A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol.
OBJECTIVE
A rare mutation in low-density lipoprotein receptor-related protein 6 gene (LRP6) was identified as the primary molecular defect underlying monogenic form of coronary artery disease. We hypothesized that common variants in LRP6 could predispose subjects to elevated LDL-cholesterol (LDL-C).


RESULTS
Twelve common (minor allele frequency > or =0.1) single nucleotide polymorphisms in LRP6 were genotyped in 703 individuals from 213 Polish pedigrees (Silesian Cardiovascular Study families). The family-based analysis revealed that the minor allele of rs10845493 clustered with elevated LDL-C in offspring more frequently than expected by chance (P=0.0053). The quantitative analysis restricted to subjects free of lipid-lowering treatment confirmed the association between rs10845493 and age-, sex-, and BMI-adjusted circulating levels of LDL-C in families as well as 2 additional populations - 218 unrelated subjects from Silesian Cardiovascular Study replication panel and 1138 individuals from Young Men Cardiovascular Association cohort (P=0.0268, P=0.0476, and P=0.0472, respectively). In the inverse variance weighted meta-analysis of the 3 populations each extra minor allele copy of rs10845493 was associated with 0.14 mmol/L increase in age-, sex-, and BMI-adjusted LDL-C (SE=0.05, P=0.0038).


CONCLUSIONS
Common polymorphism in the gene underlying monogenic form of coronary artery disease impacts on risk of LDL-C elevation.
Tomaszewski
Maciej
M
Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, LE3 9QP, UK. mt142@le.ac.uk
Charchar
Fadi J
FJ
Barnes
Timothy
T
Gawron-Kiszka
Magdalena
M
Sedkowska
Agnieszka
A
Podolecka
Ewa
E
Kowalczyk
Jacek
J
Rathbone
Wendy
W
Kalarus
Zbigniew
Z
Grzeszczak
Wladyslaw
W
Goodall
Alison H
AH
Samani
Nilesh J
NJ
Zukowska-Szczechowska
Ewa
E
D000328:Adult; D008078:Cholesterol, LDL / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics*; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000097:blood / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D011044:Poland; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000097:blood; D015854:Up-Regulation; D055815:Young Adult
D008078:Cholesterol, LDL; D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D012333:RNA, Messenger