To characterize the genetic basis of the variable response of triglycerides to two environmental contexts, one that raises triglycerides (dietary fat), and one that lowers triglycerides (fenofibrate treatment.)

BACKGROUND:

Hypertriglyceridemia is emerging as an important predictor of atherosclerosis, and recent evidence suggests related phenotypes of triglycerides (TGs), such as TG remnant particles and small lactate dehydrogenase (LDL) particles, are particularly atherogenic. There is considerable variation in the response of TGs and related phenotypes to the environment.

The study is in response to a Request for Applications (RFA) entitled " Interaction of Genes and Environment in Shaping Risk Factors for Heart, Lung, Blood, and Sleep Disorders". The RFA was released in October, 2001.

DESIGN NARRATIVE:

Measurements will be collected before and after a dietary fat challenge to assess postprandial TGs and related atherogenic phenotypes (VLDL TGs, chylomicron TGs, TG remnant particles, high-density lipoprotein(HDL) and low density lipids (LDL) particle sizes, total cholesterol, LDL-C, and HDL-C). In families with 2 or more members in a sibship with high TGs (>= 130 mg/dl), the authors will conduct a short-term, placebo-controlled, randomized trial of fenofibrate in all willing and eligible family members (anticipated sample size = 1,200). A two-period crossover design will be executed with a 2-week washout between two 3-week treatment periods (placebo or micronized fenofibrate, 160 mg). About 1,000 family members have a Marshfield genome marker set available as part of national Heart Lung and Blood (NHLBI) FHS; the remaining 1,400 will be typed using the same marker set. They will conduct genome-wide linkage analyses using state-of-the-art methods to localize novel genetic loci contributing to TG response in the context of fat loading and fenofibrate treatment. They will type 15 single nucleotide polymorphisms (SNPs) in ten candidate genes known to contribute to the response of TGs to dietary fat and fenofibrate, and create haplotypes for association studies. They will use combinatorial partitioning methods and neural networks to test association of the individual SNPs and haplotypes with response to the two environmental interventions. The identification of genetic loci that predict TG response in the presence of two disparate contexts, fat loading and fibrate therapy, may provide insights into genetic pathways (a) predisposing to hypertriglyceridemia, ultimately leading to avenues for primary prevention, and (b) predicting response to TG lowering, leading to new drug targets for hypertriglyceridemia.

Inclusion criteria:

1. ≥18 years of age
2. fasting TGs <1,500 mg/dl
3. willingness to participate in the study and attend the scheduled clinic exams
4. member of a family with at least two members in a sibship
5. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) results within normal range
6. creatinine ≤2.0 mg/dl

Exclusion criteria:

1. history of liver, kidney, pancreas, or gall bladder disease or malabsorption
2. current pregnancy
3. insulin use
4. use of lipid-lowering drugs (including prescription, over the counter, and nutriceuticals; volunteers taking these agents were withdrawn from them at least 4 weeks prior to the study with physician's approval)
5. use of warfarin
6. women of childbearing potential not using an acceptable form of contraception
7. known hyper-sensitivity to fenofibrate
8. history of pancreatitis within 12 months prior to enrollment

Subjects meeting entry criteria