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27-09-2011 | Diabetes | Article

PPAR variant linked to severity of CAD in Type 2 diabetes


Full abstract

MedWire News: A novel peroxisome proliferator-activated receptor (PPAR) pathway gene variant, TLL1, is associated with the extent of coronary artery disease (CAD) in White individuals with Type 2 diabetes, report researchers.

"The variant, TLL1 rs 1503298 shows associations with rigorous and objectively derived measures of CAD and explains more variance of the phenotype than previously determined clinical factors," they report in the journal Circulation.

Sharon Cresci ( Washington University, St Louis, Missouri, USA) and team genotyped 1045 patients, comprising 702 White and 175 Black individuals, from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, for 3351 variants of 223 transcription pathway genes.

During BARI 2D, all patients underwent coronary angiography to quantify the number and extent of stenosis of each lesion, its location in the coronary tree, and its morphology.

The authors found that in White participants, single nucleotide polymorphism (SNP) analysis identified one SNP (rs1503298) in the TLL1 gene that was highly significantly associated with the number of coronary lesions with 20% of diameter stenosis (DS) or more.

Patients with the TLL1 rs1503298 CT genotype had 22% more coronary lesions with at least 20% DS compared with those with the TT genotype, while those with the CC genotype had 37% more of such lesions.

No such association was found in the subgroup of Black BARI 2D patients.

Importantly, the authors found that in linear regression modeling, this SNP explained more variance of the phenotype than previously determined clinical factors, with the SNP explaining 2.75% of the variance, compared with 1.61% explained by gender, 0.12% by age, and 0.01% by body mass index.

Furthermore, the association was validated in the White diabetic subgroups of two independent cohorts.

In addition, the variant was associated with both number of angiographically severe coronary lesions (≥70% DS), and myocardial jeopardy index, a method used to estimate the amount of potential ischemia attributable to the location and severity of coronary lesions.

"The reproducibility of the observed association across populations, despite varied clinical manifestations of CAD and varied methods of quantifying the extent of atherosclerosis, underscores its potential importance and relevance to the fundamental pathophysiology of diabetic atherosclerosis," write Cresci and colleagues.

"Moreover, the physiological pathways affected by this genetic variant may provide novel targets for further investigation and therapeutic intervention to address the accelerated rate of progression and the high risk of adverse events associated with CAD in patients with diabetes," they conclude.

MedWire ( is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

By Sally Robertson

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