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CLINICAL RESEARCH: GENETICS/GENOMICS

Association of Genetic Variation on Chromosome 9p21 With Susceptibility and Progression of Atherosclerosis

A Population-Based, Prospective Study

Shu Ye, MD, PhD, MRCPath^_*,_*, Johann Willeit, MD, Florian Kronenberg, MD, Qingbo Xu, MD, PhD and Stefan Kiechl, MD

^_* Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, London, United Kingdom
Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
Cardiovascular Division, The James Black Centre, Kings College London, London, United Kingdom.

Manuscript received October 3, 2007; accepted November 14, 2007.

^_* Reprint requests and correspondence: Dr. Shu Ye, Clinical Pharmacology, William Harvey Research Institute, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom. (Email: s.ye{at}qmul.ac.uk).

Objectives: Following the recent novel finding from genomewide association studies that sequence variation on chromosome 9p21 is a genetic factor for coronary artery disease, we investigated whether the genetic variant influenced the development of atherosclerosis and its progression in a population-based, prospective study.

Background: Recently, several genomewide association studies revealed a highly significant association between variation on chromosome 9p21 and risk of coronary artery disease.

Methods: We studied the rs1333049 polymorphism located on chromosome 9p21 in a cohort of 769 individuals who participated in the Bruneck study with long-term follow-up data on carotid atherosclerosis measured by high-resolution duplex ultrasound and incident cardiovascular disease.

Results: The C allele was associated not only with prevalent carotid atherosclerosis (odds ratio [OR]: 1.46 [95% confidence interval (CI): 1.13 to 1.88]; OR: 1.43 [95% CI: 1.11 to 1.84]; and OR: 1.44 [95% CI: 1.11 to 1.87] for each copy of C allele, calculated from data collected in 1990, 1995, and 2000, respectively), but also with progression of atherosclerosis (OR: 1.73 [95% CI: 1.36 to 2.21] during 1990 to 1995, and OR: 1.87 [95% CI: 1.44 to 2.42] during 1995 to 2000). In addition, the C allele was related to incident cardiovascular disease (hazard ratio: 1.37 [95% CI: 1.05 to 1.79]). There was evidence of an interaction between genotype and abdominal obesity on atherosclerosis and cardiovascular risk.

Conclusions: The results of this population-based, prospective study indicate that the sequence variation on chromosome 9p21 influences atherosclerosis development and progression.

Key Words: atherosclerosis • genetics • single nucleotide polymorphism

Abbreviations and Acronyms   CAD = coronary artery disease   CI = confidence interval   CVD = cardiovascular disease   HDL = high-density lipoprotein   LDL = low-density lipoprotein   SNP = single nucleotide polymorphism   WHR = waist-to-hip ratio

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