The peroxisome proliferator-activated receptors (PPARs) consist of three related transcription factors that serve to regulate a number of cellular processes that are central to cardiovascular health and disease. Numerous pharmacologic studies have assessed the effects of specific PPAR agonists in clinical trials and have provided insight into the clinical effects of these genes while genetic studies have demonstrated clinical associations between PPAR polymorphisms and abnormal cardiovascular phenotypes. With the abundance of data available from these studies as a background, PPAR pharmacogenetics has become a promising and rapidly advancing field. This review focuses on summarizing the current state of understanding of PPAR genetics and pharmacogenetics and the important implications for the individualization of therapy for patients with cardiovascular diseases.
PPAR-alpha (PPAR
PPAR
PPAR
PPAR
The PPARs are able to bind many
different ligands including metabolic intermediates (fatty acids),
pharmacologic agents (fibrates, thiazolidinediones), and natural herbs (green
tea) [
There is considerable clinical
association data linking polymorphisms of
This review will discuss several significant
PPAR genetic and pharmacogenetic associations that have been observed with
respect to cardiovascular disease (Table
SNP | rs number | |
---|---|---|
Leu162Val | rs1800206 | |
Val227Ala | rs1800234 | |
IVS7 2498 | rs4253778 | |
IVS7 1343 | rs4253776 | |
Pro12Ala | rs1801282 | |
25,506 C > T | rs2028759 | |
54,347 C > T | rs3856806 | |
−87 T > C | rs9658134 | |
−4,401 C > T | rs2038068 | |
−48,444 C > T | rs6902123 |
Recently, the association of the
These findings confirmed previous
observations in 2373 participants of the Framingham Offspring Study. When the association of the
Other studies have also investigated
the association of the
In contrast to the aforementioned
studies, when the association of the
As discussed above, LOCAT found no association of the
The Helsinki Heart Study (Helsinki, Finland) was a primary prevention
trial that demonstrated that randomization to treatment with gemfibrozil
resulted in a 34% reduction in cumulative cardiac events and a 26% reduction in
cardiac mortality [
The Veterans Affairs High-Density
Lipoprotein Intervention Trial (VA-HIT) study of patients with known ischemic
heart disease, selected for low levels of HDL cholesterol (mean of 32 mg/dL), demonstrated
that randomization to gemfibrozil therapy resulted in a 22% reduction in relative
risk of coronary events and a 31% reduction in cerebral vascular events [
The Genetics of Lipid Lowering
Drugs and Diet Network (GOLDN) study
investigated the response to fenofibrate (160 mg) for ≥21 days
in 791 men and women enrolled in The Family Heart Study (FHS, a multicenter, family pedigree study aimed to identify genetic and environmental risk factors of
cardiovascular disease)
[
Recently, the finding of this small
study was confirmed in 2899 Chinese individuals from the 1998 Singapore National
Health Survey (NHS98) [
The
The Diabetes Atherosclerosis Intervention Study
(DAIS) was designed to investigate if fenofibrate treatment of relatively mild
dyslipidemia in 418 patients with type 2 DM would be associated with less progression
of coronary atherosclerosis after treatment for at least 3 years with
fenofibrate [
Investigators from the STOP-NIDDM trial were
interested in whether
The
The association of the
More recently, the association of the
This data, as well as very recent data from 3,548 individuals in the diabetes
prevention program (DPP) [
Several studies have investigated the
association of the
In contrast,
a study of 2,016 patients with type 2 DM from the genetic portion
of the continually updated dataset known as the Diabetes Audit and Research in
Tayside Scotland database (Go-DARTS) [
When the association of
A study of 267 Korean individuals (158 males and 109 females) referred for coronary angiography for chest pain, found
no significant association between the
An association has also been observed
between the
The
Investigators from the STOP-NIDDM trial were
interested in whether PPAR polymorphisms would be associated with the
conversion to type 2 DM in response to acarbose in patients with impaired
glucose tolerance [
The
The Lipoprotein and Coronary Atherosclerosis Study (LCAS) was a randomized,
placebo-controlled study of 429 subjects, 35–70 years old, with at least one
30–75% diameter stenosis on coronary angiography and LDL cholesterol of
115–190 mg/dL designed to assess the regression in coronary atherosclerosis (as
measured by within-patient perlesion change in minimal lumen diameter by
quantitative coronary angiography) in response to fluvastatin [
Genetic variation of
The Troglitazone in the Prevention of Diabetes
(TRIPOD) study was a placebo-controlled trial designed to test if TZD therapy
could prevent the development of type 2 DM in Hispanic women with previous
gestational DM [
In TRIPOD, 30% of women were classified as nonresponders as they were in the
lowest tertile of 3 month improvement in insulin sensitivity and did not gain
any protection from development of type 2 DM [
The
When the association of the
Skogsberg et al. investigated whether the
Genetic variation of
Genetic variation in six SNPs in
With their pleiotropic effects on lipid metabolism, glucose homeostasis, myocardial energetics, and responses to ischemia, as well as the considerable evidence linking genetic polymorphisms identified within the PPAR complex to common cardiovascular diseases, the PPAR family of transcription factors is central to the regulation of a number of key cellular pathways that impact on normal and pathologic cardiovascular physiology and thus represent very promising targets for further advances in pharmacologic intervention. Early pharmacogenetic investigations into the associations of a select few of these polymorphisms with patient responses to drug therapy have yielded important clues to commonly observed variability in both response and outcomes. Given the central role of the PPARs in critical metabolic pathways, this experience points the way to a future where knowledge of relevant PPAR genotype might be utilized to guide more appropriately tailored and individualized therapy.