Pharmacogenomic Response to Thyrotropin-Releasing Hormone Stimulation in Healthy Volunteers: The Influence of a Common Type 2 Deiodinase Genetic Polymorphism on Serum T3

This study intends to examine how a common genetic pattern affects thyroid function. Recent
studies have demonstrated that a substance (enzyme) produced by a gene has an important role
in controlling circulating thyroid hormone levels. A commonly found pattern in this gene
exists in many individuals and might affect the function of the enzyme. These individuals
need higher doses of thyroid hormone medication in certain situations (e.g. in the treatment
of thyroid cancer after the thyroid gland has been removed) than those individuals without
the variation.

We intend to study this by looking at the response to a hormone-test in healthy volunteers
with different genetic patterns.

We plan to screen healthy volunteers using a blood test to identify their genetic pattern
relating to the enzyme we are interested in. From this group, forty-five healthy volunteers
will be recruited for the hormone-test. This test (called the TRH test) uses a hormone
produced by the brain and stimulates the pituitary and thyroid gland. The response to this
test will allow us to compare the function of the thyroid system in relation to the genetic
pattern of the volunteer.

We hypothesize that the stimulation of the thyroid hormone system will be decreased in
volunteers with a specific genetic pattern and that these individuals will release less
active thyroid hormone from the thyroid gland in response to the TRH test.

This study will provide new information on the effect of a common genetic pattern on thyroid
hormone function and will help us to better understand the way in which the thyroid hormone
system operates. Ultimately, the results of this study might help to provide a more
individualized therapy for patients in need of thyroid hormone replacement.

- INCLUSION CRITERIA:

1. Subjects will be healthy male and female adult volunteers, between the ages of 18
and 65, able to provide informed consent. Patients younger than 18 are excluded
as this is a purely physiologic study and we are unable to justify any potential
risk. However, should our preliminary findings show potential clinically relevant
benefits for children, the protocol could be modified to include them. Patients
older than 65 are excluded due to intrinsic differences in thyroid hormone
dynamics, compared with younger subjects, which could confound study
interpretation.

EXCLUSION CRITERIA:

1. BMI less than or equal to 19 or greater than or equal to 35 Kg/m(2)

2. Hypothyroidism, or TSH levels above the normal limits (current replacement therapy or
TSH greater than 4.0 mcIU/mL)

3. Hyperthyroidism, or TSH levels below the normal limits (current or previous therapy or
TSH less than 0.4 mcIU/mL)

4. Autoimmune thyroid disease (as defined by a positive anti-TPO, or anti-TSH receptor
antibody titer)

5. Hypertension (Blood pressure greater than 140/90 or use of antihypertensive
medication)

6. Liver disease or ALT serum concentrations greater than 1.5 times the upper laboratory
reference limit.

7. Renal insufficiency or estimated creatinine clearance less than or equal to 50 mL/min
(MDRD equation).

8. History of, and/or current Diabetes Mellitus (fasting glucose greater than 126 mg/dL)

9. Iodine deficiency (spot urine iodine concentration less than 42 mcg/L)

10. History of, and/or current coronary artery disease

11. History of, and/or current asthma

12. History of, and/or current seizures or chronic headache

13. History of, and/or current depression

14. History of pituitary tumor

15. Pregnancy (women of child-bearing potential must have a negative pregnancy test prior
to inclusion and at the time of TRH testing)

16. Known allergy to TRH

17. Current use of prescription medication or certain non-prescription medications and
dietary supplements which could affect thyroid function and/or metabolism.