The ‘ideal’ control would be a.90 years old individual with no prior history of CAD and completely normal coronary arteries.4 However, this design appears unrealistic and would not permit the collection of sufficiently large cohorts needed for detection of small effects or even gene-interactions. Therefore, Luo et al. presented apparently less stringent criteria for phenotype categorization : Controls should be characterized by normal coronary arteries by conventional coronary angiography or multidetector computer tomography, no family history of CAD, no history of cerebrovascular or peripheral artery disease and age of controls much greater than cases. In contrast, cases for coronary artery disease and myocardial infarction, respectively, should present with at least one angiographic stenosis $70% in a major epicardial artery, family history of CAD, no history of smoking, no diabetes, normal or low LDL-cholesterol, high HDLcholesterol and normal C reactive protein. However, today no study exists that meets these criteria. From the total of 2274 subjects included in the untreated and unaffected cohort 1, only 1.5% and 8.5% fulfilled the complete set of criteria suggested by Luo et al for CAD cases and controls, respectively. A recent study has investigated the impact of heterogeneity of phenotype definition of CAD on genetic association studies. Remarkably, these investigators found that differences in phenotype definition make only a small contribution to between study heterogeneity. As a limitation, these results were mostly based on studies of candidate genes, which did not play a role in recent genome-wide association studies of CAD. The authors conclude that even though utility of a clear phenotype definition of CAD might be limited for primary analyses, it might be helpful for secondary analyses after an association with CAD has been established. The mode of recruitment of including only subjects referred to coronary angiography for suspected CAD in cohort 1 is unique to the Leipzig Heart Study and has the advantage of simultaneous collection of cases and controls under equal conditions. Other large angiographic studies have broader inclusion criteria and also recruit patients with non-atherosclerotic indications for coronary angiography such as valvular disease. Only few studies perform combined examinations of the three mostly affected WY 14643 PPAR inhibitor regions of atherosclerosis development such as coronary, carotid and peripheral arteries. These studies use computed tomography of coronary calcium as a surrogate parameter for coronary atherosclerosis. To our knowledge, the Leipzig Heart Study is currently the only largescale cohort providing angiographic assessment of coronary arteries combined with sonographic evaluation of carotid and peripheral atherosclerosis. Another important advantage is the highly standardized preanalytical process of blood sampling prior to interventional or surgical treatment of coronary stenosis. This enables valid analytical studies of blood cell gene-expression as well as profiling of mediators and biomarkers of metabolism, atherosclerotic wall pathology and myocardial function, yet unaffected by revascularization procedures and initiation of intensive pharmacological treatment. Limitations of selecting ‘controls’ from patients presenting that will develop significant.