Hypothyroidism

Dr. Lorna Kennedy at the University of Manchester’s Centre for Integrated Genomic Medical Research in England has found the haplotype (group of genes) that will double the chances of a Ridgeback becoming hypothyroid due to lymphocytic thyroiditis.  Lymphocytic thyroiditis is the overwhelming cause of hypothyroidism in Ridgebacks.

In a continuation of her CHF-sponsored study on canine hypothyroidism, Dr. Kennedy needs samples on a cross-section of Rhodesian Ridgebacks. Approximately 40 samples were collected at the 2006 National Specialty in Farmington, Utah thanks to conscientious owners who are as devoted as we are to find a genetic marker for this disease.  More are needed.

To that end, Dr. Dodds at Hemopet, who has been the collecting agent for samples coming from the United States, is offering a special discount for Rhodesian Ridgebacks IF they also participate in this research.  Normally the fee is $92.00 for complete thyroid testing, including TGAA, and Dr. Dodds’ interpretation.  She will be offering this service to owners of Rhodesian Ridgebacks for $55.00 IF they also submit samples for Dr. Kennedy’s thyroid research.  You can staple a personal check to the “2006 Test Request Form” or complete the credit card information at the bottom of the form. The research specimen can be shipped with the thyroid specimen so no additional cost for shipping will be incurred by the owner.

You can get this testing as well as OFA thyroid certification, which includes a T-4 by dialysis run at an OFA approved laboratory for $85.00.  Again attach a check to  the “2006 Test Request form for $85.00 or complete the credit card information on the bottom of the form.  Include an “OFA Application for Thyroid Database”  and attach a SEPARATE personal check for $15.00 made out to the OFA.

If you use Dr. Dodds’ services or plan to use them in the future please consider participating in this study.  The following Ridgebacks are eligible to participate:

         1.  Ridgebacks who are hypothyroid and on medication.  The samples can be drawn the next time they get their thyroid hormone levels checked.  Do not stop the medication.   Please include copies of past thyroid profiles, especially documenting elevated TGAA tests.

         2.  Ridgebacks who are getting thyroid panels done for breeding clearance and OFA clearance.

The following forms need to accompany the samples.  Collection and processing instructions are on the forms.  Print each of these forms and take them with you to your veterinarian. Ensure they accompany the samples. 

Note: the following files will require Adobe Acrobat Reader version 6 or higher to print properly. Earlier versions may work, but functionality has not been verified.

  1. Dr. Dodds’ “2006 Test Request Submission Form”
  2. Dr. Dodds’ “Instructions for sample collection and processing”
  3. “UK DNA Archive Information Sheet”
  4. “Consent Form for RR”
  5. “DNA Archive Clinical History”
  6. Application for Thyroid Database” - if you want OFA clearance. Please include a personal check made out to "OFA" for $15.00 attached to this form.

Your participation is greatly appreciated.

Thank you,
Cynthia Roethel
Senior Chair, RRCUS Health and Genetics Committee

Hypothyroidism Studies

Recombinant Thyrotropin (TSH)

CHF Grant 2434

Genetic Determinants of Susceptibility

CHF Grant 2447

For more information on Hypothyroidism, please click here.

CHF Grant 2434 (2002)

Recombinant Thyrotropin (TSH): Standard for the Next Generation of Canine TSH Immunoassays with Improved Sensitivity
Principal Investigator: Duncan C. Ferguson, VMD, PhD,DACVIM, DACVCP

The thyrotropin (TSH) immunoassay has revolutionized the way the diagnosis of hypothyroidism is made in the dog. However, the commercially available assay does not show abnormalities in about 25 percent of patients with proven hypothyroidism. Therefore, the assay lacks diagnostic sensitivity, which could be due to the lack of a widely accepted standard for this glycoprotein, could signal the need to understand more about the structure of TSH, and certainly signals for the need for assay antibodies with higher affinity. Current commercial TSH standards are derived from large numbers of pituitaries from dog cadavers.

In this study, we have used molecular genetic technology to allow production of canine TSH in cell culture, and have shown that it can be used in the place of pituitary-source TSH for the purpose of an assay standard. Furthermore, we now have evidence that antibodies produced against pituitary-source TSH do cross-react significantly with other structurally related pituitary hormones like LH and FSH which hormones which fluctuate in the cycling female. We also are in the process of evaluating previously developed antibodies against our highly purified TSH and are in the process of developing additional antibodies against recombinant TSH. With this work, we hope to improve the diagnostic sensitivity and accuracy of the canine TSH assay, and to provide a highly purified standard by which other assays can be standardized. 

                    

CHF Grant 2447 (2004)

Genetic Determinants of Susceptibility of Hypothyroidism
Principal Investigators: George Happ, PhD., Lorna Kennedy, PhD., Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK

Lay summary:

Canine hypothyroid disease is very similar to Hashimoto’s Thyroid disease in humans, which has been shown to be associated with human Major Histocompatibility Complex (MHC) tissue types. A similar association with canine MHC genes in hypothyroid dogs would provide useful genetic markers for selective breeding to reduce disease incidence in pure-bred dogs.

In this study we have shown that the presence of a particular MHC allele or variant, called DLA-DQA1*00101, doubles the risk of a dog developing hypothyroid disease.

There is a clear genetic component to canine hypothyroid disease, particularly in closely inbred lines, and a number of breeds are thought to be more susceptible. Breed susceptibility may be related to the frequency of DLA-DQA1*00101 within each breed. Interestingly, several breeds that are not represented in our disease group do not normally carry this DLA allele within their populations.

The results suggest that while MHC is associated with increased risk in some breeds, it may have less influence in other breeds.

More dogs are being recruited into a follow-up study to investigate the effect of the MHC in different breeds.

Detailed report:

MHC genes are central to the regulation of the immune response including susceptibility to autoimmune diseases such as hypothyroid disease. Variation in immunity correlates strongly with differences observed in these genes.

The specific objective of this study was to investigate whether particular canine MHC class II alleles predispose to hypothyroid disease and the production of antibodies to canine thyroid antigens. We also wished to quantify the level of disease risk associated with different variants, and to clarify whether certain breeds are more at risk from the disease than others.

We collected DNA samples from 173 dogs with hypothyroid disease. Of these, a subset of 85 dogs have good clinical data, and can be confidently assigned with primary hypothyroid disease, based on the presence of anti-thyroglobulin antibodies together with other clinical signs. The other 88 dogs have incomplete clinical data (notably lacking anti-thyroglobulin antibody data), and therefore may represent a more heterogeneous group.

The affected dogs include only 42 different breeds, compared to our control set of 873 controls which contains dogs from over 70 different breeds. Some breeds are over represented in the patient group, such as Boxer, Doberman, Rhodesian Ridgeback and English Setter, while other breeds are not represented at all in the patients, such as Siberian Husky, Shih Tzu and Yorkshire Terrier.

We compared the total set of 173 diseased dogs with two different control sets of dogs: a) 267 breed matched dogs, and b) a large panel of 873 dogs (which has a representative breed distribution for the dog UK population).

We have compared the DLA allele frequencies of the patient groups with the control groups. In all these comparisons the same allele, DLA-DQA1*00101, was shown to be significantly associated with the presence of hypothyroid disease, see Table 1.

Table 1: Association of DLA-DQA1*00101 with hypothyroid disease

Patient group

Control group

X2

OR

95% CI

P value

All affected dogs

105/173 (60.7%)

All controls

355/873 (40.7%)

22.7

2.25

1.59-3.19

<0.000002

All affected dogs

105/173 (60.7%)

Breed matched controls

122/267 (45.7%)

8.87

1.84

1.22-2.76

<0.003

Selected subset

57/85

(67.1%)

Breed matched controls

122/267 (45.7%)

10.94

1.97

1.32-2.94

<0.001

OR= Odds Ratio. CI = Confidence Interval.

The most stringent comparison of 85 dogs with putative primary hypothyroid disease with 267 breed matched controls gives an Odds Ratio of 1.97 and a p value < 0.001.

There is still a highly significant association of this allele with disease in the total patient group, suggesting that the group may not be as heterogeneous as we previously thought.

Several breeds are over-represented within this disease group, including Boxer, Doberman, Rhodesian Ridgeback and English Setter. In fact, it was difficult to find any Rhodesian Ridgebacks to use as controls, as it appears that this breed is highly susceptible to hypothyroid disease.

We have looked at each of these breeds separately with regards to the presence of DLA-DQA1*00101. It is clear that DQA1*00101 is raised in Dobermans, Rhodesian Ridgebacks and English setters with hypothyroid disease, but that it is not raised in Boxers.

These results suggest that MHC may influence the development of hypothyroid disease in some (e.g. Doberman, Rhodesian Ridgeback and English Setter), but not all (e.g. Boxer) breeds.

Interestingly, the breeds mentioned earlier as being not represented in the patient group, have low frequencies of DLA-DQA1*00101.

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