Genetic variation in cholesterol ester transfer protein, serum CETP activity, and coronary artery disease risk in Asian Indian diabetic cohort.

Dyslipidemia with low serum high-density lipoprotein cholesterol (HDL-C) and elevated low-density cholesterol (LDL-C) levels is a well established risk factor for coronary artery disease (CAD) and a leading cause of mortality in individuals with type II diabetes (T2D). In the past decade, decreasing LDL-C has been the major goal in primary and secondary prevention of CAD through treatment with HMG-CoA reductase inhibitors (statins). However, a large body of data suggests that while statin therapy can reduce CAD events by ~30%, the mortality rate due to CAD remains elevated particularly in the patients with metabolic disease and insulin resistance 1. Decreased HDL-C has been suggested to be a strong, independent, predictor of increased risk for CAD by several epidemiological studies 2. Although, hormonal, environmental, and cultural factors determine HDL-C levels within ethnic populations, a genetic component accounts up to 76% of the variation in HDL-C 3. High heritability of HDL-C and HDL-associated lipid traits provide a strong rationale for identifying genetic loci that may help uncover novel pathways crucial for HDL-C regulation and eventually for treatment or early prevention of CAD. The role of CETP in metabolism of HDL-C is well studied but still controversial. CETP mediates the exchange of lipids between lipoproteins resulting in the net transfer of cholesteryl ester from HDL-C to other lipoproteins and subsequent uptake of cholesterol by hepatocytes through reverse-cholesterol transport 4. Genetic variation in rs708272 (also called Taq1B) in CETP gene has been extensively studied for association with variation in HDL-C in different populations 4, 5. One large meta-analysis study using 147,000 individuals from published studies (between 1970 to January 2008) reported CETP genotypes to be associated with moderate inhibition of CETP activity (with modestly increased HDL-C) and inverse association with CAD 6. However, some other studies have seen greater CAD risk associated with low CETP activity in individuals with genetic deficiency 7, 8. A recent prospective investigation on a moderate size community-based sample from Framingham Heart Study also reported greater CAD risk associated with low CETP activity 9. Most of these genetic studies have been focused on rs708272 (Taq1B) and could not clearly specify the effect of this or other variants on variation in CETP activity or CAD risk. A clear understanding of how genetic variation in CETP affects HDL-C and other risk factors associated with CAD in interaction with environmental factors is still lacking especially in ethnic groups at high risk for T2D and premature CAD. More recently, GWAS studies reported the association of a promoter variant −2568 (rs3764261) with HDL-C variation in Caucasians and has been confirmed in several large meta-analysis studies including different ethnic groups 10, 11. Based on the premise that increased CETP activity decreased HDL-C levels, a new class of drugs (including torcetrapib) were developed with the intent to raise HDL-C levels through inhibition of CETP activity. However, a failure of the trial of torcetrapib, due to an unacceptable increase in CAD mortality (25%) along with 60% increase in all-cause mortality questioned the logic of CETP inhibition and urged re-evaluation of the role of CETP in possibly preventing CAD events 12. Additionally, recently published DEFINE trial of anacetrapib showing robust effect on lowering LDL-C and increasing HDL-C by CETP inhibition in a moderate size Caucasian populations (n=1,623)13 urges further investigations in other high risk ethnic population (such as this) for ensuring safe inhibition of CETP to lower CAD risk. In this context, we examined the role of three SNPs (rs3764261 [−2568], rs12447924 [−1700], and rs4783961 [−998]) located in the promoter region and a non-coding SNP (rs708272/Taq1B) located in first intron of the CETP gene. These SNPs were genotyped in a sample of 2,431 participants drawn from our unique Sikh population of Northern India (Punjab) known to have a high prevalence of T2D and CAD14, 15.