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From the Department of Psychology (M.K., M.E., L.K.-J.), University of Helsinki, Finland; the Department of Social Medicine (D.A.L., G.D.S.), University of Bristol, UK; the Departments of Medicine (J.S.A.V.) and Clinical Physiology (O.T.R.) and the Cardiovascular Research Unit (M.J.), University of Turku, Finland; and the Finnish Institute of Occupational Health (M.K., J.V.), Finland.
Correspondence to Prof. Mika Kivim?ki, Finnish Institute of Occupational Health, Topeliuksenkatu 41 aA, FIN-00250 Helsinki, Finland. E-mail mika.kivimaki@ttl.fi
Abstract
Objective— It has been suggested that confounding by socioeconomic position from across the lifecourse together with adult risk factors explain the association between C-reactive protein (CRP) and coronary heart disease, but the evidence for this is limited to elderly subjects. We examined associations between socioeconomic position in childhood and adulthood, adult CRP, and carotid intima-media thickness (IMT), a presymptomatic predictor of coronary heart disease, in a population of young adults.
Methods and Results— The association of socioeconomic indicators at age 3 to 18 and in adulthood with CRP and IMT at age 24 to 39 were examined in a prospective cohort study of 2290 (1030 men and 1260 women) participants in the Young Finns Study. After adjustment for age and sex, both childhood and adulthood socioeconomic position were inversely associated with CRP (ps0.02). There was also a direct correlation between CRP and IMT (P<0.008). However, both the association between socioeconomic position and CRP and that between CRP and IMT attenuated to the null with adjustment for BMI and waist-to-hip ratio. Controlling for other risk factors had little effect on these associations.
Conclusions— In young adults, the interrelations between socioeconomic position, CRP, and carotid atherosclerosis are accounted for by adiposity.
It has been suggested that confounding by lifecourse socioeconomic position largely explains the association between C-reactive protein (CRP) and coronary heart disease risk, but the evidence is limited to elderly subjects. In this study of 2290 young adults, the association between CRP and carotid atherosclerosis was largely explained by adiposity.
Key Words: inflammation ? atherosclerosis ? socioeconomic ? risk factors ? epidemiology
Introduction
Increasing evidence suggests that the association between C-reactive protein (CRP) and coronary heart disease risk is noncausal.1–4 Studies that report this association also indicate substantial attenuation after adjustment for risk factors.1–5 A similar observation is replicated in studies of carotid intima-media thickness (IMT), a marker of atherosclerosis and a valid presymptomatic predictor of coronary heart disease.6 The association between CRP and IMT largely disappears after adjustment for risk factors, in particular indicators of adiposity.7–9
It has been hypothesized that socioeconomic position (SEP) from across the lifecourse may be a key underlying factor in the association between CRP and coronary heart disease risk.4 Indeed, childhood and adult SEP are independently associated with coronary heart disease, and a recent study in women aged 60 to 79 years found that indicators of SEP in both childhood and adulthood were also associated with CRP levels. In that study the association between CRP and coronary heart disease was attenuated to the null after adjustment for childhood and adult SEP as well as established risk factors.4 To our knowledge no other study has examined the association of both early and later life SEP with CRP, and thus it is not known whether the hypothesis on the role of lifecourse SEP can be supported in more contemporary populations born in times of greater prosperity than individuals born in the 1920s and 1930s. Further, the one previous study4 of this hypothesis was limited by the fact that indicators of childhood socioeconomic position were recalled in adulthood some 5 to 7 decades after childhood and may therefore be inaccurate.10
We therefore prospectively collected data on childhood and adulthood SEP to examine the role of lifecourse SEP in the association between CRP and coronary heart disease risk, as indicated by IMT in a cohort of young adults. Further, we examined whether any association between early life SEP and IMT was mediated via more proximal risk factors,7–9 meaning that any confounding effect by lifecourse SEP on the association between CRP and IMT was fully captured by these more proximal risk factors (Figure).
Hypothetical model of associations between lifecourse socioeconomic position (SEP), risk factors, C-reactive protein (CRP), and intima-media thickness (IMT).
Methods
Participants
The participants were from the population-based Cardiovascular Risk in Young Finns Study (please see http://atvb.ahajournals.org).11–13 The first cross-sectional survey was conducted at age 3 to 18 in 1980, with the participation rate being 83%, ie, 3596 of those invited. Reexaminations included follow-ups in 1983 and 2001. At the latest follow-up, the participants had reached 24 to 39 years of age. The present study focused on those 2290 individuals (1030 men and 1260 women) with information about SEP and data on adult CRP or IMT. These individuals did not differ from the population at baseline in terms of age group and SEP (discrepancy in any category <2%), but women were slightly over-represented (55% in the study cohort versus 51% in the baseline population).
Socioeconomic Position
SEP in childhood or adolescence was assessed in 1980 by parental occupational status (manual; lower-grade non-manual; and higher-grade non-manual) and in 1983 by parental education (comprehensive school; secondary education, not academic; academic). Where SEP differed between parents, data on the parent with the higher occupational status/education were used. The participants’ own adult SEP was measured through occupational status and education in 2001 and categorized as for parental SEP indicators.
Adult Risk Factors
Adult risk factors were assessed in 2001. Information on smoking, physical activity, medications, and diseases was obtained from a questionnaire.12,14 Physical measurements of height, weight, waist circumference, and hip circumference were obtained to calculate body mass index (BMI; weight in kg, height in m) and waist-to-hip ratio. Blood pressure was measured using a random zero sphygmomanometer (Hawksley & Sons Ltd) in a sitting position after at least 5 minutes rest. For determination of risk factors related to lipid/insulin metabolism, all blood samples were taken after an overnight fast and analyzed in duplicate in the same laboratory. Standard enzymatic methods were used for serum HDL-cholesterol and triglycerides and plasma glucose concentrations. LDL-cholesterol concentration was calculated using the Friedewald formula.15 Serum insulin was measured by microparticle enzyme immunoassay kit (Abbott Laboratories, Diagnostic Division), and insulin resistance was estimated according to HOMA-index.16 (For more detailed description, please see http://atvb.ahajournals.org).
Adult C-Reactive Protein and Carotid IMT
We assessed serum high-sensitive CRP in 2001 using an automated analyzer (Olympus AU400) and a highly sensitive turbidimetric immunoassay kit (CRP-UL-assay; Wako Chemicals). Ultrasound studies, carried out in 2001 to 2002, were performed using Sequoia-512 ultrasound mainframes (Acuson) to measure carotid IMT and luminal diameter. The image was focused on the posterior (far) wall of the left carotid artery. A minimum of 4 measurements of the common carotid far wall were taken 10 mm proximal to the carotid bifurcation to derive mean carotid IMT. (For more detailed description, please see http://atvb.ahajournals.org).
Data Analysis
We used regression analysis to study the associations of SEP indicators with CRP and IMT. The distribution of CRP is skewed and thus the regression models were fitted with the logarithm of CRP as the dependent variable. Linear trends in the associations were tested by entering SEP indicators as continuous variables in the models. Each significant age- and sex-adjusted association of socioeconomic indicator with CRP and IMT was further adjusted for risk factors (ie, smoking and physical activity; BMI and waist-to-hip ratio; systolic and diastolic blood pressure; HDL- and LDL-cholesterol and triglycerides; insulin, glucose, and insulin resistance). The association between risk factor and CRP/IMT was examined at each SEP level for those risk factors that considerably attenuated the SEP-CRP/IMT association. Finally, we examined the extent to which adjustment for SEP and risk factors attenuated the association between CRP and IMT with comparisons of multiply adjusted models with the age- and sex-adjusted model. Plausible pathways explicated in the hypothetical model (Figure) are supported, if (1) indicators of SEP are associated with CRP and IMT; (2) these associations are substantially attenuated by adjustment for risk factors which were associated with SEP; (3) there is an association between CRP and IMT; and (4) this association attenuates to the null after adjustment for indicators of SEP and risk factors. Additional analyses involved separate tests of associations between risk factors and IMT at different levels of CRP to determine whether these associations are independent of CRP. All analyses were performed with the use of SAS software, version 8.2 (SAS Institute).
Results
For the details of sample characteristics, please see http://atvb.ahajournals.org. Mean age was 10.7 years at baseline and 31.7 years at follow-up. The mean level of CRP was 1.93 mg/L, clearly below the recommended cut-point for high cardiovascular risk (>3.00 mg/L).17 In line with this, the observed mean levels of cardiovascular risk factors and IMT characterized a low-risk population, which is to be expected in this young age group.
Table 1 shows the age- and sex-adjusted associations of various indicators of SEP with adult CRP concentration and IMT. For all SEP indicators, higher levels were associated with lower concentration of CRP. The associations of parental occupational status and participant’s educational level with CRP reached statistical significance at P level <0.05. There were no sex differences in these trends (ps for sex-interaction >0.44), and the associations remained after additional adjustment for oral contraceptive use (a correlate of CRP among women in this cohort). There was no association between any of the SEP indicators and IMT.
TABLE 1. Age- and Sex-Adjusted Means of CRP and IMT by Socioeconomic Indicators
Table 2 presents the multivariable associations of parental occupational status and participant’s education with CRP. Adjustment for BMI and waist-to-hip ratio attenuated both of these associations to the null, and additional adjustment for other cardiovascular risk factors had little effect beyond that found for BMI and waist-to-hip ratio. The magnitude of the alteration with adjustment for BMI and waist-to-hip ratio was the same for both sexes. Further analyses showed that parental occupational status and participant’s education were both associated with BMI (age- and sex-adjusted betas –0.08 and –0.11, P<0.001, respectively) and waist-to-hip ratio (–0.12 and –0.13, P<0.0001). Moreover, there were strong associations of higher BMI and waist-to-hip ratio with higher CRP levels within each parental occupational status (age- and sex-adjusted betas between 0.35 and 0.46, ps <0.0001) and within each educational stratum among participants (betas between 0.34 and 0.45, ps <0.0004).
TABLE 2. Regression Analyses of CRP* on Parental Occupation and Participant’s Education Adjusted for Various Risk Factors
The association between CRP and IMT is shown in Table 3. In the unadjusted analyses this association was weak and not statistically significant at the 5% level, with adjustment for age and sex a positive association was unmasked. This association remained unchanged (beta=0.05, P=0.04) after excluding participants with infection, as indicated by CRP>10 mg/L (n=70), self-reported infection during the past week (n=109) or diagnosed rheumatoid disease (n=33). Adjustment for BMI and waist-to-hip ratio substantially attenuated this association but additional adjustment for other cardiovascular risk factors including pack-years had little effect beyond that found for BMI and waist-to-hip ratio. Adjustment for indicators of SEP had no effect on the association between CRP and IMT. There was a sex interaction (P=0.007) in the association between CRP and IMT, with stronger effects seen in men. As shown in Table 3, the effects of adjustments were very similar among the men as in the total cohort.
TABLE 3. Regression Analyses of IMT on CRP* Adjusted for Various Risk Factors
Further testing examined whether the associations of BMI and waist-to-hip ratio with IMT were independent of CRP. These associations remained after adjustment for CRP and in separate analyses carried out for subjects in top, intermediate, and bottom thirds of CRP (age- and sex-adjusted betas between 0.11 and 0.19, ps0.01). Corresponding results were not found for CRP, as its effect on IMT was lost after adjustment for BMI and waist-to-hip ratio and when examined within strata of these variables.
Luminal diameter was associated with IMT (beta=0.05, P=0.04), but adjustment for luminal diameter did not attenuate the associations between BMI and IMT (age- and sex-adjusted beta=0.15 prior and 0.14 after the adjustment) or between waist-to-hip ratio and IMT (corresponding betas 0.16 and 0.15; all ps<0.0001). These associations also remained after adjustment for systolic and diastolic blood pressure (betas for BMI and waist-to-hip ratio 0.10 and 0.12, respectively, ps<0.0001).
Discussion
In this study of young adults, a population at low risk of coronary heart disease, we have found that both parental occupation and own education are predictive of early adulthood CRP and that there is an association between adult CRP levels and carotid IMT. All these associations appear to be largely explained by BMI and waist-to-hip ratio. Our findings support the importance of lifecourse socioeconomic circumstances as a predictor of CRP levels in young adults, but the association between CRP and IMT seems to be confounded by markers of adiposity rather than lifecourse SEP in this cohort. Thus, we received only partial support for the hypothetical model derived from the previous publication in the British Women’s Health and Heart Study; a cohort of women aged 60 to 79 years.4
At least 22 prospective studies have reported a positive association between CRP and incident cardiovascular disease.17 In young populations, the noninvasive measurement of carotid IMT has been used as a surrogate marker of cardiovascular health.6 We found a relatively weak age-adjusted association between higher CRP and higher carotid IMT in the total sample. In subgroup analyses, this association was only present for men, with statistical evidence of a sex difference. In line with our findings, previous evidence on the association between CRP and atherosclerosis is less consistent than that related to CRP and coronary heart disease,8,9,18–21 suggesting that CRP levels may act to a greater extent as a marker of plaque rupture and thrombosis than as a correlate of atherosclerosis per se.9
Beyond markers of adiposity, other risk factors (including smoking, physical inactivity, elevated blood pressure, high LDL- and low HDL-cholesterol, high triglycerides, and insulin resistance) had little effect on the association between CRP and IMT. This finding accords with a previous stratified analysis of 321 men and women from the Framingham Heart Study showing a significant correlation between CRP and coronary artery calcification after adjustment for age and Framingham risk score (composite score based on categorical values of age, total cholesterol, HDL-cholesterol, smoking, and diabetes), but a marked attenuation of the correlation after adjustment for BMI.7
Although randomized controlled trials are needed to determine causal associations, observational evidence may be used to evaluate which of any two factors is less likely a causal agent.22 We found that markers of adiposity (BMI and waist-to-hip ratio) remained significantly associated with IMT in a model also including CRP. Moreover, these associations remained in separate analyses carried out for subjects in low, intermediate, and high levels of CRP. Corresponding results were not found for CRP, as its effect on IMT was lost after control for BMI and waist-to-hip ratio, either in multivariable or stratified analyses. This implies that the association between CRP and IMT is more likely to be confounded than those between BMI, waist-to-hip ratio, and IMT.22 With adiposity, there may be an increase in luminal diameter and a compensatory increase in IMT. However, in our cohort this did not explain the associations of BMI and waist-to-hip ratio with IMT, which were not altered by adjustment for luminal diameter.
A previous study among twins shows that the link between adiposity and CRP is robust to other risk factors, including genetic influences,23 and other studies suggest that the relationship may be bidirectional.24 CRP is mainly produced by the liver and to some extent by the adipose tissue and released in response to cytokine production.25 On the one hand, a possible mechanism for the association of BMI and waist-to-hip ratio with CRP is increased interleukin-6 production by adipocytes, stimulating hepatic CRP production.24,26,27 This is in line with a causal pattern from waist-hip ratio and BMI to CRP. On the other hand, chronic inflammation, as indicated by raised CRP levels, is suggested to contribute to adiposity by inducing insulin resistance and endothelial dysfunction.25 This implies a reversed causal pathway from CRP to BMI and waist-hip ratio.
Markers of adiposity are strongly correlated with CRP in our cohort (unpublished data, 2005), and the present analysis showed that BMI and waist-hip ratio were consistently associated with CRP at each level of early and adult SEP. These findings in combination with the substantial reduction of the association between SEP and CRP after adjustment for BMI and waist-hip ratio are consistent with the hypothesis that adiposity acts as a mediator in a causal pathway "adverse SEPhigh adiposityhigh CRP." In contrast, no evidence was found for the reversed causality between adiposity and CRP, as adjustment for the potential underlying mechanism, insulin resistance, had no effect on this association.
The finding that both parental and own SEP contributed to CRP levels accords with previous studies carried out with late middle-aged or elderly people.4,28 Of interest, own education, the most robust predictor of CRP in this study, could be thought of as an early life indicator because most individuals complete their education before their mid-20s. We found no effect of SEP on the association between CRP and carotid IMT, which is in contrast to the Women’s Health and Heart Study where the association between CRP and coronary heart disease was attenuated to the null after adjustment for childhood and adult SEP as well as established risk factors.4 That study was in a cohort of 60- to 79-year-old women, and it is possible that socioeconomic effects become evident only at older age and with greater burden of underlying atherosclerosis. Indeed, both SEP and CRP are linked to type 2 diabetes mellitus, progression of atherosclerotic lesions, plaque disruptions, and coronary heart disease,29–31 all clinical conditions that are rare in young adults but common among elderly people. In addition to age differences, differences between the countries and birth cohorts in how SEP influences individuals’ behaviors, life choices, and disease processes might contribute to the differences in results between this study and the British Women’s Health and Heart Study.
At least 4 potential limitations of our study merit careful consideration. First, we lost 36% of baseline cohort to follow-up. However, generalizability should not be substantially affected because the participants were largely similar to those who were lost. Women were slightly over-represented, but this is an unlikely source of bias because we adjusted analyses for sex, and for associations with sex differences separate models for men and women were calculated. Second, in spite of the 21-year follow-up period, the study population was below 40 when the risk factors were assessed and some participants were still in the process of entering the labor market, a potential reason for more robust associations of CRP with adult educational level than with occupational status. It is possible that the relationships between lifecourse SEP, adiposity, CRP, and IMT may differ from those observed in this study at later life stages when clinical conditions become more common. Third, corresponding to the majority of Finnish population in 1980, the time of study entry, our sample was racially homogenous. Thus, the present results cannot be generalized to other ethnic groups. Fourth, an important intermediate component in the relationships of adiposity with both CRP and IMT may be the adipocytokine adiponectin. Levels of adiponectin are downregulated in adipositas and adiponectin has been reported to exert prominent antiinflammatory and antiatherosclerotic effects.32 Further research on these and other potential pathophysiological pathways, such as chronic infections,33 are needed.
In conclusion, these data on young adults suggest that the association between CRP and carotid atherosclerosis is largely driven by the effects of adiposity. Although lifecourse indicators of SEP are associated with CRP in our cohort of young adults, the association between CRP and carotid atherosclerosis seems not to be explained by lifecourse SEP in this group. In young adults, adiposity seems to be an important linking factor between SEP and CRP and a confounder in the association between CRP and atherosclerosis.
Acknowledgments
The Young Finns has been supported by the Academy of Finland (grant 53392), the Social Insurance Institution of Finland, the Finnish Work Environment Foundation, Turku University Foundation, Juho Vainio Foundation, the Finnish Foundation of Cardiovascular Research, and the Finnish Cultural Foundation, Finland. MK, LK-J and JV are supported by the Academy of Finland (grants 104891, 105195, and 1209514). JSAV and OTR were supported by research grants from Turku University Central Hospital. DAL is funded by a UK Department of Health Career Scientist Award.
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