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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0103
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 12 4753-4758
Copyright © 2007 by The Endocrine Society

Relationship between Leptin and C-Reactive Protein in Young Finnish Adults

Liisa A. Viikari, Risto K. Huupponen, Jorma S. A. Viikari, Jukka Marniemi, Carita Eklund, Mikko Hurme, Terho Lehtimäki, Mika Kivimäki and Olli T. Raitakari

Centre of Applied and Preventive Cardiovascular Medicine (L.A.V.) and Departments of Medicine (J.S.A.V.), Clinical Physiology (O.T.R.), and Pharmacology, Drug Development, and Therapeutics (R.K.H.), University of Turku, 20521 Turku, Finland; Department of Health and Functional Capacity (J.M.), National Public Health Institute, 20720 Turku, Finland; Department of Clinical Pharmacology, TYKSLAB (R.K.H.), Health Care District of Southwest Finland; Departments of Clinical Chemistry (T.L.) and University of Tampere Medical School (T.L., C.E., M.H.), 33014 Tampere, Finland; and Department of Epidemiology and Public Health (M.K.), University College London, London WC1E 6BT, United Kingdom

Address all correspondence and requests for reprints to: Olli Raitakari, Department of Clinical Physiology, P.O. Box 52, 20521 Turku, Finland. E-mail: olli.raitakari{at}utu.fi.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Leptin and C-reactive protein (CRP) concentrations are increased in inflammation, and both have been linked to increased risk for cardiovascular diseases.

Objective: The objective of the study was to explore in a population-based sample whether the relation between leptin and CRP is independent of obesity level and whether genetic causes of CRP elevation contribute to leptin levels.

Design: This was a population-based study including 1862 young adults (971 women; 891 men) aged 24–39 yr.

Setting: The study was conducted at five centers in Finland.

Main Outcome Measures: Associations between leptin and CRP adjusted for obesity indices, risk factors, genetic variables, and lifestyle variables were measured.

Results: Women had 3.0-fold higher median concentrations of leptin (12.5 vs. 4.1 ng/ml) and 1.3-fold higher median concentrations of CRP (0.75 vs. 0.56 mg/liter) than men (P < 0.0001 in both comparisons). In univariate analyses, CRP and leptin were significantly intercorrelated (r = 0.47, P < 0.0001 for women; r = 0.46, P < 0.0001 for men). In multiple regression analysis including age, body mass index, waist circumference, insulin, lipids, systolic and diastolic blood pressures, smoking status, and use of oral contraceptives in women, leptin was the main determinant of CRP in men (P < 0.0001) and the second most important determinant in women (P < 0.0001). A Mendelian randomization test based on genetic variants in the CRP gene (five single nucleotide polymorphisms) provided no support for CRP as a causal agent for leptin.

Conclusions: Leptin, obesity, and oral contraceptive use in women were the main factors related to CRP. The relation between leptin and CRP was independent of obesity and cardiovascular risk factors.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
LEPTIN WAS FIRST identified in 1994 as a hormone secreted by adipocytes (1). It participates in the regulation of appetite and energy expenditure (2), acts as a potential modulator of the hypothalamo-pituitary-adrenal axis (3), and has connections with the immune system. It has physiological importance, especially in energy-deficient states (4). Leptin induces production of several cytokines (5). At present, leptin is considered a hormone with pleiotropic actions (6). It belongs to the adipose tissue-derived adipokines connected with insulin resistance syndrome. In men (7) and patients with type 2 diabetes (8), plasma leptin levels are associated with occurrence of cardiovascular diseases.

Production of several inflammatory cytokines, such as TNF-{alpha} and ILs, and acute-phase proteins is increased in obesity, and the condition is now regarded as a chronic inflammatory state (9). C-reactive protein (CRP) is an acute phase reactant synthesized in the liver in response to cytokines (10). Inflammation may significantly contribute to the development of cardiovascular diseases, and elevated CRP level, reflecting systemic inflammation (11), is an indicator of cardiovascular risk (12).

Both leptin and CRP associate with indices of obesity and cardiovascular disease. Significant correlation between leptin and CRP has been previously reported in 179 young healthy males (13), 100 middle-aged men and women (14), and 950 elderly men and women (15). We examined the relations between leptin and CRP in a population of 1862 men and women and applied multivariate analysis to control for several variables having potential confounding effects on the correlation. To exclude the possibility of reversed causality between leptin and CRP, we applied the Mendelian randomization technique to assess whether functional genetic variants in the CRP gene regulating CRP concentrations are related to leptin levels (a null association suggests that no reversed causality exists) (16).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study population consisted of participants of the ongoing Cardiovascular Risk in Young Finns Study, a multicenter study on atherosclerosis precursors in Finnish children, adolescents, and young adults. The first cross-sectional survey was conducted in 1980 in all five university cities with medical schools in Finland (Helsinki, Kuopio, Oulu, Tampere, and Turku) and their rural vicinities. The subjects were randomly selected from the study areas. Six cohorts with ages of 3, 6, 9, 12, 15, and 18 yr at time of inclusion into the study were formed. Follow-up studies of the cohorts have been carried out in 1983, 1986, and 2001. Details of the original study design have been presented elsewhere (17, 18, 19). The results reported here are based on the follow-up visit in 2001 when the subjects (2283 participated) were 24–39 yr old. Finally, complete appropriate data were available on 1862 subjects (971 women and 891 men), which were included in this study. Genetic analyses were based on a sample of 1706 subjects (889 women and 817 men) with full data on five genetic variants of the CRP gene. The study was approved by local ethics committees, and the subjects gave written informed consent to participate.

Clinical characteristics

During the visit, height and weight as well as waist and hip circumferences were measured and body mass index (BMI; weight/squared height) calculated. Systolic and diastolic blood pressures were measured with a random zero sphygmomanometer in sitting position after a 5-min rest. The subjects filled in a questionnaire on smoking habits. The subjects were classified as nonsmokers if they had never smoked; otherwise they were classified as smokers in the analyses. Use of oral contraceptives was inquired from female participants. Blood samples for the determination of fasting plasma CRP as well as serum insulin, leptin, total cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglyceride concentrations were collected. The blood samples were drawn mainly between 0700 and 1100 h, and 1% of the samples were drawn between 1100 and 1300 h. Low-density lipoprotein (LDL)-cholesterol concentration was calculated using the Friedewald formula (20).

The fasting plasma CRP concentrations were analyzed by a high-sensitive latex turbidometric immunoassay (Wako Chemicals GmbH, Neuss, Germany). The detection limit of the assay was 0.06 mg/liter, and the coefficient of variation of repeated measurements was 3.3%. Serum leptin concentration was analyzed with a RIA (human leptin RIA kit; Linco Research, Inc., MO). In different analytical runs, the coefficient of variation of repeated measurements was between 7 and 9%. Details of the physical examination and other biochemical analyses have been presented elsewhere (19).

We excluded subjects with chronic rheumatic disease (n = 34), history of recent infection (n = 113), diabetes (n = 13), pregnant women (n = 61), and lactating women (n = 53) from the main analysis. In addition, subjects with triglycerides above 4 mmol/liter (n = 28) were excluded because the Friedewald formula could not be applied. Remaining subjects with CRP above the limit of normal (10 mg/liter, n = 55) were excluded because the elevation of CRP above 10 mg/liter was considered more likely to be due to an acute cause or an undiagnosed disease, instead of low chronic inflammation. However, by including the subjects with CRP above 10 mg/liter, the results remained essentially similar. The leptin and CRP levels in each excluded group were compared with values of the subjects included in the final analyses. Seventy-seven subjects were excluded due to missing values of parameters included in the multiple regression analysis (see Statistical methods).

CRP genotyping

We genotyped five single nucleotide polymorphisms (SNPs) in the CRP gene [CRP-717A>G (rs 2794521); CRP-286C>T>A (rs3091244); CRP+1059G>C (rs1800947); CRP+1444T>C (rs1130864); and CRP+ 1846G>A (rs1205)] using the ABI Prism 7900HT sequence detection system for both PCR and allelic discrimination (Applied Biosystems, Foster City, CA). For SNP CRP+1059G>C, a commercial kit from Applied Biosystems was used (Assay On Demand, C_177490_10 CRP). The other SNPs were genotyped using Assays By Design from Applied Biosystems under standard conditions, with the exception of the triallelic tagSNP (21), which was genotyped as described previously, except for the genotype calling, which was done manually from the PCR-run component tab.

Statistical methods

Data are presented as mean ± SD if not stated otherwise. Comparisons between the groups were performed using t test or {chi}2 test as appropriate. Due to deviation from normal distribution, nonparametric Wilcoxon rank-sum test was used for comparisons of leptin, CRP, insulin, and triglyceride concentrations between the sexes as well as between the special groups excluded and those included in the final analyses. Differences between the sexes were further analyzed with ANCOVA adjusting for BMI and waist-to-hip ratio. Univariate correlations among CRP, leptin, and the other parameters were evaluated both with Spearman’s rank order and Pearson correlation coefficients; due to skewed distributions, logarithmic transformations from leptin, CRP, insulin, and triglycerides were used in the latter analyses. Both methods gave practically identical results, and only the Pearson correlation coefficients are reported here.

Multiple regression analyses were performed thereafter to test which variables contributed significantly to the variation of CRP in plasma. As in the univariate model, serum leptin, CRP, insulin, and triglycerides were logarithmically transformed before the analysis. In addition, age, BMI, waist circumference, LDL-cholesterol, HDL-cholesterol, systolic blood pressure, diastolic blood pressure, and smoking status were included in the model.

Many of the variables included in the model are intercorrelated, which may weaken the model. Therefore, stepwise multiple regression analyses were performed to further analyze the most significant variables contributing to the variation of CRP. First, all variables were entered into the model simultaneously. In each following step, the variable having the least significant P value was excluded from the model. Finally, all variables with P ≤ 0.15 remained in the model. Standardized β-estimate was used to determine which variable had the strongest effect on CRP.

Univariate and multiple regression analyses were performed separately for men and women. P < 0.05 was considered statistically significant. All calculations were performed with SAS System 8.2 (SAS Institute Inc., Cary, NC).

We used instrumental variable methods to test reversed causality between CRP and leptin (22). According to this approach, functional genetic variants in the CRP gene (e.g. haplotypes) represent a good instrument for CRP levels that is largely free from confounding and reverse causation bias. If there is a reverse causality between CRP and leptin (CRP -> leptin), then the instrument should be related to leptin to the extent predicted by the magnitude of its association with circulating CRP levels. In the present analysis, the two-stage age- and sex-adjusted least squares to fit the instrumental variables models included an examination of F statistics from the first-stage regressions to evaluate the strength of the instrument (values greater than 10 are taken to indicate sufficient strength to ensure the validity of instrumental variable methods) and a comparison of the instrumental variable estimates with those from ordinary linear regression using the Durbin form of the Durbin-Wu-Hausman statistic (main analyses). In agreement with previous studies, we used a model that assumes each of a participant’s two haplotypes contributes additively to his/her value of CRP, excluded subjects with rare haplotypes (prevalence < 1%) (n = 51), and expressed associations per doubling the CRP level. Genetic analyses were performed with instrumental variable regression analysis installed to Stata (version 8.0; Stata Corp., College Station, TX).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The characteristics are shown in Table 1Go. Serum leptin was 3.0-fold and plasma CRP 1.3-fold higher in women than men (P < 0.0001 in both comparisons). Men and women were of similar age, but women had lower BMI, waist circumference, waist to hip ratio, and systolic and diastolic blood pressures, compared with men (P < 0.0001 in all comparisons). In addition, women had a more favorable lipid profile than men (P < 0.0001), and the proportion of smokers was lower among women when compared with men (P < 0.0001) (Table 1Go). Only 9% (n = 89) of women and 13% (n = 114) of men were obese (BMI > 30 kg/m2).


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  		TABLE 1. Characteristics of the study subjects [mean ± SD or median (interquartile range)]

 
Twenty-seven percent (n = 262) of the women used oral contraceptives. The nonuser group (n = 709) included 103 women with levonorgestrel-releasing intrauterine device. Median concentrations of CRP in plasma were significantly higher in women on oral contraceptives when compared with nonusers [1.64 (0.12–9.75) vs. 0.55 (0.05–9.90) mg/liter, respectively, P < 0.0001]. Contraceptive use did not affect serum leptin concentrations [12.85 (2.1–52.4) vs. 12.5 (1.5–63.3), respectively] (Table 2Go).


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  		TABLE 2. Characteristics of women by use of oral contraceptives [mean ± SD or median (interquartile range)].

 
In the univariate correlation analysis, CRP correlated with both leptin (r = 0.47, P < 0.0001 for women; r = 0.46, P < 0.0001 for men) and BMI (r = 0.41, P < 0.0001 for women; r = 0.44, P < 0.0001 for men). As expected, there was a strong intercorrelation between BMI and leptin (r = 0.72, P < 0.0001 for both women and men). Partial correlation coefficients for leptin and CRP adjusted for age and BMI were r = 0.25, P < 0.0001 for women and r = 0.23, P < 0.0001 for men.

The mean CRP levels stratified by tertiles of leptin and BMI are shown in Fig. 1Go. In both men and women, there was an increasing trend in CRP with increasing concentrations of leptin, except in men with low BMI.


Figure 1
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  		FIG. 1. Mean concentrations of CRP, arranged by tertiles of leptin and BMI, in 24- to 39-yr-old Finnish women and men. N varies from 12 to 234 in subgroups.

 
In the multiple regression analysis performed separately for men and women, leptin was independently associated with CRP after adjustments for age, BMI, waist circumference, insulin, triglycerides, LDL-cholesterol, HDL-cholesterol, systolic and diastolic blood pressure, smoking status, and oral contraceptive use in women. In the stepwise multiple regression analysis, leptin was the main correlate of CRP in men and the second most important correlate of CRP in women (P < 0.0001 for both men and women) (Table 3Go). When the analysis was repeated separately for women using or not using oral contraceptives, leptin was the main determinant of CRP before BMI and triglycerides.


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  		TABLE 3. Variables explaining ln(CRP) in multivariate models

 
In men, there was an unexpected relation between high CRP and low insulin. When we used the enter method in multivariate analysis, the relation between CRP and insulin was positive as expected when insulin, BMI, and various other variables were included in the model. The relation turned negative when leptin was entered into the model, which suggests that this finding was due to the strong correlation between leptin and insulin (r = 0.61, P < 0.0001).

To assure that the association between leptin and CRP was not secondary to obesity per se, we repeated the multivariate analysis in normal weight individuals with BMI from 18.5 to 25 kg/m2 (n = 435 women not using oral contraceptives, n = 185 women using oral contraceptives, n = 431 men). Leptin remained the main determinant of CRP in all groups. In addition, leptin was the main determinant of CRP in analyses using pack-years or number of cigarettes smoked per day in 2001 instead of smoking status. Also, when BMI, waist circumference, and waist to hip ratio were entered separately into multivariate models explaining CRP, leptin remained the main determinant in men and the second most important determinant in women. When subjects excluded from the final analysis due to different conditions were included, leptin was the main determinant of CRP in men and the second most important determinant of CRP after oral contraceptive use in women (P < 0.0001).

In both women and men, leptin levels were higher in the groups excluded from the final analysis except in lactating women. Accordingly, CRP levels were higher in the excluded groups except in diabetic women (data not shown).

In the genetic analysis (n = 1655), F statistics suggested sufficient strength for the haplotype instrument [F(df=4, 1648) = 12.05, P < 0.0001]. There was a statistically significant difference in the magnitude of age- and sex-adjusted association between CRP and leptin obtained from the ordinary least-squares regression analysis and the instrumental variables analysis (P = 0.001), the coefficient per doubling of CRP level being 0.19 + 0.01 (P < 0.0001) in the first analysis and 0.02 + 0.06 (P = 0.76) in the latter. The observed null association between the haplotype instrument for CRP levels and leptin suggests that CRP is not a causal agent for leptin.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our results in a large representative adult population show that serum leptin is independently associated with plasma CRP. Increasing concentrations of leptin predict the elevation of CRP both in men and women confirming the findings reported in smaller populations (13, 14, 15).

Whether the association between leptin and CRP represents a true cause-and-effect relationship or just reflects parallel changes due to a common underlying cause, such as obesity, has remained unsolved. However, there is compelling evidence suggesting that leptin might indeed regulate plasma CRP concentrations. Receptors for leptin and cytokines are structurally related, and cytokines regulate the synthesis of CRP (9). The long form of the leptin receptor resembles the glycoprotein 130 family of cytokine receptors, including the IL-6 receptor. The binding of leptin to the long form of the leptin receptor leads to intracellular activation of various signaling pathways, similar to processes seen after cytokine administration (23). Leptin can also directly induce the production of some cytokines, including IL-6 (5), which could facilitate CRP synthesis in the liver. In support of this hypothesis, the genetic variants of the leptin receptor have been observed to associate with plasma IL-6 levels (24). Cytokine TNF-{alpha} may also play a role because circulating levels of TNF-{alpha} have been shown to increase after administration of recombinant leptin to leptin-sensitive subjects (25). It is also possible that leptin directly influences the synthesis of CRP in liver. Chen et al. (26) recently demonstrated that physiological concentrations of leptin can dose-dependently stimulate expression of CRP in human primary hepatocytes. There is also evidence that administration recombinant leptin may increase in CRP levels in the absence of a generalized inflammatory response (27). An alternative explanation is that obesity per se up-regulates the production of both leptin and a cytokine regulating synthesis of CRP without a causal relationship between leptin and CRP. IL-6 and TNF-{alpha}, cytokines increasing the production of CRP, are also synthesized by adipocytes (28). Therefore, any association between leptin and CRP does not need to be a causal one but merely coincidental. Our results do not support this because the association remained independent after adjustments for BMI and waist circumference and was also seen in a subgroup analysis including the normal weight individuals only.

We were able to assess the possibility that elevation in CRP may directly influence leptin levels. Hormone replacement therapy in postmenopausal women increases CRP levels (29). In addition, a direct association between CRP and oral contraceptive use has been recently reported (30, 31, 32). In the young Finns cohort, oral contraceptive use is an independent predictor of the elevation of plasma CRP in women. However, this estrogen-mediated elevation in CRP is not reflected in leptin levels because its concentrations did not differ between users and nonusers of oral contraceptives.

Testosterone is inversely associated with leptin, and administration of testosterone decreases leptin (33). However, in the young Finns cohort, we have not measured the testosterone levels and therefore cannot analyze the relation between testosterone and either leptin or CRP in this study.

The possibility that CRP is the causal determinant of leptin was not supported by the results of the haplotypic Mendelian randomization analyses. The inherence of haplotypes in the CRP gene is not affected by those environmental factors that potentially confound the association between circulating CRP and leptin, and the haplotypes are also likely to be associated with life-long differences in average CRP levels. Therefore, use of CRP haplotypes is assumed to represent a good instrument for CRP levels that is largely free from confounding. We found that CRP haplotypes were not related to leptin to the extent predicted by the magnitude of their association with average CRP levels, suggesting that CRP is an unlikely causal agent for leptin.

High leptin levels have been reported to associate with coronary heart disease in men (7) and with type 2 diabetes in men and women (34). However, Brennan et al. (35) were unable to associate leptin with cardiovascular disease in type 2 diabetic women. Iribarren et al. (36), on the other hand, found an association between leptin and coronary artery calcification in women but not men. In our study, we found no sex-related difference in association between leptin and CRP. It is possible that leptin could affect atherosclerosis through other mechanisms than CRP.

Limitations of our study include its cross-sectional nature. Although we were able to explore the effects of CRP gene variants on its concentrations, we lacked the data to perform similar analysis for leptin, thus preventing investigation of leptin as a causal agent for CRP. However, Zhang et al. (24) recently showed that genetic variability at the leptin receptor locus was significantly related to plasma levels of CRP in a population of 630 healthy Caucasian subjects.

In conclusion, our findings suggest that leptin could be a mediator between obesity and low inflammatory state, explaining partially the mechanism of long-term clinical manifestations in patients with metabolic syndrome. Moreover, the effect of leptin may not be restricted to obesity, but it might regulate development of chronic low-grade inflammation at all levels of body weight.


   Footnotes
 
This work was supported by the Academy of Finland (Grants 117941, 77841, and 210283), the Social Insurance Institution of Finland, the Turku University Foundation, special federal grants for the Turku University Central Hospital, Tampere University Hospital Medical Fund, the Juho Vainio Foundation, the Finnish Foundation of Cardiovascular Research, the Finnish Cultural Foundation, and the Emil Aaltonen Foundation (to T.L.).

Disclosure Statement: The authors have nothing to disclose.

First Published Online September 18, 2007

Abbreviations: BMI, Body mass index; CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SNP, single nucleotide polymorphism.

Received January 16, 2007.

Accepted September 11, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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M. Bochud, F. Marquant, P.-M. Marques-Vidal, P. Vollenweider, J. S. Beckmann, V. Mooser, F. Paccaud, and V. Rousson
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