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COMPLETED RESEARCH STUDIES When a study is completed, the results are often reported in scientific journals and researchers often provide a report to the CHF and funding clubs. ACA funded studies are titled in red. This section contains the studies funded in whole or in part by the ACA which have been completed. They are in chronological order on the page and listed by subject in this index. To jump to one of interest, just click on the link under the subject:
Akita Health Survey (click here for the PDF document. Opens in new browser window) In 2001, the ACA conducted its first scientific health survey in Akitas. Orchestrated by Dr. Glickman and paid for by an anonymous donor, 603 eligible Akitas participated in this study, even though more Akita health surveys were returned. Comprehensive tables on longevity, most common diagnoses in males and females, diet, vaccine and chemicals in the environment are addressed. The top ten most common diseases as well as the most concerning health issues in our breed our discussed at length. This is a must-read for the serious breeder and researcher and is very informative for any veterinarian with any number of Akitas in practice. If you are unable to download a document this large, you can purchase it on disc or hard copy. Contact Rita Roberts to make arrangements. CHF Grant No: 2254A: Heritable
and Sporadic Genetic Lesions in Canine Lymphoma and Osteosarcoma,
Abstract Lymphoma (cancer of lymph glands) and osteosarcoma (bone cancer) are two common cancers of dogs with remarkable breed predisposition. Lymphoma accounts for approximately 20 percent of all canine tumors, and > 80 percent of cancers originating from blood cells. Osteosarcoma is the most common bone tumor in dogs, accounting for 85 percent of skeletal cancers. All cancers have a genetic basis, and in effect, these conditions represent various diseases, each sharing one or few genetic abnormalities that contribute to overall risk and treatment response. However, a means does not exist to identify individuals at risk, or tumors that are likely to respond to conventional therapy. We have identified individual genes and larger regions within the genome that appear to be important in canine cancer. For this project, we propose to confirm the frequency and significance of these genetic anomalies in lymphoma and osteosarcoma of Golden Retrievers, Rottweilers, Irish Setters, and Bernese Mountain Dogs. This work will begin to determine which of these anomalies may be heritable and which may be sporadic, and pave the way to apply this knowledge for clinical benefits by providing potential targets for treatment, and tools to define individual risk to develop these types of cancer or produce cancer-prone progeny. Status: Fully funded. Final Report Due Dec. 2005. CHF Release [Tuesday, September 27, 2005] Progress Made in Determination of Heritable Risk Factors for Canine Lymphoma Researchers have announced that prevalence of B-cell and T-cell lymphomas among certain dog breeds indicates heritable risk (Cancer Research, Vol 65, No. 13, July 2005). This research, led by Drs. Jaime Modiano, University of Colorado Health Sciences Center, and Matthew Breen, North Carolina State University, was possible in part by grants made by the Canine Health Foundation to study lymphoma in several breeds, and has been sponsored by 21 breed clubs, corporations, and individuals. According to Modiano and Breen, "The predisposition of certain breeds to develop lymphoma has been recognized for a long time, but this is the first indication that the tumors themselves harbor breed-specific genetic abnormalities. This opens new avenues for investigation that will help us to identify specific genes that contribute to the risk of lymphoma in dogs, and possibly in people." Cancer risk has long been believed to have heritable components. However, genes that may be causally related to sporadic cancers such as non-Hodgkin's lymphoma have been difficult to pinpoint. This research shows that the prevalence of B-cell and T-cell lymphomas differs among dog breeds. Additionally, it determined that these different prevalence rates are shared among dog breeds that are closely related. The article in the publication Cancer Research states "...these results indicate that recurrent genetic abnormalities that occur with significantly higher frequency in a single dog breed can assist in the identification of candidate genes that may be associated with the origin or progression of both canine and human cancers." Dogs make an excellent model to study heritability factors in cancer. According to the investigators, "The limited level of genetic heterogeneity within dog breeds, combined with the fact that the incidence and lifetime risk of naturally occurring (disease) differs among dog breeds, offers a unique opportunity to identify genetic risk factors that contribute to the pathogenesis of (disease)." "Canine cancer has long been the top concern among our clubs and individuals," states president, Wayne Ferguson. "It is so gratifying to see that we are helping to lead the charge against identifying the risk factors and genetic markers for this dreaded disease. In fact, cancer research accounts for more than 30% of the AKC Canine Health Foundation's total grant allocations in the last 10 years." Phylogenetic Study Japan, Yamazaki Veterinary School in Kanagawa, Japan, Dr. K. Yamazaki and Dr. Sato. In 2003, collections from 39 Akitas in the US were sent to them to help with a phylogenetic study utilizing mitochondrial DNA. We were told this is the very first collaborative effort made between Japanese researchers and American Akita fanciers! Last year, they sent a questionnaire regarding temperament for the participants to complete. Status: Published. Rita Roberts communicated with Dr. Yamazaki this year. The results of the study have been published in Japan. Rita has summarized the findings: The researchers in Japan knew that the genetic marker in German Shepherds at the DRD4 gene polymorphism is different from that of the Akita in Japan. They examined DNA from 39 samples submitted from across the US and found that they too were different from the German Shepherds and that there was no significant difference between American and Japanese Akitas genetically at that marker. Not only was there no significant difference present, but also the gene polymorphisms existed nearly the same in both populations. They found a periphery difference in temperament, stating Japanese pedigreed dogs appeared to be more aloof and less even tempered. This could not be separated from the obvious cultural differences in the treatment of dogs per the research. CHF Grant No: 2272 Localization of the Gene for Sebaceous Adenitis in the Akita Dog by Homology Mapping, Kelly Credille, DVM, PhD Abstract: Whenever I discuss with lay audiences the devastating effect genetic diseases can have on purebred dogs, I describe sebaceous adenitis (SA). A disease common in breeds like the Akita and Standard Poodle, severely affected dogs are largely hairless, covered in scale and smell terribly. There is no cure. Because the disease seldom shows itself until sexual maturity and because some affected dogs may never develop overt clinical signs, breeders cannot determine which dogs to breed. For these reasons, SA is a disease in need of a genetic test. However, designing such a test is challenging. Because of the difficulty distinguishing SA-affected from normal dogs, pedigree-dependent tests cannot be recommended. To accomplish the objectives of this study, we have devised an alternative protocol to associate a marker with SA. We have chosen the Akita breed to study because its history of bottlenecks and isolation make it ideal for this type of investigation. We believe this protocol will not only be successful but will result in a cost-effective and time-efficient alternative to more widely used methods in canine genetics research and will improve our ability to define those diseases in which distinguishing affected dogs can be ambiguous. Completed. Final Report on this website Genetic Structure of the Purebred Domestic Dog, Heidi G. Parker, Lisa V. Kim, Nathan B. Sutter, Scott Carlson, Travis D. Lorentzen, Tiffany B. Malek, Gary S. Johnson, Hawkins B. DeFrance, Elaine A. Ostrander, Leonid Kruglyak Abstract We used molecular markers to study genetic relationships in a diverse collection of 85 domestic dog breeds. Differences among breeds accounted for 30% of genetic variation. Microsatellite genotypes were used to correctly assign 99% of individual dogs to breeds. Phylogenetic analysis separated several breeds with ancient origins from the remaining breeds with modern European origins. We identified four genetic clusters, which predominantly contained breeds with similar geographic origin, morphology, or role in human activities. These results provide a genetic classification of dog breeds and will aid studies of the genetics of phenotypic breed differences. Status: Published in Science 21 May 2004: Vol. 304. no. 5674, pp. 1160 - 1164, Information Online Grantlet #0326 (CHF) Microphthalmia, Merle, and MITF in Dogs. Sheila M. Schmutz, Ph.D., University of Saskatchewan Abstract Microphthalmia-associated Transcription Factor (MITF) has been shown to cause microphthalmia in mice. This study investigated MITF in some detail in dogs to use polymorphisms identified in MITF to study families of dogs with microphthalmic pups to determine whether this gene is causing the disease and whether it causes merle pups. Status Published. Results in PDF Format Dr. Schmutz tells us that although MITF appeared a likely candidate, their investigation as well as anecdotal reports about incidence make it unlikely to be so, at least as an autosomal recessive. She will continue to look for a likely candidate gene to pursue further. She adds, “We very much appreciate your help with our studies! Should some other researcher cross your path with a promising gene, I'd be more than happy to share aliquots of the DNA from these litters.” Uveodermatologic (VKH-like) syndrome in American Akita dogs is associated with an increased frequency of DQA1*00201, J. M. Angles, T. R. Famula & N. C. Pedersen Abstract The Akita breed of dog is affected by a number of
distinct immune-mediated diseases, including thyroiditis, sebaceous
adenitis, pemphigus foliaceus, uveitis, polyarthritis, myasthenia gravis,
and uveodermatologic (UV) syndrome. UV syndrome is manifested by progressive
uveitis and depigmenting dermatitis that closely resembles the human
Vogt – Koyanagi – Harada syndrome. This study examined the
allelic diversity of the three DLA class II loci (DRB1, DQA1, and DQB1)
in the American Akita dog, and the relationship of specific DLA class
II alleles to the UV. Low allelic variation was demonstrated within
genes of DLA class II. American Akita dogs possessed six of the reported
16 DQA1 alleles, but only eight of 61 reported alleles in DRB1 and nine
of 47 reported alleles in DQB1. Almost one-half of American Akita dogs
were homozygous for a single allele at DQA1 and up to a quarter at DRB1
and DQB1. DLA-DQA1*00201 was associated with a significantly higher
relative risk (RR ¼ 15.3) or odds ratio (OR ¼ 15.99) for
UV syndrome than other DLA class II alleles. No significant association
was noted with haplotypes of DRB1, DQB1, and DQA1 alleles; DRB1*03201-DQA1*00201
trended toward significance. This study confirmed loss of DLA genetic
diversity in the American Akita dog in common with other pure breeds
of dog and suggested a role for certain DLA class II gene alleles in
the pathogenesis of UV. Completed - Available online in pdf CHF Grant # 615 Heritable and Sporadic Genetic Lesions in Canine Lymphoma, Jaime Modiano, VMD, Phd, U. Of Colorado Health Sciences Center and Matthew Breen, PhD, North Carolina State University. Update - This study has been divided into 615A and 615B. We have received a final report, although the study is not completed. It will be resumed as 615B. Dr. Modiano has relocated to U. Minnesota and Dr. Hunter has been added as a researcher. Although not completed, this research has already generated a number of papers, articles, and presentations. For more complete information and references to papers please visit http://www.modianolab.org/. Abstract It has been apparent for some time that certain dog breeds are prone to develop certain types of cancer. Specifically, studies completed between the late 1960s and the early 1980s defined relative risk of lymphoma for different dog breeds. Yet, there was little progress since then to define factors that account for this risk. As part of ongoing programs supported by the AKC CHF in our laboratories, we showed recently that the breed-specific risk of lymphoma extends beyond the simple disease condition to a predisposition for specific forms of lymphoma. More importantly, we showed there are recurrent chromosomal abnormalities that segregate with specific forms of lymphoma and that are more common in Golden Retrievers (with that form of the disease) than in other breeds, suggesting breed-specific profiles of genetic abnormalities will be found in canine lymphoma. To continue this work, we plan to use contemporary array-based technologies to identify genes that map to these regions and how they contribute to the disease. We anticipate that the results from this work will allow us to predict how heritable factors influence the occurrence of abnormalities in these genes, and will set the groundwork to identify specific genes associated with breed-dependent cancer risk. ACA funded, $2500 2006 and $2500 2007. Note: This is a continuation of their completed research study. SAMPLES NEEDED - Researchers need samples from any affected dog that has an AKC registration number. Eligible dogs will undergo standard of care treatment and provide blood samples as well. Availability of 2 or more unaffected relatives that are >6 years old is desirable. They also would encourage people who have dogs that are related to study subjects that are affected to participate. For information on what is needed and how you can help, please see Dr. Modiano's website CHF Acorn Grant #705 - A Characterization of Fluorine-18-Fluoredeoxyglucose Uptake in Dogs with Cutaneous Mast Cell Tumors and Malignant Lymphoma, Dr. Amy Leblanc, U of Tennessee. Update - The
investigator had begun her analysis when the machine with which she
looked at the tumors developed problems that have yet to be fixed.
She has completed some of the study and will be publishing
something based on her initial data; however, because she has been
unable to finish in a timely fashion, the grant has been cancelled. Most of the
funding had been provided, but the unused residue will be redeposited
into our Donor Advised Fund (DAF) by the end of October.
Abstract The U. of Tennessee's College of Veterinary Medicine (UTCVM) has a unique opportunity for collaboration with the Cancer Imaging and Tracer Development Research Program (CITDRP) at the U. of Tennessee Medical Center. The UTCVM has established a strong collaboration with the CITDRP for the benefit of human and veterinary patients. We will use PET imaging to study cutaneous mast cell tumor (MCT) and canine lymphoma (LSA) in dogs. Whole body PET scanning is uniquely suited for staging with evaluation of the skin, lymph nodes, spleen, and liver for early signs of metastatic spread. All of these sites can be imaged in one non-invasive procedure, using uptake of the 18-Flourine-labeled glucose analog 1-deoxy-D-glucose (18-FDG) to identify sites of metastasis. The proposed pilot study will evaluate the uptake if 18-FDG in 30 tumor-bearing dogs (15 with MCT, 15 with LCA) suing PET. All dogs will have their cancer diagnosed and staged using standard imaging techniques and results will be compared with whole-body PET results. ACA Funded $500 in 2006. CHF Grant #634 Genetic Determinants of Canine Malignant Melanoma, Michael Kent, DVM, UC Davis (California) Update - This study has been withdrawn with no expenditures. The $1000 from CHF DAF removed for this study will be returned to the DAF by the end of Oct. 2007 Abstract Malignant melanoma in the dog is a highly aggressive cancer that affects many breeds of dogs. Despite intensive therapy with radiation therapy, surgery and chemotherapy it is often rapidly fatal. It is essential that new treatment protocols be developed for this devastating disease. With the information available from the canine genome project it will now be possible to identify the genes which make canine malignant melanoma such a bad disease. Through the use of a canine specific array we plan to identify a genetic profile for malignant melanoma. This will allow the use of newly developed drugs aimed at these abnormally expressed genes to be tested. Not only do we plan to identify specific pathways involved in making this tumor so malignant but we also plan to develop a profile of 5-20 genes that can act as a marker for disease presence. We will then test if this profile will be a useful diagnostic test to identify metastasis and predict prognosis by using the array to look for the presence of circulating tumor cells or RNA in the blood. COMMENT—Although melanoma isn’t reported as common in Akitas, the course of the disease is so rapid in affected dogs and the mortality rate so high, that it may not be detected. . Again, now that the sequencing is complete, different research labs are going to be doing much more with dogs and we will all benefit from it. The mortality rate from diagnosis of melanoma to death is 75% within 8 months of diagnosis according to two studies I looked at. This study has a lot of value in human medicine as well as for dogs. ACA Funding $1,000 2006 Coat Color Study to Identify the gene responsible for the brindle and non-brindle coat colors, Greg Barsh and Sophie Candille, Lab: Genetics Department, Stanford University What's needed: Visit http://barshlab.stanford.edu/DogCoatColorIndex.htm for more information on this project. Please contact Sophie Candille, scand@stanford.edu, to participate. In your email, include your address, how many Akitas you would like to enroll in the study, and their pictures. Status: Open for participation. Analysis of data on hold until Sophie Candille returns. Update - Dr.
Sophie Candille thanks all the Akita people who sent her hair samples.
The abstract below summarizes the findings of the research team
investigating the genetics of brindle coat color.
They’ve found the controlling genes are actually located on a
new locus, K with three alleles. Previously,
the alleles for brindle were thought to be at E.
“Mutations
of pigment type switching have provided basic insight into melanocortin
physiology and evolutionary adaptation. In all vertebrates that have
been studied to date, two key genes, Agouti and Melanocortin 1 receptor
(Mc1r), encode a ligand-receptor system that controls the switch between
synthesis of red-yellow pheomelanin vs. black-brown eumelanin. However,
in domestic dogs, historical studies based on pedigree and segregation
analysis have suggested that the pigment type-switching system is more
complicated and fundamentally different from other mammals. Using a
genomewide linkage scan on a Labrador x greyhound cross segregating for
black, yellow, and brindle coat colors, we demonstrate that pigment type
switching is controlled by an additional gene, the K locus. Our results
reveal three alleles with a dominance order of black (K(B)) > brindle
(k(br)) > yellow (k(y)), whose genetic map position on dog chromosome
16 is distinct from the predicted location of other pigmentation genes.
Interaction studies reveal that Mc1r is epistatic to variation at Agouti
or K and that the epistatic relationship between Agouti and K depends on
the alleles being tested. These findings suggest a molecular model for a
new component of the melanocortin signaling pathway and reveal how
coat-color patterns and pigmentary diversity have been shaped by recent
selection.” PMID: 17483404 [PubMed - in process] WHITE
COAT COLOR This
investigates the genetics of the typical path for white coat color in
several breeds, including most Akitas.
Dr. Sheila Schmutz is very appreciative of all the Akita owners
who sent her hair samples. Here
is the abstract of the study. The
full text is available freely online. “Cream
dogs of several breeds require a genotype of e/e at MC1R based on 27
individuals in this study. All Akita, Caucasian Mountain Dogs, German
Shepherd Dogs, Miniature Schnauzer, and Puli with this genotype are
cream, suggesting they are fixed at a second locus which causes the
phaeomelanin pigmentation caused by this genotype to be diluted or pale.
Conversely, although all Chinese Shar-Pei and Poodles that were cream
had an e/e genotype at MC1R, not all dogs with this genotype are cream.
Today, many Golden Retrievers and Labrador Retrievers with an e/e
genotype are cream instead of the traditional yellow to golden color
seen in the past. The second gene in these breeds must have multiple
alleles, only one of which causes phaeomelanin pigment to be diluted or
pale. Tyrosinase (TYR) and solute carrier family 45, member 2 (SLC45A2)
have been shown to cause cream coat color in other species and were
therefore investigated in dogs as candidate genes for this second locus.
Although polymorphisms were detected in cDNA sequence from TYR and
SLC45A2, no polymorphism was consistently associated with cream dogs or
cosegregated with cream coat color in any of the families used in this
study. A microsatellite was detected in a published BAC sequence (GenBank
no. AAEX01017083) in intron 2 and was used to map SLC45A2 to CFA4.”
Full text available at: http://jhered.oxfordjournals.org/cgi/content/full/98/5/544
Updated on 02/20/2009 |
