The Genetics of Evoked Responses to Niacin and Endotoxemia: The GENE Study

Niacin is a vitamin that has beneficial effects on cholesterol (a type of fat in the blood)
when used in high doses. Different people respond differently to cholesterol lowering doses
of niacin, some people have a side effect termed flushing (similar to a hot flash) while
others do not and some people have more pronounced effects on cholesterol. Endotoxin or
lipopolysaccharide (LPS) is a small part of bacteria (that is no longer living) that can
cause many of the effects similar to bacterial infections in humans. However, it can be
administered in very small amounts to produce a mild inflammatory response much the same as
a 'flu-like" illness. Within 1 ½ -3 hours after giving LPS by vein, a response consisting of
fever, chills, headache, nausea and vomiting and generalized aches and pains will occur
which lasts up to 6-8 hours. In addition to the flu like symptoms, the inflammation causes
changes in cholesterol, triglycerides and glucose clearance. Different people respond
differently to endotoxin and inflammation. We are performing this study to see if there are
genetic factors that predict how people will respond to niacin and to endotoxin and its
inflammatory response.

Inclusion Criteria:

1. Men and non-pregnant/lactating women between the ages of 18 and 45.

2. Self reported African American or Caucasian racial-ethnic background.

3. Body Mass Index (BMI) of ≥ 18 and ≤ 30.

4. Participants who are able to give written informed consent and willing to comply with
all study-related procedures.

Exclusion Criteria:

1. Known clinically manifest atherosclerotic cardiovascular disease, including coronary
disease, cerebrovascular disease, or peripheral vascular disease.

2. History of diabetes mellitus.

3. Fasting glucose > 126 mg/dL.

4. History of a non-skin malignancy within the previous 5 years.

5. Renal insufficiency as defined by creatinine > 1.5 mg/dl at Screening Visit.

6. History of liver disease or abnormal liver function tests (LFTs) (AST, ALT, Alk.
Phos., GGT > 1.5x upper limit of normal (ULN); bilirubin > 2x ULN) at Screening
Visit.

7. Men who are unwilling to limit alcohol consumption to <14 alcoholic drinks per week
or < 4 alcoholic drinks per occasion (AMA / NIAAA criteria for "at risk" usage
levels) while participating in the study.

8. Women who are unwilling to limit alcohol consumption to < 7 alcoholic drinks per week
or < 3 alcoholic drinks per occasion (AMA / NIAAA criteria for "at risk" usage
levels) while participating in the study.

9. Total white blood cell count less than or equal to 3.0 THO/uL.

10. Hemoglobin below 11.0 g/dL.

11. Any major active rheumatologic, pulmonary, or dermatologic disease or inflammatory
condition or minor active infection.

12. History of HIV positive.

13. First degree family history of premature cardiovascular disease event (father or
brother if diagnosed at before 55 years of age; mother or sister if diagnosed before
65 years of age).

14. Patients who have undergone any organ transplant.

15. Individuals who currently use tobacco products or have done so in the previous 30
days.

16. Treatment with aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), COX-2
inhibitors, steroids or any immunomodulatory therapy 2 weeks prior to the Screening
Visit.

17. Treatment with statins, fibrates or niacin 4 weeks prior to the Screening Visit.

18. Current daily use of Vitamin C > 1000 mg, Beta carotene > 1000 IU, vitamin A > 5000
IU, vitamin E > 400 IU, and selenium > 200 mcg.

19. Positive urine pregnancy at the Screening Visit.

20. Participation in another clinical trial within the previous 6 weeks prior to the
Screening Visit.

21. Poorly controlled blood pressure (BP > 160/110) or on any anti-hypertensive
medications.

22. A diagnosis of metabolic syndrome using updated 2004 NCEP ATPIII criteria.

23. A history of severe lactose intolerance (e.g., intolerance of any milk intake).

24. Any medical condition or abnormal laboratory value that is judged clinically
significant by an investigator.