Published online before print December 11, 2006, doi: 10.1161/01.HYP.0000252664.24294.ff
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(Hypertension. 2007;49:304.)
© 2007 American Heart Association, Inc.
Original Articles |
Comparison of Interleukin-6 and C-Reactive Protein for the Risk of Developing Hypertension in Women
From the Divisions of Preventive Medicine (H.D.S., L.W., J.E.B., P.M.R., J.M.G.), Aging (H.D.S., J.E.B., J.M.G.), and Cardiovascular Medicine (P.M.R., J.M.G.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; and the Department of Epidemiology (H.D.S., J.E.B., P.M.R.), Harvard School of Public Health, Boston, Mass.
Correspondence to Howard D. Sesso, Brigham and Women’s Hospital, 900 Commonwealth Ave East, Boston, MA 02215-1204. E-mail hsesso{at}hsph.harvard.edu
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Abstract |
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Although markers of systemic inflammation may have a role in the development of hypertension, supportive clinical data remain limited. We, therefore, examined interleukin (IL)-6 and C-reactive protein (CRP) in a nested case-control study of 400 women developing hypertension and an equal number of age-matched normotensive control subjects during 10 years of follow-up as part of the Women’s Health Study. All of the women initially had nonhypertensive blood pressure values and no history of diagnosis or treatment. Subjects provided self-reported risk factors, and IL-6 and CRP were measured from baseline bloods. Case subjects reported elevated systolic (
140 mm Hg) or diastolic (90 mm Hg) blood pressure, newly diagnosed hypertension, or initiating antihypertensive treatment during follow-up. In crude-matched models, IL-6 and CRP quartiles were each strongly associated with hypertension risk (both Ps for trend <0.0001). In multivariate models, the linear trends became nonsignificant, and the relative risks (95% CIs) of hypertension for IL-6 reduced to 1.00 (ref), 1.29 (0.76 to 2.19), 2.14 (1.23 to 3.73), and 1.70 (0.92 to 3.13) and for CRP were 1.00 (ref), 2.09 (1.16 to 3.76), 2.51 (1.42 to 4.44), and 2.44 (1.29 to 4.64), primarily because of confounding by body mass index. Simultaneous adjustment for IL-6 and CRP modestly attenuated both sets of relative risks, although more for IL-6. Finally, there was no effect modification by baseline blood pressure or other risk factors (all Ps for interaction >0.05). Therefore, after multivariate adjustment and strong confounding by body mass index, IL-6 was weakly associated and CRP strongly associated with hypertension risk. In models simultaneously examining IL-6 and CRP, only CRP remained strongly associated with an increased risk of hypertension.
Key Words: inflammation • hypertension • women • prevention • epidemiology • follow-up studies
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Introduction |
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Inflammation has been hypothesized to play a role in the development of hypertension.1,2 Cross-sectional evidence demonstrates elevations in plasma inflammatory markers among individuals with elevated blood pressure (BP).2–6 Higher levels of C-reactive protein (CRP), a common, easily measured inflammatory marker for which clinical cut points have been recommended,7 have been prospectively associated with an increased risk of hypertension.8–10 However, the relationship of other inflammatory markers, other than CRP, with the risk of developing hypertension remains largely untested.
IL-6 is a central mediator of the acute-phase response and a primary determinant of hepatic production of CRP. Plasma IL-6 concentrations have been found to be elevated among those who have features of the insulin resistance syndrome,11,12 suggesting that IL-6 may directly or indirectly impact the pathogenesis of atherosclerosis and hypertension. Prospective studies have shown that plasma concentrations of IL-6 are significantly associated with elevations in systolic and diastolic BP.3,11,13 Circulating IL-6 also stimulates the hypothalamic-pituitary-adrenal axis, which, when activated, is associated with the development of hypertension.14
Therefore, plasma IL-6 may have an important role apart from CRP in the pathogenesis of hypertension that has not been prospectively examined. Building on previous findings of a positive association between CRP and the risk of hypertension in the Women’s Health Study (WHS),8 we conducted a nested case-control study to examine and compare the effect of plasma IL-6 and CRP levels and risk of developing hypertension in middle-aged and older women.
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Methods |
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Study Population
The WHS is a completed, randomized, double-blind, placebo-controlled clinical trial of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer,15,16 with the beta-carotene component terminated in 1996.17 In 1992, a total of 39 876 female US health professionals, aged
45 years and free from self-reported cardiovascular disease and cancer (except nonmelanoma skin cancer), were randomly assigned into the WHS. Fasting baseline blood samples were collected from 28 345 women (71%) and stored in liquid nitrogen freezers.
A prospective, nested, case-control design identified 400 hypertension case-control pairs of WHS participants with baseline blood samples. Case subjects were women free of baseline hypertension who developed incident hypertension defined as meeting any of the 4 criteria: (1) self-reports of a physician diagnosis of hypertension at years 1, 3, and all annual questionnaires thereafter; (2) self-reports of antihypertensive treatment at years 1, 3, and 4; (3) self-reports of systolic BP 140 mm Hg; or (4) self-reports of diastolic BP 90 mm Hg. Individuals who developed cardiovascular disease, for which the management may impact BP levels, after baseline but before the development of hypertension were censored at that date of diagnosis and not considered to have developed hypertension. For each case, 1 control subject was randomly chosen among women who provided a baseline blood sample and remained free of hypertension during follow-up. Each case-control pair was matched on age (±1 years) and follow-up time (±3 months). The study protocol was approved by the Brigham and Women’s Hospital Institutional Review Board. Written informed consent was obtained from all of the participants.
Blood Assays
Baseline blood samples were stored in liquid nitrogen until analysis. All of the investigators and laboratory personnel were blinded to the subjects’ case-control status. All of the baseline blood samples were handled identically throughout the processes of blood collection, long-term storage, sample retrieval, and assays. Samples were assayed for IL-6 with the use of ELISA (R&D Systems). In addition to plasma IL-6, assays were also available for high-sensitivity CRP (Denka Seiken) and lipids (Roche Diagnostics), including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol.
Other Baseline Covariates
On the baseline questionnaire, women provided self-reports of age (years), weight and height (represented as body mass index [BMI] in kilograms per meter squared), smoking status (never, former, or current), alcohol use (rarely/never, 1 to 3 drinks per month, 1 to 6 drinks per week, or 1 drink per day), vigorous exercise (rarely/never, <1 time per week, 1 to 3 times per week, or 4 times per week), parental history of myocardial infarction before age of 60 years (no or yes), personal history of diabetes (no or yes), menopausal status (no, yes, or uncertain), and postmenopausal hormone use (never, former, or current). Hypercholesterolemia (no or yes) was defined as having a physician diagnosis, or self-reported cholesterol level 6.22 mmol/L (240 mg/dL) or current treatment for high cholesterol. Baseline systolic BP was reported in 1 of 9 ordinal categories ranging from <110 mm Hg to 180 mm Hg; diastolic BP was reported in 1 of 7 ordinal categories ranging from <65 mm Hg to 105 mm Hg. Self-reported BP in health professionals has been shown to be highly correlated with measured systolic BP (r=0.72) and diastolic BP (r=0.60).18
Data Analyses
Statistical analysis was performed using SAS software (SAS Institute) version 8. All of the P values were 2-sided with a significance level of 
=0.05. Case subjects were first compared with control subjects on the basis of mean values or proportions of major hypertension risk factors and plasma measurements, using paired t tests for means and McNemar’s tests for proportions. Because of the highly skewed distribution, the geometric means were used for IL-6 and CRP.
All of the analyses were conducted in parallel for plasma concentrations of IL-6 and CRP, which were each divided into quartiles based on the distribution in 400 selected control subjects. Hypertension risk factors were then compared according to quartiles of plasma IL-6 or CRP among control subjects to assess potential confounding, using ANOVA for means and 
2 tests for proportions.
Conditional logistic regression was performed to calculate relative risks (RRs) and 95% CIs for incident hypertension according to quartiles of plasma IL-6 or CRP concentrations, with the lowest quartile serving as the reference. Crude models matched for age. Subsequent models further adjusted for lifestyle factors, including smoking, alcohol use, exercise, menopausal status, postmenopausal hormone use, parental history of myocardial infarction, and personal history of diabetes and hypercholesterolemia (multivariate model 1); then, BMI was added (multivariate model 2). We also considered individual adjustment for baseline self-reported BP, plasma concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, and the total:HDL cholesterol ratio, as well as various dietary factors. Multivariate models also simultaneously considered quartiles of IL-6 and CRP. Linear trends across increasing quartiles of plasma measurements were tested using the median value of each quartile as an ordinal variable. Finally, analyses were stratified on baseline BMI, history of hypercholesterolemia, and postmenopausal hormone use using unconditional logistic regression, and the presence of interactions with IL-6 or CRP was tested.
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Results |
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Compared with women who remained free of hypertension, those who developed hypertension had higher baseline BMIs, exercised less, and were more likely to have a personal history of hypercholesterolemia at baseline (Table 1). Case subjects of hypertension were also nonsignificantly less likely to consume alcohol and more likely to have diabetes at baseline. As expected, women who developed hypertension had significantly higher systolic and diastolic BP at baseline. Among plasma lipids, HDL cholesterol was significantly lower in women who developed hypertension during follow-up, whereas neither total nor LDL cholesterol differed significantly. The geometric means of plasma CRP (2.11 versus 1.36 mg/L; P<0.0001) and IL-6 (1.08 versus 0.93 µg/L; P=0.0007) were higher in case subjects than in control subjects.
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We next considered the relationship between plasma IL-6 levels and various baseline characteristics among the 400 control subjects that remained free of hypertension throughout follow-up. Plasma IL-6 levels ranged from 0.26 to 26.4 µg/dL. Age, BMI, frequency of exercise, and being postmenopausal were each significantly higher across increasing quartiles of plasma IL-6 among control subjects (Table 2). Although the differences were not statistically significant, women in higher quartiles of IL-6 also seemed to consume less alcohol and have higher baseline BP levels. Plasma HDL cholesterol significantly decreased with higher IL-6, whereas total and LDL cholesterol were nonsignificantly higher among the higher quartiles of plasma IL-6.
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Among 400 control subjects, IL-6 was correlated with CRP (Spearman r=0.45; P<0.0001), and the geometric means of CRP levels increased markedly (P<0.0001) from 0.71 to 2.70 from the first to fourth quartile of IL-6. Quartile cut points for CRP among 400 normotensive control subjects were <0.55, 0.55 to 1.32, 1.33 to 3.40, and >3.40 mg/L, which corresponded closely with previous cohort-wide results in this cohort.8 An examination of increasing quartiles of plasma CRP levels with various baseline factors revealed a similar strong (P<0.05) positive association with age and BMI as IL-6, but unlike IL-6, CRP was also significantly associated with being postmenopausal and current use of postmenopausal hormones. The proportions of women currently using postmenopausal hormones among 400 control subjects were 26.7%, 37.0%, 47.5%, and 67.0% for increasing quartiles of CRP (P<0.0001). Similar nonsignificant associations were present for higher levels of CRP and lower alcohol consumption and elevated baseline BP. Finally, CRP exhibited a similar association with lipids as IL-6.
We next examined the associations for IL-6 and CRP with the risk of developing hypertension. In crude models matched for age, the RRs and 95% CIs of hypertension across increasing quartiles of plasma IL-6 and CRP were highly significant (both Ps for linear trends <0.0001) and roughly compatible (Table 3). When we further adjusted for lifestyle factors and clinical factors aside from BMI in multivariate model 1, the RRs of hypertension for IL-6 remained similar (P for linear trend=0.01), whereas the RRs of hypertension for CRP strengthened (P for linear trend <0.0001). After adding BMI in multivariate model 2, IL-6 became weakly associated with the risk of hypertension (P for linear trend=0.36), and women in the highest quartile of IL-6 had a nonsignificant RR of hypertension of 1.70. IL-6 now had a weaker association with hypertension than for CRP. Although the linear trend for CRP was marginally significant (P=0.07), a level of CRP at or above the second quartile (0.55 mg/L) remained significantly associated with a >2-fold increase in the risk of developing hypertension. Confounding by BMI was very similar, whether we included BMI as a continuous variable or as a categorical variable reflecting clinically relevant cut points. We further simultaneously modeled quartiles of IL-6 and CRP to examine their independent contributions to the risk of hypertension. In these multivariate models that included BMI, plasma CRP, but not IL-6, remained associated with the risk of developing hypertension.
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In additional analyses, we considered adjustment for randomized treatment assignment; plasma lipids including total cholesterol, LDL cholesterol, HDL cholesterol, or the total: HDL cholesterol ratio; and various dietary factors, all of which had a marginal impact on the RRs in Table 3. Had we adjusted for baseline BP, the RRs of hypertension were further attenuated for increasing quartiles of IL-6 to 1.00, 1.27, 2.05, and 1.21 (P for linear trend=0.79). In contrast, the RRs for CRP remained nearly identical (P for linear trend=0.10). To minimize any impact of the metabolic syndrome or insulin sensitivity on our results, we performed unmatched analyses excluding women who were obese, diabetic, or hypercholesterolemic at baseline. Aside from wider 95% CIs, the RRs of hypertension remained similar for elevations in IL-6 or CRP. Data were also available on self-reported waist and hip circumference, albeit from the 6-year follow-up questionnaire. Adding waist circumference or waist:hip ratio to multivariate model 2 moderately changed the RRs of hypertension for the upper quartiles of IL-6 and CRP.
We also limited analyses to women with a systolic BP <130 mm Hg or diastolic BP <85 mm Hg, excluding initially high prehypertensive BP levels. The RRs of hypertension using multivariate model 2 for IL-6 were attenuated and were each nonsignificant. Increasing CRP quartiles remained associated with an increased risk of hypertension, particularly among women with a baseline systolic BP <130 mm Hg. However, when we examined the joint association for IL-6 and CRP with baseline systolic and diastolic BP using multivariate model 2, we found no significant interactions between IL-6 or CRP with BP (all Ps for interaction >0.05).
Table 4 presents stratified analyses for IL-6 and CRP by baseline BMI (<25 versus 25 kg/m2), postmenopausal hormone use (current versus never or past), and history of hypercholesterolemia (yes versus no), with no significant interactions (all Ps for interaction >0.05) observed, although there were some modest differences in the RRs across strata. All of the stratum-specific crude, age-adjusted models exhibited a strong association between IL-6 or CRP with the risk of developing hypertension, except for IL-6 and hypertension in women with a BMI <25 kg/m2 (P for linear trend=0.70). Transitioning from crude to multivariate-adjusted analyses reduced the magnitude of the RRs.
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Discussion |
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In this prospective, nested case-control study of initially normotensive middle-aged and older women, we found that higher plasma levels of IL-6, an inflammatory cytokine, were initially associated with an increased risk of developing hypertension but became nonsignificant on adjustment for BMI. On the other hand, higher quartiles of plasma CRP levels retained a significant increased risk of hypertension, although of lower magnitude after BMI was added to the multivariate model. When we simultaneously examined IL-6 and CRP, the magnitude of RRs remained strong for CRP while finding that IL-6 does not add substantial predictive power beyond CRP for hypertension risk. Finally, there was no strong evidence of effect modification by baseline BP or other risk factors for hypertension.
Mostly cross-sectional studies have linked inflammatory markers, such as IL-6 or CRP, with BP and hypertension.4,19,20 In the Physicians’ Health Study, IL-6 was positively correlated with both systolic BP (r=0.27) and diastolic BP (r=0.21).13 Earlier cross-sectional analyses of 340 WHS participants reported that both IL-6 and CRP were strongly associated with increasing categories of systolic BP (both Ps for trend <0.001) and diastolic BP (both Ps for trend=0.005),3 a finding confirmed in this nested case-control study. The simultaneous adjustment for other coronary risk factors revealed that both IL-6 and CRP still predicted systolic BP levels. In 6814 participants from the Multi-Ethnic Study of Atherosclerosis, no gender differences were noted, and the association between CRP and hypertension was strongest in Chinese and weakest among Hispanic participants.6 Finally, in British women aged 60 to 79 years, the positive correlations among CRP, systolic BP, and hypertension became nonsignificant after adjustment for risk factors and socioeconomic position.21
Data from prospective studies are limited, with this analysis the first to examine plasma IL-6 and risk of hypertension. Earlier prospective studies have raised important questions regarding the role of adiposity when considering whether inflammation is associated with the risk of developing hypertension. Previously in the WHS, we observed a strong, positive association between increasing levels of CRP and the risk of developing hypertension in initially normotensive women.8 A small cohort study of 379 Finnish middle-aged normotensive men10 confirmed the WHS results, even after adjustment for abdominal obesity, which had been raised as a potentially strong residual confounder of the WHS analyses.22 In contrast, an analysis of younger adults in the Coronary Artery Risk Development in Young Adults Study found an association between CRP and the risk of developing hypertension that disappeared on adjustment for BMI.23 In the present study, BMI strongly confounded the association for IL-6 and CRP with hypertension risk, with the RRs only for CRP quartiles remaining statistically significant. In fact, there is increasing evidence that excess adiposity, already a major risk factor for hypertension, is characterized by a broad inflammatory response11,24,25 that induces adipose tissue to release various cytokines and adipokines proteins26 and to create a chronic state of inflammation that may lead to hypertension.
Other biological pathways linking inflammation with hypertension remain to be elucidated, with various lines of evidence providing partial insights. Increases in inflammatory markers, such as IL-6 and CRP, not only coincide with higher BMI, but also adverse lipids and other risk factors related to atherosclerosis. This process decreases NO in the endothelium27,28 and may indirectly promote vasodysregulation, which is manifested as hypertension.29–31 These structural and functional changes in the endothelium may, therefore, lead to the development of hypertension.32 IL-6 is a central mediator of the acute-phase response and a primary determinant of hepatic production of CRP, plus, IL-6 modulates the production of tumor necrosis factor- and regulates the immune response.33 Circulating IL-6 also stimulates the hypothalamic- pituitary-adrenal axis, which, when activated, is also associated with hypertension.14 Several factors predispose IL-6 production, including infection, interferon-
, and tumor necrosis factor.
There are several explanations why, when considered simultaneously, the association with hypertension remained for CRP but not for IL-6. This observation generally parallels that for coronary heart disease34 and may reflect either differences in stability or susceptibility to confounding by coronary risk factors between these 2 correlated inflammatory markers. CRP has a longer plasma half-life than IL-6, which may enable CRP to represent a more reliable indicator of chronic inflammation.35 Alternatively, the release of IL-6 is more susceptible to diurnal variation, and because the plasma samples were collected at different times during the day, there may have been greater random misclassification of IL-6 that biased our RRs toward the null.36 CRP, but not IL-6, was associated with hormone replacement therapy, which has been supported in rat models showing that estrogens do not impact IL-6 production.37
Our findings remain susceptible to potential limitations. First, we only had baseline assessments of IL-6 and CRP, without knowledge of how these inflammatory markers changed over time. Any significant variation in baseline IL-6 or CRP over time has the potential to bias our reported RRs. Second, residual confounding may persist, despite adjusting for major risk factors for hypertension. Neither dietary factors nor plasma lipids affected our RRs. Other measures of adiposity, such as waist and hip circumference, may explain a portion of our observed associations22 and deserve more comprehensive consideration given the observed magnitude of confounding of our RRs by BMI. Next, we relied on self-reported BP and hypertension status. However, in a brief standardized telephone interview to confirm the presence or absence of a self-reported hypertension diagnosis, we found high sensitivity (96%) and specificity (98%) of self-reported hypertension in the WHS, consistent with other studies indicating quality of self-reported BP38 and hypertension among health professionals.39,40 Finally, the WHS cohort consists of largely white women, so additional studies in men and other ethnic groups can determine whether inflammation plays a role in the development of hypertension.
Perspectives
Extending earlier findings that CRP was associated with an increased risk of hypertension in multivariate models,8 this nested case-control study also found that higher IL-6 levels were initially associated with the risk of developing hypertension, but not after adjustment for BMI. Our observation of strong confounding by BMI underscores our need to better understand how obesity and its associated metabolic processes may impact the association between inflammation and hypertension. With the prevalence of high BP rising in the United States41 and primary prevention guidelines largely limited to behavioral risk factors,42,43 inflammation represents a novel, promising process by which to identify those at higher risk for developing hypertension.
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Acknowledgments |
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We are grateful to the staff of the Women’s Health Study and to the 39 876 dedicated and conscientious female health professionals who are participating in this trial.
Sources of Funding
This work was supported by research grants CA-47988 and HL-43851 from the National Institutes of Health, Scientist Development Grant 0130290N from the American Heart Association, the Donald W. Reynolds Foundation, the Leducq Foundation, and the Doris Duke Charitable Foundation.
Disclosures
P.M.R. has received federal (National Heart, Lung, and Blood Institute), industry (Astra-Zeneca and Sanofi-Aventis), and nonprofit (Doris Duke Charitable Foundation, Donald W. Reynolds Foundation, and Leducq Foundation) sources; received honoraria from Schering-Plough, Sanofi-Aventis, Astra-Zeneca, Isis Pharmaceuticals, and Novartis; and is listed as a coinventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease. All of the coauthors are employed by Brigham and Women’s Hospital, which holds patents that relate to the use of inflammatory biomarkers in cardiovascular disease.
Received August 31, 2006; first decision September 16, 2006; accepted November 6, 2006.
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