Mendelian Reverse Cholesterol Transport Study

The study will use 3H-cholesterol bound to albumin (particulate cholesterol) to assess the
ability of HDL to transport cholesterol from the periphery to the liver to be eliminated.
This process is called reverse cholesterol transport (RCT) and is one of the main mechanisms
by which HDL protect against atherosclerotic cardiovascular disease. Mutations in some of the
genes affecting HDL metabolism, may results in changes in RCT. The validation of a method
assessing RCT is important for the development of new drugs which affect RCT and may result
in useful treatments for atherosclerosis.

Subjects carrying mutations in genes known to affect HDL metabolism and healthy controls will
be enrolled in the study. Changes in the tracer activity in total plasma, lipoproteins
fractions and feces will be analyzed following the intravenous administration of radiolabeled
particulate cholesterol.

Inclusion Criteria:

1. Men and women between the ages of 18 and 75

2. Subjects must be:

1. Carriers of functional mutations of genes encoding proteins affecting HDL
metabolism;

2. Healthy control subjects with HDL cholesterol levels within the normal range of
the lab where screening tests are run, or at the discretion of the investigator,
and matched for gender, race, age (± 5 years) to the patients.

3. Negative screening pregnancy test if female of child bearing potential (females of
child-bearing potential must be following a medically accepted form of contraception)

4. Subjects must be able to comprehend and willing to provide a signed IRB approved
Informed Consent Form.

5. Subjects must be willing and able to comply with all study-related procedures.

Exclusion Criteria:

1. Known cardiovascular disease, including coronary disease, cerebrovascular disease, or
peripheral vascular disease (control subjects only)

2. History of diabetes mellitus or fasting glucose > 126 mg/dL at the screening visit
(control subjects only).

3. Any current, unstable endocrine disease as assessed by collection of medical history
during screening. Subjects with rare Mendelian disorders with thyroid disease that is
well controlled by stable treatment may be considered for enrollment at the discretion
of the principal investigator

4. History of previous malignancy, other than basal cell or squamous cell carcinoma of
the skin, from which the patient has been disease free for less than 5 years as
assessed by collection of medical history during screening

5. Current diagnosis of anemia as assessed by collection of medical history during
screening or hemoglobin less than 10 g/dL as evaluated during safety lab at screening

6. History of kidney disease or chronic renal insufficiency, as defined as estimated
glomerular filtration rate (eGFR) < 60 ml/min/1.73m2 in control subjects and patients
with other disorders of HDL metabolism and eGFR < 30 ml/min/1.73m2 in subjects with
Lecithin-Cholesterol Acyltransferase (LCAT) deficiency.

7. Any active rheumatologic, pulmonary, or dermatologic disease or inflammatory condition
as assessed by collection of medical history during screening, and judged by the
investigator to be a major condition.

8. Sustained uncontrolled hypertension (Systolic >160 mm Hg and/or Diastolic BP >100
mmHg) at screening. Blood pressure may be re-tested twice after initial assessment in
the supine position at five minute intervals (for a total of 3 blood pressure
assessments). The pressure elevation is considered sustained if either the systolic or
the diastolic pressure values are outside the stated limits for all three assessments

9. Use of warfarin, or any known coagulopathy and /or elevated prothrombin time/partial
thromboplastin time (PT/PTT) >1.5 x upper limit of normal (ULN)

10. Self-reported history of human immunodeficiency virus (HIV) positive

11. History of previous organ transplantation, as assessed by collection of medical
history during screening

12. Clinical evidence of liver disease or liver injury as indicated by abnormal liver
function tests such as alanine transaminase (ALT) or aspartate transaminase (AST) >
1.5x ULN, or self-reported history of positive Hepatitis B or Hepatitis C test result

13. Any surgical procedure that occurred within the previous 3 months of the screening
visit, as assessed by collection of medical history during screening, and judged by
the investigator to be a major procedure.

14. History of drug abuse (< 1 year), as assessed by collection of medical history during
screening procedures

15. Regular abuse of alcoholic beverages (> 2 drinks/day), as assessed by collection of
medical history during screening procedures

16. Self-reported participation in an investigational drug study within 6 weeks prior to
the screening visit

17. Serious or unstable medical or psychological conditions that, in the opinion of the
investigator, would compromise the subject's safety or successful participation in the
study will be excluded.

18. Use of lipid lowering drugs expected to affect RCT (e.g. fibrates) within the 6 weeks
prior to dosing or during the study, as assessed by collection of medical history
during screening and concomitant medication checks at each study visit. Use of statins
(stable dose for at least 30 days) is permitted.

19. Male subjects who plan to conceive a child within 3 months of the conclusion of the
study.

20. Women who are pregnant or lactating or who are planning to become pregnant