1 (2014): 7.)
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Safra
et al., suggest that Cox-2 variants are present in healthy dogs, which
I do not dispute as it has already been determined in my 2011 PLOS ONE
paper's pedigree study in Lhasa Apsos demonstrates that most dogs
with one or two copies of a mutant allele exhibit a mild kidney defect
on renal wedge biopsy and live a normal life without signs of renal
inpairment. These results are in agreement with a 10-year biopsy
study in the Shih Tzu breed by Bovee.
The results of the Safra et al paper were derived from dogs by blood biochemistry or were considered healthy from the
opinion of their owners. No biopsy data was included for the
selected cohorts. The
dogs included in this study were 46 samples from various breeds over the
age of 6 years with normal kidney blood values, 84 samples from
Flat-Coated retreivers, 22 samples from dogs that had no sigsn of renal
dysplasia from necropsy, and 7 wolves.
They
also claimed that renal dysplasia was a juvenile disorder with the age
of onset between 3 months and 3 years. This is simply not true
based on the biopsy studies. Safra et al., are referring to dogs
with clinical symptoms of kidney disease not those with a mild kidney defect that are only detected by a renal wedge biopsy.
The importance of the wolf in identifying a wild type allele is unclear.
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Safra et al., did publish
a correction to their paper, however in this correction they stated
that "Our interpretation is that there is no relation between different
sequence variations in the 5’UTR of canine Cox-2 and canine renal
dysplasia. The random methylation pattern in provides yet another piece
of evidence to support a benign role for these DNA variants"
Again this is incorrect.
The DNA methylation pattern is not random as described in my paper
since the DNA methylation is limited to clinical cases of renal
dysplasia and is allele specific for amutant allelic variant
chromosome. The wild type Cox-2 promoter is never methylated even
in the case of heterozygous dogs. The variable methylation explains the
wide range of RD phenotypes.
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There
are other errors in the Safra et al, manuscript, including a completely
wrong figure (Figure 2). These authors attempted to define the wild
type COX-2 promoter by comparing the canine and wolf COX- with the
COX-2 promoter from other species (eg human, horse, cow, mouse and
chicken), however COX-2 promoter sequences are not conserved between
species, only within members of a family (wolf, dog, coyote,
fox). Therefore, the conclusions from this figure are
meaningless.
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For scientists this analysis is available at ResearchGate
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