Functional haplotypes of the hTERT gene, leukocyte telomere length shortening, and the risk of peripheral arterial disease.
BACKGROUND
The development of peripheral arterial disease (PAD) is heterogeneous even in the presence of similar risk factors. Our aim was to determine whether inter-individual differences in leukocyte telomere length contribute to the susceptibility of PAD.


METHODS
A total of 485 patients with PAD (defined by the ankle-brachial index) and 970 age- and gender-matched controls were recruited from seven rural communities in Henan Province in China. The relative leukocyte telomere length was determined by a quantitative PCR-based method. Two common promoter variants of the hTERT gene were genotyped to assess their effects on telomere length and the risk of PAD. In vivo luciferase assay was performed to study the transcriptional activity.


RESULTS
After adjustment for vascular risk factors and genetic variants in the hTERT gene, individuals in the lowest and middle tertiles of telomere length had a significantly higher risk of PAD than did those in the highest tertile (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.29-2.49 in the middle tertile; 3.15, 95%CI 2.31-4.29 in the lowest tertile). Haplotype analysis using the 2 variants (rs2735940 and rs2853669) showed that subjects with the at-risk C-C haplotype had shorter telomere length than those individuals with the T-T haplotype and consistently had 1.30-fold (OR 1.30, 95%CI 1.06-1.58; P=0.005) increased risk for PAD. The C-C haplotype had 43% lowered transcription activity of hTERT promoter (P<0.001).


CONCLUSIONS
The associations between the functional haplotype of hTERT gene and telomere length and the risk of atherosclerotic PAD suggested that mean leukocyte telomere length may independently serve as a potential predictor of PAD.
Sino-German Laboratory for Molecular Medicine, FuWai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. zhangwl1747@yahoo.com.cn
Weili
W
Zhang
Yu
Y
Chen
Xiaomin
X
Yang
Jingyao
J
Fan
Xuenan
X
Mi
Jizheng
J
Wang
Channa
C
Zhang
Frank B
FB
Hu
Rutai
R
Hui
D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D058729:Peripheral Arterial Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D019098:Telomerase / Q000235:genetics*; D059506:Telomere Shortening / Q000235:genetics*; D014158:Transcription, Genetic
C509186:TERT protein, human; D019098:Telomerase