Plasma total and high molecular weight adiponectin levels and risk of coronary heart disease in women
Introduction
Adiponectin is an adipose tissue-derived collagen-like protein that beneficially affects many pathways that may be relevant for the development of atherosclerosis, including glucose and lipid metabolism, inflammation, endothelial function, as well as thrombogenesis, and it may therefore potentially protect from coronary heart disease (CHD) [1]. However, results from prospective studies in humans provide inconsistent results, with only some showing significant inverse associations between adiponectin and risk of CHD [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. The basis for these inconsistent results are likely due to over adjustment for other biological markers, including glucose, high density lipoprotein cholesterol (HDL-C) and C-reactive protein (CRP), thought to be in the causal pathway between adiponectin and CHD. Further, most prior studies have been conducted among predominantly male populations, and thus, limited information exists for women. In a previous analysis from the Health Professionals Follow-up Study we found a statistically significant inverse association between plasma adiponectin levels and risk of myocardial infarction (MI) among men [2]. In that analysis, adjustment for history of diabetes or plasma levels of hemoglobin A1c (HbA1c) or CRP had little impact, whereas adjustment for HDL-C modestly attenuated the relationship, although it remained statistically significant.
The effects of adiponectin may depend on its quaternary structure in plasma. It was suggested that high molecular weight (HMW) adiponectin may be a better measure of metabolically active adiponectin and therefore more closely related to insulin sensitivity and risk of type 2 diabetes [12], [13]. However, in the only report published thus far on HMW adiponectin and risk of incident CHD (including 167 cases and 333 controls over a follow-up period of 4 years), the association was not statistically significant [14].
The aim of the present study was therefore to examine the association of total and HMW adiponectin, and HMW/total adiponectin ratio with risk of incident CHD in the Nurses’ Health Study (NHS), a well-described cohort study of women. Because animal studies suggest that adiponectin affects several downstream metabolic pathways that may be relevant for cardiovascular risk, we were particularly interested to examine to what extent adjustment for these potentially intermediary variables related to glucose (HbA1c, history of diabetes) and lipid metabolism (HDL-C) and inflammation (CRP) would explain the inverse association between adiponectin and CHD in a human population.
Section snippets
Study population
The NHS is a prospective cohort investigation involving 121,700 female U.S. registered nurses who were 30–55 years old at baseline in 1976. Information about anthropometry, health and disease is assessed biennially, and information about diet is obtained every four years using self-administered questionnaires [15]. The questionnaires and the validity and reproducibility of measurements have been described previously [16]. From 1989 to 1990, a blood sample was requested from all participants in
Results
Cases had a significantly higher BMI and were more likely to have a history of hypertension or diabetes and to use cholesterol lowering drugs (Table 1). Alcohol consumption was significantly lower among cases. Cases had significantly lower plasma levels of total and HMW adiponectin, and a lower HMW/total adiponectin ratio. TC, LDL-C, TG, CRP, and HbA1c levels were significantly higher and HDL-C levels significantly lower among cases than among controls.
Plasma levels of total and HMW adiponectin
Discussion
In this prospective nested case–control study, higher total or HMW adiponectin levels, or higher HMW/total adiponectin ratios were associated with a lower risk of CHD over a follow-up period of 14 years among women without CVD at baseline. These associations appeared to be largely explained by potential intermediary variables, including parameters related to glucose and lipid metabolism and inflammation, especially HDL-C levels.
Experimental in vitro and animal studies have shown that
Acknowledgements
This study was supported by research grants HL34594 and AA11181 from the National Institutes of Health. Additional support was provided by Merck Research Laboratories (MRL) but MRL had no access to the data and the academic institutions had full and final right to publish. Dr. Girman is an employee of Merck & Co., Inc., which manufactures or is developing pharmaceutical products for the treatment of cardiovascular disease and diabetes.
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