Intra-Individual Variation of Plasma Adipokine Levels and Utility of Single Measurement of These Biomarkers in Population-Based Studies
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2464 Intra-individual Variation of Plasma Adipokine Levels and Utility of Single Measurement of These Biomarkers in Population-Based Studies Sang-Ah Lee,1 Asha Kallianpur,1 Yong-Bing Xiang,3 Wanqing Wen,1 Qiuyin Cai,1 Dake Liu,3 Sergio Fazio,2 MacRae F. Linton,2 Wei Zheng,1 and Xiao Ou Shu1 1Vanderbilt Epidemiology Center and 2Department of Medicine, Cardiovascular Division, Vanderbilt University Medical Center, Nashville, Tennessee;and 3Department of Epidemiology, Shanghai Cancer Institute, Shanghai, P.R. China Abstract Adipokines, soluble mediators produced by adipo- of a single, random sample with the mean levels from cytes, may link adipose tissue to the inflammatory, the remaining three samples using a bootstrap approach metabolic, and immune dysregulation that characterize and using intra-class correlation coefficients (ICC). many obesity-related diseases. The stability of plasma Spearman correlations between adipokine levels, age, adipokine levels within individuals, their seasonal body mass index (BMI), and waist-to-hip ratio (WHR) variability, intercorrelations, and relationships to well- were estimated. Correlations between plasma adipo- established measures of adiposity are incompletely kine levels from one random sample and the mean of defined. We measured levels of 12 adipokines [inter- the remaining three seasonal samples ranged from 0.57 leukin 1B (IL-1B), IL-6, IL-8, tumor necrosis factor-A to 0.89. Over the 1-year study period, the ICCs for (TNF-A), plasminogen activator inhibitor-1 (PAI-1), adipokine levels ranged from 0.44 (PAI-1) to 0.83 (HGF). high-sensitivity C-reactive protein (hsCRP), monocyte IL-8, MCP-1, and resistin levels were positively associ- chemoattractant protein-1 (MCP-1), nerve growth factor ated with age; HGF and PAI-1 levels were correlated (NGF), leptin, adiponectin, hepatocyte growth factor with BMI and WHR. This study suggests that adipokine (HGF), and resistin] in four seasonal random plasma levels in a single blood sample may be useful bio- samples of 48 male participants of a population-based markers of inflammation in population-based studies cohort study. The representativeness of single measure- of obesity-related disease. (Cancer Epidemiol Biomarkers ments was assessed by correlating the adipokine levels Prev 2007;16(11):2464–70) Introduction Evidence has accumulated from recent studies that obe- cyte chemoattractant protein-1 (MCP-1), resistin, and adi- sity is associated with increased circulating levels of cyto- ponectin (1, 3-7). An increasing number of other can- kines, chemokines, and acute-phase proteins, and with didate adipokines are also being reported, including the activation of pro-inflammatory pathways (1). Adipo- hepatocyte growth factor (HGF), the angiogenic protein kines constitute a growing list of soluble polypeptides vascular endothelial growth factor (VEGF), migration- that are involved in complex signaling between white inhibitory factor (MIF), and the iron-regulatory peptide adipose tissue and systemic inflammatory, metabolic, hepcidin (3, 8). and immunoregulatory pathways (2). Several subgroups Obesity has emerged as an important risk factor for of adipokines are currently recognized: (a) classic cyto- many chronic diseases and cancers. Numerous studies kines and chemokines such as tumor necrosis factor-a have suggested that the low-grade inflammation asso- (TNF-a), interleukin-1h (IL-1h), IL-6, IL-8, IL-10, and ciated with obesity (9, 10) contributes to the pathogenesis tumor growth factor-h (TGF-h);( b) acute-phase proteins of many chronic diseases or conditions, including athe- such as haptoglobin, serum amyloid-A, C-reactive rosclerotic vascular disease, cancer, and components of protein, and plasminogen activator inhibitor-1 (PAI-1); the metabolic syndrome such as insulin resistance and c and ( ) other adipocyte- or macrophage-derived pro- type 2 diabetes mellitus (3-6, 11, 12). teins, including leptin, nerve growth factor (NGF), mono- Although the levels of many pro-inflammatory adipo- kines have been shown to correlate with obesity, the variability of adipokine levels within individuals, their intercorrelations, and the relationships of some adipo- Received 4/25/07;revised 8/7/07;accepted 9/6/07. kines to BMI and waist-to-hip ratio (WHR) have not been Grant support: U.S. Public Health Service grant R01CA82729 from the National fully characterized. If adipokine levels are reliable Cancer Institute. measures of inflammation, the measurement of specific The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance adipokine levels may be useful in epidemiologic studies with 18 U.S.C. Section 1734 solely to indicate this fact. and may significantly improve methods of characterizing Requests for reprints: Xiao Ou Shu, Department of Medicine, Vanderbilt disease risk among overweight and obese individuals. Epidemiology Center, 2525 West End Ave., Suite 600, Nashville, TN 37203-1738. Phone: 615-936-0713;Fax: 615-936-8291. E-mail: [email protected] The purpose of this analysis was therefore to facilitate Copyright D 2007 American Association for Cancer Research. future studies by evaluating the stability of a wide range doi:10.1158/1055-9965.EPI-07-0374 of plasma adipokine levels in a sample of middle-aged Cancer Epidemiol Biomarkers Prev 2007;16(11). November 2007 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2007 American Association for Cancer Research. Cancer Epidemiology,Biomarkers & Prevention 2465 and elderly men over time and to better define their cor- circumferences of the waist and hips, were taken at relations with other adipokines and to accepted meas- baseline recruitment according to a standard protocol by ures of adiposity. trained interviewers who were retired medical profes- sionals. The study was approved by the Institutional Review Boards of all participating institutions, and all Materials and Methods subjects provided written informed consent. Analysis of Adipokine Levels. Blood samples were Subjects. The subjects in this study were a subset of collected from study subjects using BD Vacutainer serum participants in the Shanghai Men’s Health Study tubes at the time of their in-person interview. Samples (SMHS), a population-based cohort study consisting of were transported in portable insulated bags containing 61,582 men that was conducted in Shanghai, China, from ice packs (at 0-4jC) and processed by centrifugation April 2002 to June 2006. The overall participation rate in within 6 h of collection. Plasma was stored at À70jC. the SMHS was 74.1%, non-participation was mainly due All adipokine levels with the exception of high- to refusals (21.1%), absence during the study period sensitivity C-reactive protein (hsCRP) levels were (3.1%), and miscellaneous reasons, including poor health determined by immunoassay using the LINCOplex kit or hearing difficulties (1.7%). All men residing in the (Luminex xMAP Technology) at the Vanderbilt Hormone eight communities of urban Shanghai chosen for the Assay & Analytical Services Core. Human Serum study and who were between the ages of 40 and 74 years Adipokine Panel B (HADK2-61K-B) was used for IL-1h, were eligible for the SMHS. IL-6, IL-8, TNF-a, MCP-1, HGF, leptin, and NGF, and The current study was based on the data of the SMHS Human Serum Adipokine Panel A (HADK1-61K-A) was dietary validation study, which included administration used for adiponectin, resistin, and total PAI-1. The of two food frequency questionnaires (FFQ), 12 monthly sensitivities of these assays were 0.1 pg/mL for IL-1h, 24-hour dietary recalls and collection of four seasonal 1.6 pg/mL for IL-6, 0.2 pg/mL for IL-8, 0.14 pg/mL for blood and urine samples (13). Participants of the TNF-a and MCP-1, 19.2 pg/mL for HGF, 50.9 pg/mL for validation study were randomly selected from the SMHS leptin, 2.5 pg/mL for NGF, 145.5 pg/mL for adiponectin, rosters of study subjects who lived in two of the eight 6.7 pg/mL for resistin, and 1.3 pg/mL for PAI-1. The study communities;the response rate was 69.3%. levels of hsCRP were measured using the ACE High Of 214 subjects recruited by the dietary validation Sensitivity C-Reactive Protein Reagent (ACI-22) on ACE study, 196 subjects (91.6%) completed all associated Clinical Chemistry System (Alfa Wassermann, Inc.) surveys. Of these, 48 were randomly selected from those following the manufacturer’s protocol. The minimum who had provided one blood sample in each season (four detectable concentration of hsCRP by this method is samples in total) throughout the year for the current 0.1 mg/L. Coefficients of variation (CV) for intra-assay study. These 48 individuals will henceforth be referred to variation ranged from 1.4% to 7.9%, and CVs for inter- as the adipokine study sample. Information on major assay variation were <21%. All four seasonal samples obesity-related chronic diseases was obtained by asking from each study participant were measured in the study subjects at the baseline survey whether a physician same batch. had ever diagnosed them as having type 2 diabetes mellitus, cardiovascular disease, and/or stroke. Anthro- Statistical Analysis. Subjects with an undetectable pometric measurements, including weight, height, and level of adipokines were assigned an averaged value Table 1. Comparison of adipokine study participants with the parent cohort and dietary validation study participants on selected baseline characteristics Current study Diet validation