TY - JOUR
T1 - Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease-a Mendelian Randomisation study
AU - Wellcome Trust Case Control Consortium (WTCCC)
AU - Linsel-Nitschke, Patrick
AU - Götz, Anika
AU - Erdmann, Jeanette
AU - Braenne, Ingrid
AU - Braund, Peter
AU - Hengstenberg, Christian
AU - Stark, Klaus
AU - Fischer, Marcus
AU - Schreiber, Stefan
AU - El Mokhtari, Nour Eddine
AU - Schaefer, Arne
AU - Schrezenmeir, Jürgen
AU - Schrezenmeier, Jürgen
AU - Rubin, Diana
AU - Hinney, Anke
AU - Reinehr, Thomas
AU - Roth, Christian
AU - Ortlepp, Jan
AU - Hanrath, Peter
AU - Hall, Alistair S
AU - Mangino, Massimo
AU - Lieb, Wolfgang
AU - Lamina, Claudia
AU - Heid, Iris M
AU - Doering, Angela
AU - Gieger, Christian
AU - Peters, Annette
AU - Meitinger, Thomas
AU - Wichmann, H-Erich
AU - König, Inke R
AU - Ziegler, Andreas
AU - Kronenberg, Florian
AU - Samani, Nilesh J
AU - Schunkert, Heribert
PY - 2008/8/20
Y1 - 2008/8/20
N2 - 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 = 1.5x10(-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 = 2.1x10(-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.
AB - 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 = 1.5x10(-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 = 2.1x10(-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.
U2 - 10.1371/journal.pone.0002986
DO - 10.1371/journal.pone.0002986
M3 - Journal articles
C2 - 18714375
SN - 1553-7390
VL - 3
SP - e2986
JO - PLoS ONE
JF - PLoS ONE
IS - 8
ER -
