Remnant Cholesterol, Low-Density Lipoprotein Cholesterol, and Blood Pressure as Mediators From Obesity to Ischemic Heart Disease
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Remnant Cholesterol, Low-Density Lipoprotein Cholesterol, and Blood Pressure as Mediators From Obesity to Ischemic Heart Disease. / Varbo, Anette; Benn, Marianne; Smith, George Davey; Timpson, Nicholas J; Tybjaerg-Hansen, Anne; Nordestgaard, Børge G.
In: Circulation Research, Vol. 116, No. 4, 02.2015, p. 665-673.Research output: Contribution to journal › Journal article › Research › peer-review
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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
N1 - © 2014 American Heart Association, Inc.
PY - 2015/2
Y1 - 2015/2
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
VL - 116
SP - 665
EP - 673
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 4
ER -
ID: 156084331