The ABCG5/8 Cholesterol Transporter and Myocardial Infarction Versus Gallstone Disease

Stefan Stender; Ruth Frikke-Schmidt; Børge G Nordestgaard; Anne Tybjaerg-Hansen

doi:10.1016/j.jacc.2013.12.055

The ABCG5/8 Cholesterol Transporter and Myocardial Infarction Versus Gallstone Disease

Stefan Stender, Ruth Frikke-Schmidt, Børge G Nordestgaard, Anne Tybjaerg-Hansen

Institut for Klinisk Medicin

29 Citationer (Scopus)

Abstract

Objectives The study sought to test the hypothesis that genetic variation in ABCG5/8, the transporter responsible for intestinal and hepatobiliary cholesterol efflux, may simultaneously influence plasma and biliary cholesterol levels, and hence risk of myocardial infarction (MI) and gallstone disease in opposite directions. Background High plasma levels of low-density lipoprotein (LDL) cholesterol are a causal risk factor for MI, whereas high levels of biliary cholesterol promote gallstone formation. Methods A total of 60,239 subjects from Copenhagen were included, including 5,647 with MI and 3,174 with symptomatic gallstone disease. Subjects were genotyped for 6 common, nonsynonymous and functional variants in ABCG5/8, and a combined weighted genotype score was calculated. Results Combined, weighted genotype scores were associated with stepwise decreases in LDL cholesterol of up to 5.9% (0.20 mmol/l) for individuals with a score >8.0 (prevalence = 11%) versus <2.0 (prevalence = 9%; p for trend across 5 groups = 2 × 10E-35). The cumulative incidences of MI and gallstone disease as a function of age and increasing genotype score were decreased and increased (log-rank ps for trend: 6 × 10E-4 and 9 × 10E-45), respectively. The multifactorially adjusted odds ratios were 0.83 (95% confidence interval: 0.73 to 0.94) for MI and 2.85 (95% confidence interval: 2.39 to 3.39) for symptomatic gallstone disease for individuals with a genotype score >8.0 versus <2.0. Conclusions Genetic variation in ABCG5/8, which associates with decreased levels of plasma LDL cholesterol protects against MI, but increases the risk of symptomatic gallstone disease. These results suggest that MI and gallstones, 2 seemingly unrelated diseases, are intrinsically linked via the function of the ABCG5/8 cholesterol transporter.

Originalsprog	Engelsk
Tidsskrift	Journal of the American College of Cardiology
Vol/bind	63
Udgave nummer	20
Sider (fra-til)	2121-2128
Antal sider	8
ISSN	0735-1097
DOI	https://doi.org/10.1016/j.jacc.2013.12.055
Status	Udgivet - 27 maj 2014

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10.1016/j.jacc.2013.12.055

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title = "The ABCG5/8 Cholesterol Transporter and Myocardial Infarction Versus Gallstone Disease",

abstract = "Objectives The study sought to test the hypothesis that genetic variation in ABCG5/8, the transporter responsible for intestinal and hepatobiliary cholesterol efflux, may simultaneously influence plasma and biliary cholesterol levels, and hence risk of myocardial infarction (MI) and gallstone disease in opposite directions. Background High plasma levels of low-density lipoprotein (LDL) cholesterol are a causal risk factor for MI, whereas high levels of biliary cholesterol promote gallstone formation. Methods A total of 60,239 subjects from Copenhagen were included, including 5,647 with MI and 3,174 with symptomatic gallstone disease. Subjects were genotyped for 6 common, nonsynonymous and functional variants in ABCG5/8, and a combined weighted genotype score was calculated. Results Combined, weighted genotype scores were associated with stepwise decreases in LDL cholesterol of up to 5.9% (0.20 mmol/l) for individuals with a score >8.0 (prevalence = 11%) versus <2.0 (prevalence = 9%; p for trend across 5 groups = 2 × 10E-35). The cumulative incidences of MI and gallstone disease as a function of age and increasing genotype score were decreased and increased (log-rank ps for trend: 6 × 10E-4 and 9 × 10E-45), respectively. The multifactorially adjusted odds ratios were 0.83 (95% confidence interval: 0.73 to 0.94) for MI and 2.85 (95% confidence interval: 2.39 to 3.39) for symptomatic gallstone disease for individuals with a genotype score >8.0 versus <2.0. Conclusions Genetic variation in ABCG5/8, which associates with decreased levels of plasma LDL cholesterol protects against MI, but increases the risk of symptomatic gallstone disease. These results suggest that MI and gallstones, 2 seemingly unrelated diseases, are intrinsically linked via the function of the ABCG5/8 cholesterol transporter.",

keywords = "ATP-Binding Cassette Transporters, Aged, Denmark, Female, Gallstones, Genetic Variation, Genotype, Humans, Lipoproteins, Male, Middle Aged, Myocardial Infarction, Prevalence",

author = "Stefan Stender and Ruth Frikke-Schmidt and Nordestgaard, {B{\o}rge G} and Anne Tybjaerg-Hansen",

year = "2014",

month = may,

day = "27",

doi = "10.1016/j.jacc.2013.12.055",

language = "English",

volume = "63",

pages = "2121--2128",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier",

number = "20",

}

TY - JOUR

T1 - The ABCG5/8 Cholesterol Transporter and Myocardial Infarction Versus Gallstone Disease

AU - Stender, Stefan

AU - Frikke-Schmidt, Ruth

AU - Nordestgaard, Børge G

AU - Tybjaerg-Hansen, Anne

PY - 2014/5/27

Y1 - 2014/5/27

N2 - Objectives The study sought to test the hypothesis that genetic variation in ABCG5/8, the transporter responsible for intestinal and hepatobiliary cholesterol efflux, may simultaneously influence plasma and biliary cholesterol levels, and hence risk of myocardial infarction (MI) and gallstone disease in opposite directions. Background High plasma levels of low-density lipoprotein (LDL) cholesterol are a causal risk factor for MI, whereas high levels of biliary cholesterol promote gallstone formation. Methods A total of 60,239 subjects from Copenhagen were included, including 5,647 with MI and 3,174 with symptomatic gallstone disease. Subjects were genotyped for 6 common, nonsynonymous and functional variants in ABCG5/8, and a combined weighted genotype score was calculated. Results Combined, weighted genotype scores were associated with stepwise decreases in LDL cholesterol of up to 5.9% (0.20 mmol/l) for individuals with a score >8.0 (prevalence = 11%) versus <2.0 (prevalence = 9%; p for trend across 5 groups = 2 × 10E-35). The cumulative incidences of MI and gallstone disease as a function of age and increasing genotype score were decreased and increased (log-rank ps for trend: 6 × 10E-4 and 9 × 10E-45), respectively. The multifactorially adjusted odds ratios were 0.83 (95% confidence interval: 0.73 to 0.94) for MI and 2.85 (95% confidence interval: 2.39 to 3.39) for symptomatic gallstone disease for individuals with a genotype score >8.0 versus <2.0. Conclusions Genetic variation in ABCG5/8, which associates with decreased levels of plasma LDL cholesterol protects against MI, but increases the risk of symptomatic gallstone disease. These results suggest that MI and gallstones, 2 seemingly unrelated diseases, are intrinsically linked via the function of the ABCG5/8 cholesterol transporter.

AB - Objectives The study sought to test the hypothesis that genetic variation in ABCG5/8, the transporter responsible for intestinal and hepatobiliary cholesterol efflux, may simultaneously influence plasma and biliary cholesterol levels, and hence risk of myocardial infarction (MI) and gallstone disease in opposite directions. Background High plasma levels of low-density lipoprotein (LDL) cholesterol are a causal risk factor for MI, whereas high levels of biliary cholesterol promote gallstone formation. Methods A total of 60,239 subjects from Copenhagen were included, including 5,647 with MI and 3,174 with symptomatic gallstone disease. Subjects were genotyped for 6 common, nonsynonymous and functional variants in ABCG5/8, and a combined weighted genotype score was calculated. Results Combined, weighted genotype scores were associated with stepwise decreases in LDL cholesterol of up to 5.9% (0.20 mmol/l) for individuals with a score >8.0 (prevalence = 11%) versus <2.0 (prevalence = 9%; p for trend across 5 groups = 2 × 10E-35). The cumulative incidences of MI and gallstone disease as a function of age and increasing genotype score were decreased and increased (log-rank ps for trend: 6 × 10E-4 and 9 × 10E-45), respectively. The multifactorially adjusted odds ratios were 0.83 (95% confidence interval: 0.73 to 0.94) for MI and 2.85 (95% confidence interval: 2.39 to 3.39) for symptomatic gallstone disease for individuals with a genotype score >8.0 versus <2.0. Conclusions Genetic variation in ABCG5/8, which associates with decreased levels of plasma LDL cholesterol protects against MI, but increases the risk of symptomatic gallstone disease. These results suggest that MI and gallstones, 2 seemingly unrelated diseases, are intrinsically linked via the function of the ABCG5/8 cholesterol transporter.

KW - ATP-Binding Cassette Transporters

KW - Aged

KW - Denmark

KW - Female

KW - Gallstones

KW - Genetic Variation

KW - Genotype

KW - Humans

KW - Lipoproteins

KW - Male

KW - Middle Aged

KW - Myocardial Infarction

KW - Prevalence

U2 - 10.1016/j.jacc.2013.12.055

DO - 10.1016/j.jacc.2013.12.055

M3 - Journal article

C2 - 24657701

SN - 0735-1097

VL - 63

SP - 2121

EP - 2128

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 20

ER -

The ABCG5/8 Cholesterol Transporter and Myocardial Infarction Versus Gallstone Disease

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