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Association between C-reactive protein, metabolic cardiovascular risk factors, obesity and oral contraceptive use in young adults

Abstract

OBJECTIVE: This study sought to determine the relationship between levels of the inflammatory marker, C-reactive protein (CRP), cardiovascular risk factors and oral contraceptive use in young adults.

DESIGN: Cross-sectional study of a community cohort.

SUBJECTS: A total of 822 men and women aged 26 y.

MEASUREMENTS: CRP, body mass index (BMI), blood pressure, lipid and lipoprotein levels, smoking status, socioeconomic status, health status, and hormonal contraceptive use in women.

RESULTS: Multiple regression analysis showed that obesity was independently related to CRP with an increase in ratio CRP of 1.03 (95% CI 1.01, 1.05) for men and 1.07 (1.05, 1.09) for women associated with a 1 kg/m2 increase in BMI. In women, combined oral contraceptive use was associated with a ratio change in CRP of 1.52 (1.27, 1.82) compared with nonusers. Other independent determinants of CRP in men and women were apolipoprotein B level, systolic blood pressure and apolipoprotein A1 in men. Univariate analysis showed that the relationship between CRP and BMI, systolic blood pressure and apolipoprotein B was significantly stronger in women than men.

CONCLUSION: These findings suggest that obesity is associated with inflammation independent of other cardiovascular risk factors that may contribute to an increased risk for cardiovascular disease in men and women. Elevated CRP related to combined oral contraceptive use may influence the rate of cardiovascular events in young women.

Introduction

Inflammation appears to mediate all stages of atherosclerosis. C-reactive protein (CRP), a marker of low-grade chronic inflammation,1 is associated with an increased risk of cardiovascular events in apparently healthy men and women2 and has recently been shown to provide additional prognostic information to low-density lipoprotein cholesterol in women.3 Although it has been shown that other cardiovascular risk factors are associated with elevated CRP,4, 5 the inter-relationship between and relative importance of such risk factors remain uncertain.

Obesity, which is an increasing problem in childhood and early adulthood,6 is associated with multiple cardiovascular risk factors and a higher risk of cardiovascular events.7, 8 It has been suggested that low-grade inflammation may contribute to the association of obesity with cardiovascular disease.9 Previous studies in middle-aged and elderly people have shown an association between body mass index (BMI) and CRP level.4, 10 These findings have been confirmed in young adults who generally have a low prevalence of confounding subclinical disease.9

Important insights have been gained into the relationship between obesity and inflammation. Adipose tissue synthesizes tumour necrosis factor-α (TNF-α) and interleukin 6 (Il-6) which are associated with chronic inflammation and elevated CRP levels.11 However, there are also relationships between CRP and smoking, insulin resistance, high-density lipoprotein (HDL) cholesterol, triglycerides, blood pressure and markers of endothelial dysfunction.4, 11 This raises the possibility that the relationship between inflammation and obesity is influenced by confounding factors.

An evolving area of interest concerns the effect of oestrogens/progestogens on indices of inflammation in women.12 Recent studies have shown that hormone replacement therapy in postmenopausal women is associated with elevated CRP13, 14 with a potential adverse cardiovascular risk. Early reports suggested that there may be a link between oral contraceptives and CRP15, 16 and an open label study has suggested increases in CRP in young women treated with third-generation combined oral contraceptives.17 There have been long-standing concerns about the possible cardiovascular risks associated with combined oral contraceptive use18 but limited understanding of possible mechanisms of arterial disease in a predominantly younger age group of women. There is little information regarding the significance of oestrogen/progestogen-mediated increases in CRP in young women.

The aim of this study was to determine the inter-relationship and relative importance of predictors of CRP levels in young men and women. The study assessed the relationship between CRP, obesity, metabolic and other cardiovascular risk factors including hormonal contraceptive use in women, in a cohort of young adults.

Methods

Sample

Participants are members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal investigation of health and behaviour in a birth cohort.19 The study members were born in Dunedin, New Zealand between April 1972 and March 1973. Of these, 1037 children (91% of eligible births; 52% male) participated in the first follow-up assessment at age 3 y, constituting the base sample for the remainder of the study. Cohort families represent the full range of socioeconomic status (SES) in the general population of New Zealand's South Island and are primarily white of European descent. Follow-ups have been carried out at ages 5, 7, 9, 11, 13, 15, 18, 21 y, and most recently at age 26 y when we assessed 980 (96%) of the 1019 study members still alive. The study was approved by the Otago Ethics Committee and participants gave written informed consent. At the age 26 y assessment, venepuncture was performed at the same time each day (between 1615 and 1645 hours). In all, 90% (n=882) consented to venepuncture, with complete results available for 866 participants. Pregnant women, those who had very low BMI (<18.5 kg/m2), and those who refused anthropometry (total n=44) were excluded from the analysis, leaving complete observations for 822 participants.

Chemical analyses

Nonfasting CRP (mg/l), total cholesterol, HDL cholesterol, triglycerides, apolipoprotein A1 and apolipoprotein B were measured in serum. The following assays were performed on a Hitachi 917 analyser: total cholesterol (coefficient of variation (CV) ranged from 2.7 to 2.9%), HDL cholesterol (CV 2.9–3.4%) and triglycerides were measured using a homogenous enzymatic colorimetric assay. CRP (CV 5.6–12.9%), apolipoprotein A1 (CV 3.7–3.8%) and apolipoprotein B (CV 1.4–1.8%) were measured using an immunoturbidimetric assay (Boehringer Mannheim). The lower detection limit for CRP was 1 mg/l.

Anthropometry

Body size measures were obtained in the standing position with head and eyes directed forward and upper limbs hanging by the sides with palms forward. Height was measured in stocking feet to the nearest millimetre. Body weight was recorded using calibrated scales (Tanita, Model No. 1609N) in light clothing to the nearest 0.1 of a kilogram. Height and body weight measurements were taken twice and the mean of two readings was calculated. The values were used to calculate BMI as weight in kilograms divided by height in metres squared. Waist girth was taken as the perimeter at the level of the noticeable waist narrowing located approximately half-way between the costal border and the iliac crest, and was measured using a steel tape calibrated in centimetres with millimetre gradations. Measurements were taken twice and the mean of two readings was calculated.

Blood pressure

Blood pressure assessment was conducted according to standard protocols20 using a Hawksley Random-zero Sphygmomanometer with a constant deflation valve. Cuffs were chosen on the basis of the circumference of an individual's arm. Study members were seated in a quiet room with their right arm resting at heart level. A 5-min rest period preceded the first measurement, followed by two further measures 5 min apart. Systolic blood pressure and diastolic blood pressure were calculated as the mean of the three measurements.

Smoking

Those who had smoked daily for a month or more during the previous year were considered smokers (n=315, 38%).

Number of health problems

At age 26 y, study members reported whether they had any of the following problems during the previous five years: anaemia, arthritis, cancer, diabetes, epilepsy, heart trouble, kidney/ bladder infections and major surgery. The number of health problems was summed. Most (n=460, 56%) study members reported no health problems, 265 (32%) reported one, 82 (10%) reported two and 15 (2%) reported three or more.

Socioeconomic circumstances in adulthood

SES was determined by the occupation of the study members at age 26 y, using the Elley–Irving scale.21 The scale places each occupation into one of six categories (6=unskilled labourer, 1=professional) based on the educational levels and income associated with that occupation in data from the New Zealand census. Those in groups 5 and 6 were classified as having low SES.

Statistical analysis

Because of the skewed nature of its distribution, data for CRP were log transformed for all analyses. To allow transformation of 0 values, 1 was added to CRP values before log transformation. Geometric means, medians and interquartile range (IQR) are reported. Arithmetic means and prevalence are reported for all other measures. Regression analysis, including an interaction term with sex, was used to compare the relationship between CRP and the other variables for men and women. Multiple regression was used to examine the association between CRP, BMI and the other variables of interest. The data for men and women were analysed separately. Statistical significance for all analyses was defined as P<0.05.

Results

The geometric mean for CRP levels was 1.8 (median 2, IQR 1, 3) mg/l in men and 3.3 (median 3, IQR, 1, 7) mg/l in women (P<0.001; Table 1). Men and women had similar BMI. Men had higher waist circumference, blood pressure, triglycerides and lower HDL cholesterol and apolipoprotein A1 than women (all P<0.001). Of the women using oral contraceptives, 152 were taking a combined oral contraceptive (59 second generation and 93 third generation) and 30 a progestogen only contraceptive.

Table 1 Characteristics of the study population

In men, univariate analyses showed a statistically significant relationship between CRP and BMI, waist circumference, triglycerides, apolipoprotein B, and an inverse relationship with HDL cholesterol and apolipoprotein A1 (Table 2). In women, univariate analyses showed that CRP was positively associated with BMI, waist circumference, systolic blood pressure, total cholesterol, triglycerides, apolipoprotein A1, apolipoprotein B and combined oral contraceptive use and inversely associated with HDL cholesterol. The association between CRP and BMI, waist circumference, systolic blood pressure, total cholesterol, triglycerides and apolipoprotein B was significantly stronger in women than in men. The relationship between CRP and apolipoprotein A1 was in the opposite direction in men and women, with higher levels of apolipoprotein A1 being associated with lower CRP levels in men.

Table 2 Univariate analyses in men and women showing change as ratio (95% CI) in CRP related to change in anthropometric measures, blood pressure, metabolic cardiovascular risk factors, smoking, adult SES, health problems and hormonal contraceptive use

Results of the multiple regression presented in Table 3 show that CRP is independently associated with BMI and apolipoprotein B in men, increasing levels of these variables being associated with higher levels of CRP. CRP was also inversely associated with systolic blood pressure and apolipoprotein A1. Adjustments for low SES and health problems were included. The model explained 8.4% of the variance in log(CRP) in men. Multiple regression showed that BMI, combined oral contraceptive use, apolipoprotein B and systolic blood pressure were all independent predictors of CRP in women. The association with apolipoprotein A1 was not significant after adjusting for the other variables. These variables explained 28.2% of the variance in log(CRP) in women. Table 3 includes the standardized regression coefficients showing change in log(CRP), in terms of standard deviations (z-scores), that are associated with a 1 standard deviation increase in the independent variables. For example, in women a 1 standard deviation increase in BMI is associated with a 0.37 standard deviation increase in log(CRP) provided the other variables are held constant. Combined oral contraceptive use was associated with a 0.23 standard deviation increase and apolipoprotein B with a 0.17 standard deviation increase in log(CRP). There was no difference in the ratio change of log(CRP) in women taking second-generation compared to third-generation combined oral contraceptives; so an estimate for the combined group is presented.

Table 3 Multiple regression analysis in men and women with changes as ratio (95% CI) in CRP related to change in BMI adjusting for systolic blood pressure, apolipoproteins A1 and B, SES, health problems and combined oral and progestogen only contraceptive use

A closer examination of the women's data showed that the mean for apolipoprotein A1 in the group of women using progestogen only contraceptive was 0.18 g/l (95% CI 0.08, 0.27) lower than those not using hormonal contraceptives at all, while the mean for apolipoprotein A1 in women using the second-generation contraceptive was 0.10 g/l (0.03, 0.18) higher and the third-generation contraceptive was 0.22 g/l (0.16, 0.28) higher than women not using hormonal contraceptives. The mean for apolipoprotein A1 for the group using the third-generation contraceptive was significantly higher than that for women using the second-generation pill. The association between log(CRP) and apolipoprotein A1 within each contraceptive group was not statistically significant, which suggests that the overall positive association between CRP and apolipoprotein A1 shown in Table 2 was the result of confounding due to combined oral contraceptive use.

Discussion

We have found CRP to be related to obesity in a cohort of men and women in their 20s, and to combined oral contraceptive use in young women. These associations remained after adjustment for socioeconomic class, metabolic and general cardiovascular risk factors, and self-reported health. These findings support the possibility that inflammation may contribute to the increased risk of cardiovascular events in obese persons and users of combined oral contraception from early adulthood.

There has been controversy about whether or not obesity is an independent risk factor for cardiovascular disease. The traditional metabolic risk factors of dyslipidaemia, hypertension and diabetes are all more prevalent in obese people, making it unclear whether obesity independently contributes to the risk of cardiovascular disease. Initial studies suggested that obesity did not predict cardiovascular events after adjustment for blood pressure, smoking and cholesterol.22 However, a few studies have shown a higher rate of cardiovascular events in obese subjects even after adjustment for other cardiovascular risk factors.7, 23 Our finding that CRP level was significantly associated with BMI after controlling for other cardiovascular risk factors suggests inflammation as a potential mechanism by which obesity may independently lead to an increased risk of cardiovascular events.

It is increasingly recognized that the distribution of body fat is an important determinant of cardiovascular risk, and in this respect BMI may not be the best measure of obesity.24 Waist circumference is a marker of visceral adiposity, which is associated with a higher risk for cardiovascular disease than other forms of adiposity.24 We found that waist circumference (P<0.001) was also significantly associated with CRP after appropriate controls for SES, other cardiovascular risk factors including use of the combined oral contraceptive in women, and number of health problems.

Elevated levels of CRP have been shown to be of prognostic significance for cardiovascular disease in apparently healthy subjects, emphasizing the importance of inflammation in the pathogenesis of atherosclerosis.1 Levels of CRP are related to IL-6 and other cytokines such as TNF-α, which mediate inflammation and potentiate atherogenesis.11, 25 These factors can also affect endothelial function, and influence the endothelial expression of chemokines and adhesion molecules.26 Adipose tissue synthesizes both TNF-α and IL-6, and this represents a potential mechanism whereby inflammation may mediate the independent risk of obesity for cardiovascular disease.

In the present study, the associations between CRP and measures of obesity were stronger in women than in men. These findings are consistent with those previously reported.9, 27 Potential explanations for the difference include the different distributions of body fat in men and women. Although women in the present study had a similar mean BMI to men, at similar levels of BMI, women have more body fat.28 There were higher mean CRP levels in overweight and obese women than men. Higher levels of CRP in this and other studies in women may also relate to an influence of hormonal status on markers of inflammation. Oestrogen administration in postmenopausal women is associated with elevated CRP levels,13, 14 but this effect is modulated to different degrees by different progestogens.12 An oestrogen-mediated effect may explain our findings of higher levels of CRP in women using the combined oral contraceptive. There did not appear to be a differential effect of progestogen type as second-generation combined oral contraceptive users had similar ratio change in CRP to third-generation combined oral contraceptive users. Although oral contraceptive use does not appear to cause arterial disease, it may synergize with endothelial dysfunction to promote arterial occlusions resulting in cardiovascular events.29

This study also confirms previous findings that CRP levels are associated with elevated triglyceride concentrations, low concentrations of HDL cholesterol and high concentrations of apolipoprotein B. In this combination of risk factors, plasma concentrations of low-density lipoprotein cholesterol are often normal, but there is an increased proportion of atherogenic small, dense low-density lipoprotein particles.30 The lipid profile of the study members with increased CRP in this study has been shown to be atherogenic.31 In men, higher levels of CRP levels were associated with lower levels of apolipoprotein A1. In women using a combined oral contraceptive, mean apolipoprotein A1 levels were higher than nonusers, implying an effect of combined oral contraceptive use on lipid metabolism. There was, however, no independent relationship between apolipoprotein A1 and CRP in women.

Our findings have important clinical implications. Weight loss and exercise have been shown to decrease CRP26, 32 in obese subjects, emphasizing the significant influence of obesity on CRP levels. Long-term intervention programmes supporting sustained lifestyle changes offer the possibility of decreasing cardiovascular risk in obese subjects. It is unknown whether the increased CRP levels in users of the combined oral contraceptive are associated with a systemic pro-inflammatory condition. Further information is required before CRP can be considered to influence the pathogenesis of thrombosis in combined oral contraceptive users.

There are limitations to this study, which is cross-sectional without longitudinal follow-up of cardiovascular end points. Thus the risk of cardiovascular morbidity is inferred rather than measured. Also the CRP analysis was not performed with a high-sensitivity assay and this potentially could lead to underestimation of differences between study members particularly in men who had lower levels of CRP.

In conclusion, this study suggests an independent relationship between the inflammatory marker CRP and obesity in young men and women, and combined oral contraceptive use in women after adjustment for confounding cardiovascular risk factors. Inflammation may contribute to the increased risk for cardiovascular events observed in obese subjects and users of the combined oral contraceptive.

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Acknowledgements

We thank the Dunedin Study members, Unit research staff, Air New Zealand and the study founder Phil Silva. The Dunedin Multidisciplinary Health and Development Research Unit is supported by the New Zealand Health Research Council. Data collection was supported by grants from the National Heart Foundation of New Zealand and the University of Otago (Otago Research Grant).

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Williams, M., Williams, S., Milne, B. et al. Association between C-reactive protein, metabolic cardiovascular risk factors, obesity and oral contraceptive use in young adults. Int J Obes 28, 998–1003 (2004). https://doi.org/10.1038/sj.ijo.0802713

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Keywords

  • inflammation
  • hormones
  • lipids

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