A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol

Maciej Tomaszewski; Fadi J Charchar; Timothy Barnes; Magdalena Gawron-Kiszka; Agnieszka Sedkowska; Ewa Podolecka; Jacek Kowalczyk; Wendy Rathbone; Zbigniew Kalarus; Wladyslaw Grzeszczak; Alison H Goodall; Nilesh J Samani; Ewa Zukowska-Szczechowska

doi:10.1161/ATVBAHA.109.185355

A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol

Maciej Tomaszewski, Fadi J Charchar, Timothy Barnes, Magdalena Gawron-Kiszka, Agnieszka Sedkowska, Ewa Podolecka, Jacek Kowalczyk, Wendy Rathbone, Zbigniew Kalarus, Wladyslaw Grzeszczak, Alison H Goodall, Nilesh J Samani, Ewa Zukowska-Szczechowska

Division of Cardiovascular Sciences (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

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).

METHODS AND 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.

Original language	English
Pages (from-to)	1316-21
Number of pages	6
Journal	Arteriosclerosis, Thrombosis, and Vascular Biology
Volume	29
Issue number	9
DOIs	https://doi.org/10.1161/ATVBAHA.109.185355
Publication status	Published - Sept 2009

Keywords

Adult
Cholesterol, LDL/blood
Coronary Artery Disease/blood
Dyslipidemias/blood
Female
Gene Frequency
Genetic Predisposition to Disease
Humans
LDL-Receptor Related Proteins/blood
Lipid Metabolism/genetics
Low Density Lipoprotein Receptor-Related Protein-6
Male
Middle Aged
Monocytes/metabolism
Pedigree
Phenotype
Poland
Polymorphism, Single Nucleotide
RNA, Messenger/blood
Up-Regulation
Young Adult

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1161/ATVBAHA.109.185355

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Tomaszewski, M., Charchar, F. J., Barnes, T., Gawron-Kiszka, M., Sedkowska, A., Podolecka, E., Kowalczyk, J., Rathbone, W., Kalarus, Z., Grzeszczak, W., Goodall, A. H., Samani, N. J., & Zukowska-Szczechowska, E. (2009). A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol. Arteriosclerosis, Thrombosis, and Vascular Biology, 29(9), 1316-21. https://doi.org/10.1161/ATVBAHA.109.185355

@article{b1771ebc237c4bc08bcb63cde2adaacf,

title = "A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol",

abstract = "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).METHODS AND 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.",

keywords = "Adult, Cholesterol, LDL/blood, Coronary Artery Disease/blood, Dyslipidemias/blood, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, LDL-Receptor Related Proteins/blood, Lipid Metabolism/genetics, Low Density Lipoprotein Receptor-Related Protein-6, Male, Middle Aged, Monocytes/metabolism, Pedigree, Phenotype, Poland, Polymorphism, Single Nucleotide, RNA, Messenger/blood, Up-Regulation, Young Adult",

author = "Maciej Tomaszewski and Charchar, {Fadi J} and Timothy Barnes and Magdalena Gawron-Kiszka and Agnieszka Sedkowska and Ewa Podolecka and Jacek Kowalczyk and Wendy Rathbone and Zbigniew Kalarus and Wladyslaw Grzeszczak and Goodall, {Alison H} and Samani, {Nilesh J} and Ewa Zukowska-Szczechowska",

year = "2009",

month = sep,

doi = "10.1161/ATVBAHA.109.185355",

language = "English",

volume = "29",

pages = "1316--21",

journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",

issn = "1079-5642",

publisher = "Lippincott Williams & Wilkins",

number = "9",

}

Tomaszewski, M, Charchar, FJ, Barnes, T, Gawron-Kiszka, M, Sedkowska, A, Podolecka, E, Kowalczyk, J, Rathbone, W, Kalarus, Z, Grzeszczak, W, Goodall, AH, Samani, NJ & Zukowska-Szczechowska, E 2009, 'A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 9, pp. 1316-21. https://doi.org/10.1161/ATVBAHA.109.185355

TY - JOUR

T1 - A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol

AU - Tomaszewski, Maciej

AU - Charchar, Fadi J

AU - Barnes, Timothy

AU - Gawron-Kiszka, Magdalena

AU - Sedkowska, Agnieszka

AU - Podolecka, Ewa

AU - Kowalczyk, Jacek

AU - Rathbone, Wendy

AU - Kalarus, Zbigniew

AU - Grzeszczak, Wladyslaw

AU - Goodall, Alison H

AU - Samani, Nilesh J

AU - Zukowska-Szczechowska, Ewa

PY - 2009/9

Y1 - 2009/9

N2 - 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).METHODS AND 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.

AB - 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).METHODS AND 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.

KW - Adult

KW - Cholesterol, LDL/blood

KW - Coronary Artery Disease/blood

KW - Dyslipidemias/blood

KW - Female

KW - Gene Frequency

KW - Genetic Predisposition to Disease

KW - Humans

KW - LDL-Receptor Related Proteins/blood

KW - Lipid Metabolism/genetics

KW - Low Density Lipoprotein Receptor-Related Protein-6

KW - Male

KW - Middle Aged

KW - Monocytes/metabolism

KW - Pedigree

KW - Phenotype

KW - Poland

KW - Polymorphism, Single Nucleotide

KW - RNA, Messenger/blood

KW - Up-Regulation

KW - Young Adult

U2 - 10.1161/ATVBAHA.109.185355

DO - 10.1161/ATVBAHA.109.185355

M3 - Article

C2 - 19667113

SN - 1079-5642

VL - 29

SP - 1316

EP - 1321

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 9

ER -

A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol

Abstract

Keywords

UN SDGs

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