Remnant Cholesterol, Low-Density Lipoprotein Cholesterol, and Blood Pressure as Mediators From Obesity to Ischemic Heart Disease

Anette Varbo; Marianne Benn; George Davey Smith; Nicholas J Timpson; Anne Tybjaerg-Hansen; Børge G Nordestgaard

doi:10.1161/circresaha.116.304846

Remnant Cholesterol, Low-Density Lipoprotein Cholesterol, and Blood Pressure as Mediators From Obesity to Ischemic Heart Disease

Anette Varbo, Marianne Benn, George Davey Smith, Nicholas J Timpson, Anne Tybjaerg-Hansen, Børge G Nordestgaard

Institut for Klinisk Medicin

70 Citationer (Scopus)

Abstract

RATIONALE: Obesity leads to increased ischemic heart disease (IHD) risk, but the risk is thought to be mediated through intermediate variables and may not be caused by increased weight per se.

OBJECTIVE: To test the hypothesis that the increased IHD risk because of obesity is mediated through lipoproteins, blood pressure, glucose, and C-reactive protein.

METHODS AND RESULTS: Approximately 90 000 participants from Copenhagen were included in a Mendelian randomization design with mediation analyses. Associations were examined using conventional measurements of body mass index and intermediate variables and using genetic variants associated with these. During ≤22 years of follow-up 13 945 participants developed IHD. The increased IHD risk caused by obesity was partly mediated through elevated levels of nonfasting remnant cholesterol and low-density lipoprotein cholesterol, through elevated blood pressure, and possibly also through elevated nonfasting glucose levels; however, reduced high-density lipoprotein cholesterol and elevated C-reactive protein levels were not mediators in genetic analyses. The 3 intermediate variables that explained the highest excess risk of IHD from genetically determined obesity were low-density lipoprotein cholesterol with 8%, systolic blood pressure with 7%, and remnant cholesterol with 7% excess risk of IHD. Corresponding observational excess risks using conventional body mass index were 21%, 11%, and 20%, respectively.

CONCLUSIONS: The increased IHD risk because of obesity was partly mediated through elevated levels of nonfasting remnant and low-density lipoprotein cholesterol and through elevated blood pressure. Our results suggest that there may be benefit to gain by reducing levels of these risk factors in obese individuals not able to achieve sustained weight loss.

Originalsprog	Engelsk
Tidsskrift	Circulation Research
Vol/bind	116
Udgave nummer	4
Sider (fra-til)	665-673
Antal sider	9
ISSN	0009-7330
DOI	https://doi.org/10.1161/circresaha.116.304846
Status	Udgivet - 13 feb. 2015

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10.1161/circresaha.116.304846

CIRCRESAHA.116.304846Forlagets udgivne version, 661 KB

https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.116.304846

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title = "Remnant Cholesterol, Low-Density Lipoprotein Cholesterol, and Blood Pressure as Mediators From Obesity to Ischemic Heart Disease",

abstract = "RATIONALE: Obesity leads to increased ischemic heart disease (IHD) risk, but the risk is thought to be mediated through intermediate variables and may not be caused by increased weight per se.OBJECTIVE: To test the hypothesis that the increased IHD risk because of obesity is mediated through lipoproteins, blood pressure, glucose, and C-reactive protein.METHODS AND RESULTS: Approximately 90 000 participants from Copenhagen were included in a Mendelian randomization design with mediation analyses. Associations were examined using conventional measurements of body mass index and intermediate variables and using genetic variants associated with these. During ≤22 years of follow-up 13 945 participants developed IHD. The increased IHD risk caused by obesity was partly mediated through elevated levels of nonfasting remnant cholesterol and low-density lipoprotein cholesterol, through elevated blood pressure, and possibly also through elevated nonfasting glucose levels; however, reduced high-density lipoprotein cholesterol and elevated C-reactive protein levels were not mediators in genetic analyses. The 3 intermediate variables that explained the highest excess risk of IHD from genetically determined obesity were low-density lipoprotein cholesterol with 8%, systolic blood pressure with 7%, and remnant cholesterol with 7% excess risk of IHD. Corresponding observational excess risks using conventional body mass index were 21%, 11%, and 20%, respectively.CONCLUSIONS: The increased IHD risk because of obesity was partly mediated through elevated levels of nonfasting remnant and low-density lipoprotein cholesterol and through elevated blood pressure. Our results suggest that there may be benefit to gain by reducing levels of these risk factors in obese individuals not able to achieve sustained weight loss.",

keywords = "Adult, Aged, Biomarkers, Blood Pressure, Body Mass Index, Cholesterol, Cholesterol, LDL, Denmark, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Myocardial Ischemia, Obesity, Phenotype, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, Time Factors",

author = "Anette Varbo and Marianne Benn and Smith, {George Davey} and Timpson, {Nicholas J} and Anne Tybjaerg-Hansen and Nordestgaard, {B{\o}rge G}",

note = "{\textcopyright} 2014 American Heart Association, Inc.",

year = "2015",

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doi = "10.1161/circresaha.116.304846",

language = "English",

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pages = "665--673",

journal = "Circulation Research",

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TY - JOUR

T1 - Remnant Cholesterol, Low-Density Lipoprotein Cholesterol, and Blood Pressure as Mediators From Obesity to Ischemic Heart Disease

AU - Varbo, Anette

AU - Benn, Marianne

AU - Smith, George Davey

AU - Timpson, Nicholas J

AU - Tybjaerg-Hansen, Anne

AU - Nordestgaard, Børge G

PY - 2015/2/13

Y1 - 2015/2/13

N2 - RATIONALE: Obesity leads to increased ischemic heart disease (IHD) risk, but the risk is thought to be mediated through intermediate variables and may not be caused by increased weight per se.OBJECTIVE: To test the hypothesis that the increased IHD risk because of obesity is mediated through lipoproteins, blood pressure, glucose, and C-reactive protein.METHODS AND RESULTS: Approximately 90 000 participants from Copenhagen were included in a Mendelian randomization design with mediation analyses. Associations were examined using conventional measurements of body mass index and intermediate variables and using genetic variants associated with these. During ≤22 years of follow-up 13 945 participants developed IHD. The increased IHD risk caused by obesity was partly mediated through elevated levels of nonfasting remnant cholesterol and low-density lipoprotein cholesterol, through elevated blood pressure, and possibly also through elevated nonfasting glucose levels; however, reduced high-density lipoprotein cholesterol and elevated C-reactive protein levels were not mediators in genetic analyses. The 3 intermediate variables that explained the highest excess risk of IHD from genetically determined obesity were low-density lipoprotein cholesterol with 8%, systolic blood pressure with 7%, and remnant cholesterol with 7% excess risk of IHD. Corresponding observational excess risks using conventional body mass index were 21%, 11%, and 20%, respectively.CONCLUSIONS: The increased IHD risk because of obesity was partly mediated through elevated levels of nonfasting remnant and low-density lipoprotein cholesterol and through elevated blood pressure. Our results suggest that there may be benefit to gain by reducing levels of these risk factors in obese individuals not able to achieve sustained weight loss.

AB - RATIONALE: Obesity leads to increased ischemic heart disease (IHD) risk, but the risk is thought to be mediated through intermediate variables and may not be caused by increased weight per se.OBJECTIVE: To test the hypothesis that the increased IHD risk because of obesity is mediated through lipoproteins, blood pressure, glucose, and C-reactive protein.METHODS AND RESULTS: Approximately 90 000 participants from Copenhagen were included in a Mendelian randomization design with mediation analyses. Associations were examined using conventional measurements of body mass index and intermediate variables and using genetic variants associated with these. During ≤22 years of follow-up 13 945 participants developed IHD. The increased IHD risk caused by obesity was partly mediated through elevated levels of nonfasting remnant cholesterol and low-density lipoprotein cholesterol, through elevated blood pressure, and possibly also through elevated nonfasting glucose levels; however, reduced high-density lipoprotein cholesterol and elevated C-reactive protein levels were not mediators in genetic analyses. The 3 intermediate variables that explained the highest excess risk of IHD from genetically determined obesity were low-density lipoprotein cholesterol with 8%, systolic blood pressure with 7%, and remnant cholesterol with 7% excess risk of IHD. Corresponding observational excess risks using conventional body mass index were 21%, 11%, and 20%, respectively.CONCLUSIONS: The increased IHD risk because of obesity was partly mediated through elevated levels of nonfasting remnant and low-density lipoprotein cholesterol and through elevated blood pressure. Our results suggest that there may be benefit to gain by reducing levels of these risk factors in obese individuals not able to achieve sustained weight loss.

KW - Adult

KW - Aged

KW - Biomarkers

KW - Blood Pressure

KW - Body Mass Index

KW - Cholesterol

KW - Cholesterol, LDL

KW - Denmark

KW - Female

KW - Gene Frequency

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Humans

KW - Male

KW - Middle Aged

KW - Myocardial Ischemia

KW - Obesity

KW - Phenotype

KW - Prognosis

KW - Prospective Studies

KW - Risk Assessment

KW - Risk Factors

KW - Time Factors

U2 - 10.1161/circresaha.116.304846

DO - 10.1161/circresaha.116.304846

M3 - Journal article

C2 - 25411050

SN - 0009-7330

VL - 116

SP - 665

EP - 673

JO - Circulation Research

JF - Circulation Research

IS - 4

ER -

Remnant Cholesterol, Low-Density Lipoprotein Cholesterol, and Blood Pressure as Mediators From Obesity to Ischemic Heart Disease

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