RESEARCH ARTICLE
Plasma Leptin Levels and Risk of Incident Cancer: Results from the Dallas Heart Study Arjun Gupta1, Yehuda Herman2, Colby Ayers3, Muhammad S. Beg4, Susan G. Lakoski5, Shuaib M. Abdullah6, David H. Johnson1, Ian J. Neeland6* 1 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America, 2 Collin College, Preston Road, Frisco, Texas, United States of America, 3 Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America, 4 Division of Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America, 5 Department of Clinical Cancer Prevention & Cardiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America, 6 Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
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[email protected]
Abstract OPEN ACCESS Citation: Gupta A, Herman Y, Ayers C, Beg MS, Lakoski SG, Abdullah SM, et al. (2016) Plasma Leptin Levels and Risk of Incident Cancer: Results from the Dallas Heart Study. PLoS ONE 11(9): e0162845. doi:10.1371/journal.pone.0162845
Purpose Leptin dysregulation has been postulated to affect cancer risk through its effects on obesity and inflammation. Epidemiological data evaluating this relationship are conflicting and studies in non-white cohorts is lacking. Therefore, we examined the association of leptin with the risk of incident cancer in the multiethnic Dallas Heart Study (DHS).
Editor: David Meyre, McMaster University, CANADA Received: July 5, 2016
Methods
Accepted: August 29, 2016
Copyright: © 2016 Gupta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Participants enrolled in the DHS without prevalent cancer and with baseline leptin measurements were included. Incident cancer cases were identified through a systematic linkage of the DHS and the Texas Cancer Registry. Leptin was evaluated both as a continuous variable and in sex-specific quartiles. Multivariable Cox proportional hazards modeling was performed to examine the association between leptin levels with incident cancer after adjusting for age, sex, race, smoking status, alcohol use, family history of malignancy, body mass index (BMI), diabetes mellitus and C-reactive protein.
Data Availability Statement: All relevant data are within the paper and its Supporting Information file.
Results
Funding: This work was supported by grant 1K23DK106520 from the National Institute of Diabetes and Digestive and Kidney Diseases to Dr. Neeland, by grants UL1DE019584 and PL1DK081182 from the National Institutes of Health, and by grant number UL1TR001105 from the National Center for Advancing Translational Sciences. Dr. Neeland is supported as a Dedman Family Scholar in Clinical Care at UT Southwestern Medical Center.
Among 2,919 participants (median age 44 years; 54% women; 70% nonwhite; median BMI 29.4 kg/m2), 190 (6.5%) developed cancer after median follow- up of 12 years. Median leptin levels were 12.9 (interquartile range [IQR] 5.8–29.5) ng/ml in the incident cancer group vs. 12.3 (IQR 5.4–26.4) ng/ml those without an incident cancer (p = 0.34). Leptin was not associated with cancer incidence in multivariable analysis (unit standard deviation increase in log-transformed leptin, hazard ratio 0.95; 95% confidence interval, 0.77–1.16; p = 0.60). No association was observed in analyses stratified by sex, race/ethnicity, diabetes, or obesity status.
Published: September 16, 2016
PLOS ONE | DOI:10.1371/journal.pone.0162845 September 16, 2016
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Competing Interests: The authors have declared that no competing interests exist.
Conclusions In this study of a predominantly minority population, no association between premorbid leptin levels and cancer incidence was demonstrated. Despite preclinical rationale and positive findings in other studies, this association may not replicate across all racial/ethnic populations.
Introduction Leptin, a polypeptide hormone predominantly secreted by white adipose tissue, is a key regulator of body weight homeostasis due to its effects on food intake and energy expenditure. Dysregulation in leptin metabolism has been linked to obesity, hyperinsulinemia and diabetes mellitus [1]. More recently its role in chronic inflammation, immunity, neoangiogenesis and tumorigenesis has been demonstrated [2]. The leptin receptor has been detected in both normal and malignant tissue [3]. Thus, it is hypothesized that leptin dysregulation may contribute to cancer risk. Obesity, as defined by body mass index (BMI) >30 kg/m2 is associated with increased cancer risk, and leptin may be a potential mediator of this association [3]. Studies evaluating the association of leptin and cancer have largely been retrospective and may be biased due to reverse causation due to the effect of cancer-associated weight loss on leptin levels [4]. Existing prospective studies reporting the association between leptin and cancer have lacked external validity due to relative lack of racial diversity in the cohorts. Results of these studies have been conflicting [5–13]. Only a single study conducted in Hong Kong evaluated pre-morbid leptin levels and risk of all-incident cancer and found no difference in leptin levels between individuals who developed cancer versus those who did not [14]. We aimed to prospectively study the relationship between pre-diagnostic plasma leptin levels and the risk of incident cancer among relatively young, multiethnic participants in the Dallas Heart Study (DHS).
Materials and Methods Study Population Details on the design of the DHS have been previously described [15]. Briefly, the DHS is a single site, multiethnic, population based probability sample of Dallas County residents (aged 18– 65 years) with deliberate oversampling of non- Hispanic black participants. The current study population was drawn from 3557 participants who completed DHS phase 1 (DHS-1) visits from 2000 to 2002, which included a computer-assisted survey, anthropometric and blood pressure measurements and laboratory testing. Participants without plasma leptin level assessment were excluded. Of the remaining participants, those with history of or present diagnosis of malignancy were also excluded. To account for cancers that may have been undetected at baseline, new cases of cancer diagnosed within 1 year after date of enrollment to DHS were excluded from the analysis (blanking period). After these exclusions, 2,919 participants were eligible for follow-up (Figure A in S1 File). All participants provided written informed consent, and the University of Texas Southwestern Medical Center Institutional Review Board approved the protocol. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Demographics, lifestyle and other risk factors were determined from a baseline questionnaire. Ethnicity was self-assigned in accordance with U.S. census categories. BMI was calculated as weight (kilograms) divided by the square of height (meters). Waist circumference (WC) and hip circumference (HC) were measured in centimeters and waist hip ratio (WHR) was calculated as ratio of WC/HC. Hypertension was defined as BP 140/90 mm Hg or taking antihypertensive medication(s). Diabetes mellitus was defined as a fasting serum glucose 126 mg/dl, self-reported diabetes, or taking hypoglycemic medication. Smoking was defined as cigarette use within the previous 30 days and/ or a lifetime history of having smoked 100 cigarettes. Alcohol use was determined in grams/week by self-report. Comorbid conditions were determined from self report, medication history and clinical assessment.
Assessment of Leptin and other Biomarkers Fasting blood samples were obtained from participants and collected in EDTA-containing tubes and stored at -80°C. A commercially available radioimmunoassay (Linco Research Inc., St. Charles, Missouri) was used to quantify total leptin levels according to manufacturer’s specification [16]. The lowest level of leptin that can be detected by this assay is 0.5 ng/mL and all values = 35 kg/m2).Cox proportional hazards models were used to examine the unadjusted and multivariable adjusted associations between leptin and incident cancer and are reported as hazard ratios (HR) and 95% confidence intervals (CI). Leptin measures were analyzed both continuously per unit standard deviation (SD) increase in log-transformed variables, and as sexspecific quartiles. The primary outcome was any incident cancer. The secondary outcome was development of obesity-associated cancer. Cox proportional models were constructed such that the unadjusted model (model 1) was univariable in continuous analysis and sex-specific in quartile analysis. Models were sequentially adjusted for race (and sex in the case of continuous analysis) (model 2), age (model 3), family history of cancer; smoking and alcohol use (model 4), BMI (model 5), and diabetes mellitus and CRP levels (model 6). Formal testing for statistical interaction by sex, race (black/non-black), diabetes status, and obesity status was performed. Sensitivity analyses were performed by extending the blanking period to 2 years, including cancers diagnosed within the 1 year blanking period, excluding lung and esophageal cancers (associated with lower BMI), and hematological cancers from the analysis, excluding breast and prostate cancers (associated with screening procedures) from the analysis, and analyzing nonsmokers only. Since the association between leptin and cancer may be mediated via obesity or inflammation, we also analyzed the relation of BMI, waist circumference, waist-hip ratio, CRP levels and interleukin-6 levels with incident cancer. P-values of
