Clinical trial NCT00083369: Genetic and Environmental Determinants of Triglycerides (GOLDN)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Atherosclerosis
Cardiovascular Diseases
Heart Diseases
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2004-05-24
Enrollment: 1327
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Subjects meeting entry criteria

Brief summary: 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.)

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: describe the association between blood lipids and gene variants
timeFrame: 3 weeks after start of fenofibrate intervention // 3 weeks after start of fenofibrate intervention
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: University of Alabama at Birmingham
name: Donna Arnett
role: PRINCIPAL_INVESTIGATOR
References:
citation: Slade E, Irvin MR, Xie K, Arnett DK, Claas SA, Kind T, Fardo DW, Graf GA. Age and sex are associated with the plasma lipidome: findings from the GOLDN study. Lipids Health Dis. 2021 Apr 3;20(1):30. doi: 10.1186/s12944-021-01456-2.
citation: Aslibekyan S, Almasy L, Province MA, Absher DM, Arnett DK. Data for GAW20: genome-wide DNA sequence variation and epigenome-wide DNA methylation before and after fenofibrate treatment in a family study of metabolic phenotypes. BMC Proc. 2018 Sep 17;12(Suppl 9):35. doi: 10.1186/s12919-018-0114-0. eCollection 2018.
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