Background Rare mutations of the low-density lipoprotein receptor gene (LDLR) cause familial hypercholesterolemia, which increases the risk for coronary artery disease (CAD). Less is known about the implications of common genetic variation in the LDLR gene regarding the variability of cholesterol levels and risk of CAD. Methods Imputed genotype data at the LDLR locus on 1 644 individuals of a population-based sample were explored for association with LDL-C level. Replication of association with LDL-C level was sought for the most significant single nucleotide polymorphism (SNP) within the LDLR gene in three European samples comprising 6 642 adults and 533 children. Association of this SNP with CAD was examined in six case-control studies involving more than 15 000 individuals. Findings Each copy of the minor T allele of SNP rs2228671 within LDLR (frequency 11%) was related to a decrease of LDL-C levels by 0.19 mmol/L (95% confidence interval (CI) [0.13–0.24] mmol/L, p = 1.5×10−10). This association with LDL-C was uniformly found in children, men, and women of all samples studied. In parallel, the T allele of rs2228671 was associated with a significantly lower risk of CAD (Odds Ratio per copy of the T allele: 0.82, 95% CI [0.76–0.89], p = 2.1×10−7). Adjustment for LDL-C levels by logistic regression or Mendelian Randomisation models abolished the significant association between rs2228671 with CAD completely, indicating a functional link between the genetic variant at the LDLR gene locus, change in LDL-C and risk of CAD. Conclusion A common variant at the LDLR gene locus affects LDL-C levels and, thereby, the risk for CAD. ; This study was funded by the European Union sponsored projects Cardiogenics (LSHM-CT 2006-037593) and Diabesity (LSHMCT-2003-503041), by the National Genome Network (01GS0418 to Drs Schunkert, Erdmann, and Hengstenberg; 01GR0466 to Dr. Ziegler; 01GS0482 to Dr. Hinney) and by the National Genome Network Plus to Dr. Hinney (01GS0820) sponsored by the German Federal Ministry of Education and Research (BMBF). Recruitment for the WTCCC Study CAD collection was funded by grants from the British Heart Foundation and the UK Medical Research Council. The MONICA/KORA Augsburg studies were financed by the Helmhotz Zentrum Mu¨nchen (former GSF)-National Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the BMBF and Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. Recruitment of the Bonn Childhood Obesity Cohort was funded by the Bonfor Research Foundation, University of Bonn, Germany. This work was also supported by the ‘‘Genomics of Lipid-associated Disorders GOLD’’ of the ‘‘Austrian Genome Research Programme GEN-AU’’ (to F.K.). ; 20976