Increased HDL-c/Apolipoprotein A-I Ratio and Mortality
Increased HDL-c/Apolipoprotein A-I Ratio and Mortality
Objective High-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (Apo A-I) are key cardiovascular risk factors, but whether the ratio of HDL-C/Apo A-I concentrations affects risk of cardiovascular disease (CVD) and other diseases is uncertain. To investigate whether HDL-C and Apo A-I concentrations and the ratio of HDL-C/Apo A-I affect risk of death from CVD, cancer and all causes.
Design, setting and patients Data were analysed from an occupational cohort of 263 340 people between 2002 and 2009. Cox proportional hazards models were used to estimate HRs (and 95% CIs) for mortality using the sex-specific lowest quartiles of HDL-C, Apo A-I concentrations and HDL-C/Apo A-I ratio as the reference groups.
Main outcome measures 1012 participants died (median follow-up 4.2 years). There were no significant associations between HDL quartiles and all mortality outcomes. In contrast, there was a positive trend for the association across increasing HDL/Apo A-I ratio quartiles and mortality from CVD, cancer and all cause (p values for trends across quartiles=0.016, 0.001 and <0.001, respectively). The adjusted HRs for highest HDL/Apo A-I ratio quartile versus the lowest were 2.37 (95% CI 0.89 to 6.37) (CVD); 2.32 (95% CI 1.34 to 4.03) (cancer) and 1.87 (95% CI 1.32 to 2.66) (all-cause mortality).
Conclusions These data show for the first time that an increased HDL-C/Apo A-I ratio may be a shared risk factor for CVD, cancer and all-cause mortality.
Recent developments have brought the potential protective role of high-density lipoprotein cholesterol (HDL-C) into question. Several clinical trials testing drugs that increase HDL-C concentration have shown that increasing HDL-C concentration does not decrease cardiovascular event rates. The relationship between HDL-C and cardiovascular disease (CVD) are more complex than had previously been thought, and it has been suggested that an inverse relationship between HDL-C concentration and CVD risk may not hold true at high HDL-C levels. HDL-C is carried within lipoprotein particles that are particularly heterogeneous compared, for example, with LDL-C, varying in size, charge, lipid and proteomic composition, metabolism and function. Consequently, alternative indices of HDL besides HDL-C, such as HDL function, size or composition of HDL particles, may be better clinical markers of the role of the HDL particle in vivo.
Increased HDL particle size has been associated with increased risk of coronary artery disease. Other investigators have shown in a multiethnic study that, after adjustment for HDL particle size, HDL-C concentration was not associated with incident vascular disease (carotid intima medial thickness or coronary heart disease) during 6 years of follow-up in contrast to the inverse association observed prior to adjustment. Recently, we have shown in a subset of ~12 000 people from the same Asian cohort used for this study that an increased HDL-C/apolipoprotein A-I (Apo A-I) ratio was associated with preclinical atherosclerosis defined by the presence of coronary artery calcium (identified by high-resolution CT imaging). Furthermore, we showed that controlling for Apo A-I concentrations reversed the inverse direction of the relationship between high HDL-C concentration and this measure of preclinical atherosclerosis.
To date, it is still not clear what the key function of HDL is in vivo, and multiple candidate functions have been proposed. Examples of these key functions have included, among others, HDL-mediated reductions in tissue inflammation, reductions in cellular oxidative stress and increases in reverse cholesterol transport. Given that these functions potentially affect many other disease states beyond CVD, it is important to test whether alterations in HDL-C and Apo A-I concentrations as components of the HDL particle are associated with alterations in risk of diseases and outcomes other than CVD. Thus, we tested the hypothesis that an increased HDL-C/Apo A-I ratio was associated with increased mortality from CVD, and from other diseases in the general population. Specifically, in a large Korean occupational cohort of a quarter of a million people, we tested associations between HDL-C/Apo A-I ratios and CVD, cancer and all-cause mortality. We also investigated associations between HDL-C concentrations and each mortality outcome and between Apo A-I concentrations and mortality outcomes.
Abstract and Introduction
Abstract
Objective High-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (Apo A-I) are key cardiovascular risk factors, but whether the ratio of HDL-C/Apo A-I concentrations affects risk of cardiovascular disease (CVD) and other diseases is uncertain. To investigate whether HDL-C and Apo A-I concentrations and the ratio of HDL-C/Apo A-I affect risk of death from CVD, cancer and all causes.
Design, setting and patients Data were analysed from an occupational cohort of 263 340 people between 2002 and 2009. Cox proportional hazards models were used to estimate HRs (and 95% CIs) for mortality using the sex-specific lowest quartiles of HDL-C, Apo A-I concentrations and HDL-C/Apo A-I ratio as the reference groups.
Main outcome measures 1012 participants died (median follow-up 4.2 years). There were no significant associations between HDL quartiles and all mortality outcomes. In contrast, there was a positive trend for the association across increasing HDL/Apo A-I ratio quartiles and mortality from CVD, cancer and all cause (p values for trends across quartiles=0.016, 0.001 and <0.001, respectively). The adjusted HRs for highest HDL/Apo A-I ratio quartile versus the lowest were 2.37 (95% CI 0.89 to 6.37) (CVD); 2.32 (95% CI 1.34 to 4.03) (cancer) and 1.87 (95% CI 1.32 to 2.66) (all-cause mortality).
Conclusions These data show for the first time that an increased HDL-C/Apo A-I ratio may be a shared risk factor for CVD, cancer and all-cause mortality.
Introduction
Recent developments have brought the potential protective role of high-density lipoprotein cholesterol (HDL-C) into question. Several clinical trials testing drugs that increase HDL-C concentration have shown that increasing HDL-C concentration does not decrease cardiovascular event rates. The relationship between HDL-C and cardiovascular disease (CVD) are more complex than had previously been thought, and it has been suggested that an inverse relationship between HDL-C concentration and CVD risk may not hold true at high HDL-C levels. HDL-C is carried within lipoprotein particles that are particularly heterogeneous compared, for example, with LDL-C, varying in size, charge, lipid and proteomic composition, metabolism and function. Consequently, alternative indices of HDL besides HDL-C, such as HDL function, size or composition of HDL particles, may be better clinical markers of the role of the HDL particle in vivo.
Increased HDL particle size has been associated with increased risk of coronary artery disease. Other investigators have shown in a multiethnic study that, after adjustment for HDL particle size, HDL-C concentration was not associated with incident vascular disease (carotid intima medial thickness or coronary heart disease) during 6 years of follow-up in contrast to the inverse association observed prior to adjustment. Recently, we have shown in a subset of ~12 000 people from the same Asian cohort used for this study that an increased HDL-C/apolipoprotein A-I (Apo A-I) ratio was associated with preclinical atherosclerosis defined by the presence of coronary artery calcium (identified by high-resolution CT imaging). Furthermore, we showed that controlling for Apo A-I concentrations reversed the inverse direction of the relationship between high HDL-C concentration and this measure of preclinical atherosclerosis.
To date, it is still not clear what the key function of HDL is in vivo, and multiple candidate functions have been proposed. Examples of these key functions have included, among others, HDL-mediated reductions in tissue inflammation, reductions in cellular oxidative stress and increases in reverse cholesterol transport. Given that these functions potentially affect many other disease states beyond CVD, it is important to test whether alterations in HDL-C and Apo A-I concentrations as components of the HDL particle are associated with alterations in risk of diseases and outcomes other than CVD. Thus, we tested the hypothesis that an increased HDL-C/Apo A-I ratio was associated with increased mortality from CVD, and from other diseases in the general population. Specifically, in a large Korean occupational cohort of a quarter of a million people, we tested associations between HDL-C/Apo A-I ratios and CVD, cancer and all-cause mortality. We also investigated associations between HDL-C concentrations and each mortality outcome and between Apo A-I concentrations and mortality outcomes.
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