Abstract
Objective: to study the association between soluble tumour necrosis factor receptor 1 (sTNFR1) levels and mortality in the population-based Northern Manhattan Study (NOMAS).
Methods: NOMAS is a multi-ethnic, community-based cohort study with mean 8.4 years of follow-up. sTNFR1 was measured using ELISA. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (HR, 95% CI) for the association of sTNFR1 with risk of all-cause mortality after adjusting for relevant confounders.
Results: sTNFR1 measurements were available in 1,862 participants (mean age 69.2 ± 10.2 years) with 512 all-cause deaths. Median sTNFR1 was 2.28 ng/ml. Those with sTNFR1 levels in the highest quartile (Q4), compared with those with sTNFR1 in the lowest quartile (Q1), were at an increased risk of all-cause mortality (adjusted HR: 1.8, 95% CI: 1.4–2.4) and non-vascular mortality (adjusted HR: 2.5, 95% CI: 1.5–3.6), but not vascular mortality (adjusted HR: 1.3, 95% CI: 0.9–1.9). There were interactions between sTNFR1 quartiles and medical insurance-status [likelihood ratio test (LRT) with 3 degrees of freedom, Pinteraction = 0.02] and alcohol consumption (LRT with 3 degrees of freedom, Pinteraction < 0.01) for all-cause mortality. In participants with no insurance or Medicaid, those with sTNFR1 in the top quartile had nearly a threefold increased risk of total mortality than the lowest quartile (adjusted HR: 2.9, 95% CI: 1.9–4.4).
Conclusion: in this multi-ethnic cohort, sTNFR1 was associated with all-cause and non-vascular mortality, particularly among those of a lower socioeconomic status.
Keywords: inflammation, insurance status, mortality risk, alcohol use, older people
Introduction
Tumour necrosis factor (TNF) is a major pleiotropic regulator of immunity. Endogenous soluble TNF-receptor-1 (sTNFR1) increases in response to TNF-mediated inflammation; however, its exact role remains unclear [1–3]. In healthy individuals, sTNFR1 exists in concentrations orders of magnitude greater than circulating sTNF levels, and these concentrations are even higher in individuals with inflammatory disorders [4, 5]. The ubiquitous expression of TNFR1 in many tissue types and its increased serum levels in response to TNF-induced inflammation make it an ideal predictor of mortality across several disease categories [6–8]. Several TNF-mediated disorders have been targeted by exogenous recombinant sTNFR therapies, with possible implications for risk modification [9]. We previously reported on the association between sTNFR1 and vascular risk factors and atherosclerosis [10, 11]. In this analysis, for both vascular and non-vascular endpoints, we present sTNFR1 findings on mortality. We sought to determine whether sTNFR1 levels are associated with the risk of all-cause mortality in the multi-ethnic urban Northern Manhattan Study (NOMAS) cohort, after adjusting for demographic and traditional risk factors.
Methods
Study population and study sample
As previously reported, NOMAS is a population-based, prospective cohort study (n = 3,298) [10–12]. Participants were identified using random digit dialling and selected using the following eligibility criteria: (i) no prior diagnosis of stroke, (ii) >39 years old and (iii) resided in Northern Manhattan for >3 months. Recruitment began in 1993 and ended in 2003. The race-ethnic distribution of this cohort consists of 63% Hispanic, 20% non-Hispanic black and 15% non-Hispanic white residents. This study received approval from the Institutional Review Board at Columbia University Medical Center and all participants provided informed consent. An analytic subsample was selected based on the availability of blood samples for sTNFR1 assays (n = 1,862).
Mortality outcomes
Annual telephone follow-up was conducted for all participants. All deaths were prospectively evaluated and classified into either vascular or non-vascular causes. Cause of death was established by (i) medical-records/death-certificates (MRDC); (ii) family-members/nursing home staff (FMNHS) interviews or (iii) other sources. Deaths arising from stroke, myocardial infarction, congestive heart failure, pulmonary embolism, arrhythmia/sudden death, aortic aneurysm, aortic or mitral stenosis, and left ventricular hypertrophy were considered vascular death endpoints. Deaths ruled not of vascular origin were deemed non-vascular, and deaths without sufficient records were deemed unknown aetiology. The primary outcome was all-cause mortality. The two secondary outcome measures were vascular and non-vascular mortality.
sTNFR1 serum levels
Serum sTNFR1 levels were determined in baseline blood samples using an enzyme-linked immunosorbent assay (Biosource International, Camarillo, CA, USA). Whole blood was collected in 5cm3 EDTA/anti-coagulated tubes by a trained phlebotomist. Blood samples were centrifuged at 3,000 r.p.m. for 10 min, with serum samples immediately aliquoted and stored in 1.2-ml cryule vials at −70°C until ready for batch testing. External commercial testing on a subset of NOMAS blood samples and internal testing on control bloods with known sTNFR1 values, confirmed reliability and validity of sTNFR1 assays (correlation with external testing: r = 0.98).
Covariates
Covariate definitions are described in Table 1, and were previously reported [10].
Table 1.
Population characteristics (n = 1,862)
| Parameter | Overall, n = 1862 [n (%)] OR [mean (SD)] | sTNFR1 Q1 [n (%)] OR [mean (SD)] | sTNFR1 Q2 [n (%)] OR [mean (SD)] | sTNFR1 Q3 [n (%)] OR [mean (SD)] | sTNFR1 Q4 [n (%)] OR [mean (SD)] | K–W or X2 (P-value) | |
|---|---|---|---|---|---|---|---|
| A. Baseline descriptive statistics (overall and sTNFR1 quartiles) | |||||||
| Demographics | Age, mean, SD, y | 69 (10.2) | 66.8 (10) | 67.2 (9.6) | 68.9 (9.4) | 73.2 (10.6) | <0.001 |
| Sex, | |||||||
| Male | 633 (34.0) | 170 (36.5) | 165 (35.3) | 143 (30.8) | 155 (33.4) | 0.21 | |
| Race/ethnicity | |||||||
| Non-Hispanic White | 353 (19.0) | 79 (22.4) | 71 (20.1) | 90 (25.5) | 113 (32.0) | <0.01 | |
| Non-Hispanic Black | 426 (23.6) | 133 (31.2) | 101 (23.7) | 93 (21.8) | 99 (23.2) | ||
| Hispanic | 1029 (56.9%) | 244 (53.5%) | 279 (61.9%) | 269 (59.5%) | 237 (52.8%) | ||
| Education level | |||||||
| >High school | 816 (43.9) | 232 (28.4) | 199 (24.4) | 197 (24.1) | 188 (23.0) | 0.03 | |
| Insurance status | |||||||
| No insurance/medicaid | 872 (47.1) | 203 (23.3) | 213 (24.4) | 231 (26.5) | 225 (25.8) | 0.22 | |
| Private insurance/medicare | 978 (52.9) | 262 (26.8) | 249 (25.5) | 232 (23.7) | 235 (24) | ||
| Behavioural risk factors | Smoking status | ||||||
| Non-smoker | 896 (48.2) | 225 (25.1) | 231 (25.8) | 213 (23.8) | 227 (25.3) | 0.95 | |
| Past smoker | 646 (34.7) | 159 (24.6) | 159 (24.6) | 170 (26.3) | 158 (24.5) | ||
| Current smoker | 318 (17.1) | 82 (25.8) | 77 (24.2) | 81 (25.5) | 78 (24.5) | ||
| Moderate alcohol consumption | |||||||
| Yes | 605 (32.6) | 166 (27.4) | 173 (28.6) | 155 (25.6) | 111 (18.4) | <0.001 | |
| Physical activity | |||||||
| Moderate or heavy | 145 (7.8) | 55 (37.9) | 37 (25.5) | 27 (18.6) | 26 (17.9) | <0.01 | |
| Waist, inches, mean, SD | 36.6 (4.9) | 35.7 (4.8) | 36.2 (4.3) | 36.8 (4.7) | 37.7 (5.3) | <0.001 | |
| Clinical risk factors | Hx coronary artery disease | 409 (22) | 78 (19.1) | 92 (22.5) | 102 (24.9) | 137 (33.5) | <0.001 |
| Diabetes mellitus | 400 (21.5) | 92 (23) | 79 (19.8) | 93 (23.3) | 136 (34) | <0.001 | |
| Cholesterol Rx | 264 (14.2) | 43 (16.3) | 58 (22.0) | 75 (28.4) | 88 (33.3) | <0.01 | |
| HDL, mg/dl, mean, SD | 46.9 (14.5) | 48.9 (15.3) | 47.5 (14.3) | 46.6 (14.3) | 44.6 (13.6) | <0.001 | |
| LDL, mg/dl, mean, SD | 129.5 (36.3) | 131.7 (37.8) | 132.9 (35.1) | 130.9 (37.0) | 122.7 (34.4) | <0.001 | |
| Systolic blood pressure, mm Hg mean + SD | 143.7 (21.1) | 142.9 (20.7) | 141.2 (20.6) | 143.5 (20.5) | 147.3 (22.3) | <0.001 | |
| hsCRP, mg/l, mean, SD | 5.5 (9.3) | 3.6 (4.4) | 4.0 (5.1) | 5.3 (8.1) | 9.0 (14.7) | <0.001 | |
| Model parameters | sTNFR1, ng/ml, mean, SD | 2.57 (1.7) | Q1 < 1.75 | 1.75 < Q2 < 2.28 | 2.28 < Q3 < 2.97 | Q4 > 2.97 | |
| Events | |||||||
| All-cause deaths | 512 (27.5) | 98 (21.0) | 96 (20.6) | 100 (21.5) | 218 (47.0) | <0.001 | |
| Non-vascular deaths | 267 (14.3) | 41 (15.4) | 47 (17.6) | 57 (21.4) | 122 (45.7) | <0.001 | |
| Vascular deaths | 207 (11) | 48 (23.2) | 41 (19.8) | 34 (16) | 84 (40.6) | <0.001 | |
| Time to all-cause mortality, mean, SD, years | 8.4 (2.5) | 9.0 (2.0) | 8.7 (2.2) | 8.6 (2.3) | 7.1 (3.1) | <0.001 | |
| B. Covariates: acronyms, measurements, categorisation for modelling | |||||||
| # | Parameter | Measurement | Categorisation | ||||
| 1,2 | Age; sex | Self-report during standardised interview | Continuous; male, female (ref) | ||||
| 3 | Race/ethnicity | Self-report during standardised interview | Hispanic, Black, White(REF) | ||||
| 4 | Education level | Self-report during standardised interview | >High school, <High school (ref) | ||||
| 5 | Insurance status | Self-report during standardised interview | No insurance or medicaid, private insurance or medicare (ref) | ||||
| 6 | Smoking status | Self-report during standardised interview | Current smokers, past smokers, never smokers (ref) | ||||
| 7 | Alcohol consumption | National Cancer Institute Food Frequency Questionnaire | Moderate use ( >1 drink/month and <2 drinks daily), all others (ref). | ||||
| 8 | Physical activity | National Health Interview Survey | Moderate to heavy activity, no activity to low activity (ref) | ||||
| 9 | Waist size | Measured by trained study researcher | Continuous | ||||
| 10 | Hx coronary artery disease | Self-report or provider Dx | History of coronary artery diease, no history (ref) | ||||
| 11 | Diabetes mellitus | Fasting glucose >126 mg/dl, self-report or hypoglycaemic drug | Diabetes mellitus, no diabetes mellitus (ref) | ||||
| 12 | Cholesterol Rx | Self-report during standardised interview | Any cholesterol medications at baseline, no cholesterol medications (ref) | ||||
| 13,14 | HDL, LDL | Fasting lipid panels, Hitachi 705 spectrometer (Boehringer) | | Continuous | ||||
| 15 | Systolic blood pressure | Mean of 2× calibrated aneroid sphygmomanometer measures | Continuous | ||||
| 16 | hsCRP | BNII nephelometric assay system (Dade-Behring, Deerfield, IL, USA) | >3 mg/l, <3 mg/l (ref) | ||||
Q, quartile; SD, standard deviation; K–W, Kurts–Wallace test; X2, Chi-squared test; y, years.
Data analysis
The baseline characteristics and their relations to sTNFR1 were calculated. We fitted Cox proportional hazard regression models to estimate hazard ratios and 95% confidence intervals (HR, 95% CI) for sTNFR1 levels, unadjusted and after adjusting for demographics, medical and behavioural risk factors: age, sex, race-ethnicity, education, insurance status, history of coronary artery disease, blood sugar, systolic blood pressure, waist circumference, HDL, LDL, cigarette smoking, alcohol consumption, physical activity, cholesterol medication and hsCRP levels. sTNFR1 was modelled by quartiles with the lowest quartile (Q1) as the reference. The primary outcome was all-cause mortality, and secondary outcomes were vascular and non-vascular mortality. Final models and models with interactions of sTNFR1 levels with covariates were examined using the likelihood ratio test (LRT) with specified degrees of freedoms (df) to ensure overall effects of sTNFR1 on mortality. After examining the proportional hazards assumption in final models, we censored follow-up at 10 years. All statistical analyses were conducted using SAS, version 9.2.3 (Cary, NC, USA).
Results
Baseline descriptive statistics, risk factors and associations with sTNFR1 are shown in Table 1. The median sTNFR1 was 2.28 (IQR: 1.75–2.97) ng/ml. There were 512 deaths, including 267 vascular deaths, 207 non-vascular deaths and 38 deaths of unknown aetiology during the mean follow-up of 8.4 years. For mortality assessment, 215 records were confirmed by FMNHS only, 112 records by MRDC only, 137 by both MRDC and FMNHS and 48 by other sources.
sTNFR1 quartiles and mortality: all-cause, vascular and non-vascular
Participants with sTNFR1 levels in the highest quartile had an increased risk of all-cause (adjusted HR: 1.8, 95% CI: 1.4–2.4) and non-vascular mortality (adjusted HR: 2.5, 95% CI: 1.5–3.6), but not vascular mortality (adjusted HR: 1.3, 95% CI: 0.9–1.9) in fully adjusted main effects models, when compared with the referent quartile (Table 2A). There were mild violations for proportionality among Q2 and Q3 of TNFR1, which was mainly due to cross-over after 10 years of the follow-up. Analyses were thus limited to 10 years of the follow-up. Quartiles 2 and 3 were not associated with mortality. Secondary analysis for a possible threshold effect found the highest quartile of sTNFR1 was associated with vascular mortality, when compared with the remaining quartiles combined (adjusted HR = 1.4, 95% CI: 1.1–2.0). Sensitivity analysis restricting outcomes to those confirmed by MRDC did not materially affect the results.
Table 2.
Tumour necrosis factor receptor 1 (TNFR1) quartiles as a predictor of mortality
| Model 1. All-cause mortality |
Model 2. Non-vascular mortality |
Model 3. Vascular mortality |
||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Unadjusted |
Adjusteda |
Unadjusted |
Adjusteda |
Unadjusted |
Adjusteda |
|||||||||||||
| sTNFR1 quartile | HR | 95% CI | P-value* | HR | 95% CI | P-value* | HR | 95% CI | P-value* | HR | 95% CI | P-value* | HR | 95% CI | P-value* | HR | 95% CI | P-value* |
| A. Association of soluble tumour necrosis factor 1 and mortality | ||||||||||||||||||
| Quartile 1 (referent) | 1 | <0.01 | 1 | <0.01 | 1 | <0.01 | 1 | <0.01 | 1 | <0.01 | 1 | 0.07 | ||||||
| Quartile 2 | 1.02 | 0.77–1.35 | 1.11 | 0.83–1.49 | 0.94 | 0.51–1.73 | 0.88 | 0.47–1.65 | 2.35 | 1.48–3.72 | 1.11 | 0.64–1.95 | ||||||
| Quartile 3 | 1.08 | 0.82–1.43 | 1.03 | 0.76–1.38 | 1.30 | 0.74–2.28 | 1.17 | 0.65–2.09 | 0.75 | 0.50–1.11 | 0.52 | 0.27–0.99 | ||||||
| Quartile 4 | 2.97 | 2.33–3.77 | 1.81 | 1.39–2.36 | 4.03 | 2.49–6.53 | 2.42 | 1.45–4.04 | 2.26 | 1.63–3.14 | 1.10 | 0.65–1.85 | ||||||
| B. Association of soluble tumour necrosis factor 1 and all-cause mortality, stratified by insurance status and alcohol consumption | ||||||||||||||||||
| Model 1. All-cause mortality | Model 1. All-cause mortality | |||||||||||||||||
| Stratum-specific estimates | sTNFR1 quartile | Adjusteda | Stratum-specific estimates | sTNFR1 quartile | Adjusteda | |||||||||||||
| HR | 95% CI | P-value** | HR | 95% CI | P-value** | |||||||||||||
| Private insurance or medicare | Quartile 1 (referent) | 1 | Low or no alcohol consumption | Quartile 1 (referent) | 1 | |||||||||||||
| Quartile 2 | 1.06 | 0.74–1.53 | 0.74 | Quartile 2 | 1.19 | 0.84–1.68 | 0.34 | |||||||||||
| Quartile 3 | 0.95 | 0.65–1.37 | 0.77 | Quartile 3 | 1.30 | 0.93–1.82 | 0.12 | |||||||||||
| Quartile 4 | 1.35 | 0.97–1.87 | 0.07 | Quartile 4 | 1.79 | 1.32–2.42 | <0.01 | |||||||||||
| Uninsured or medicaid | Quartile 1 (referent) | 1 | Moderate alcohol consumption | Quartile 1 (referent) | 1 | |||||||||||||
| Quartile 2 | 1.27 | 0.77–2.11 | 0.57 | Quartile 2 | 0.93 | 0.53–1.62 | 0.47 | |||||||||||
| Quartile 3 | 1.24 | 0.66–2.31 | 0.39 | Quartile 3 | 0.49 | 0.26–0.91 | <0.01 | |||||||||||
| Quartile 4 | 2.86 | 1.85–4.43 | <0.01 | Quartile 4 | 2.00 | 1.23–3.24 | 0.70 | |||||||||||
CI, confidence interval; HR, hazard ratio.
aModels were adjusted for age, sex, race-ethnicity, education, insurance status, smoking, alcohol consumption, physical activity, diabetes mellitus, cholesterol treatment, high-density lipoprotein, low-density lipoprotein, systolic blood pressure and high-sensitivity C-reactive protein.
*P-value: based on the likelihood ratio test; df, degrees of freedom.
**P-value: based on the Wald Chi-square test following a significant likelihood test.
Interactions of sTNFR1 with covariates on all-cause mortality
The insurance status (LRT, df = 3, Pinteraction = 0.02) as well as moderate alcohol consumption (LRT, df = 3, Pinteraction < 0.01) were the only interactions detected with quartiles of sTFNR1 (Table 2B). Compared with the lowest, the effects of highest quartile of sTNFR1 with all-cause mortality, was greater among those with no insurance or Medicaid (adjusted HR: 2.9, 95% CI: 1.9–4.4) than among participants with private insurance or Medicare (adjusted HR: 1.4, 95% CI: 1.0–1.9). Among participants with moderate amounts of alcohol consumption, compared with the lowest, a protective effect in sTNFR1 third quartile against all-cause mortality (adjusted HR: 0.5, 95% CI: 0.3–0.9, P < 0.01) was observed, while there were no associations among their counterpart.
Discussion
In this well-characterised population-based cohort study, elevated sTNFR1 levels predicted all-cause mortality. For example, sTNFR1 levels >2.97 ng/ml (upper quartile) were associated with a 1.8 times higher risk of dying from all causes, compared with those with levels <1.75 ng/ml (referent quartile). The effect of sTNFR1 on mortality differed by some population characteristics: the effect of sTNFR1 on mortality was greater among those with no insurance or Medicaid than among those with private insurance or Medicare. The absence of effect among intermediate quartiles and risk elevation in the highest quartile of sTNFR1 suggests a threshold pattern relationship with mortality, and it is unclear whether the association persists for longer than 10 years of the follow-up.
Our findings of elevated sTNFR1 and mortality risk are supported by other studies. sTNFR1 has been linked to non-vascular mortality through neurodegenerative processes [13, 14], cancer survival [15, 16] and autoimmune disease [17]. TNFR1 has been linked to vascular mortality through several risk factors and cardiovascular disorders, including pulmonary embolism [18], left ventricular hypertrophy [11], homocysteine [19], carotid atherosclerosis [10] and heart failure [20]. Having Medicaid or no insurance is likely a proxy for a socioeconomic status and correlates with poor management of health conditions, and may lead to increased mortality [21]. Alcohol consumption suppresses inflammatory responses [22] and may confer protective effects below a critical sTNFR1 threshold, above which may correlate with advanced disease and mortality risk [23].
Only the highest quartile of sTNFR1 was predictive of mortality, and this was similar in our secondary analysis for vascular mortality. sTNFR1 is believed to have dual roles, responsible for sequestering TNF and inhibiting inflammation [1], and alternately, enhancing TNF function by protecting active TNF trimer states [2, 3, 24]. It may be that high concentrations of sTNFR increase mortality risk through induction of pro-inflammatory pathways.
Convergence of the hazard functions for Q2 and Q3 occurred after 10 years. We were therefore only able to demonstrate the effects of sTNFR1 on all-cause death out to 10 years.
Limitations
There are limitations in this study. First, cause of death was reported by family members or nursing home staff in 50% of deaths, raising measurement error concerns. However, restricting samples to only those with medically confirmed cause of death did not change the results. Secondly, several potential confounders were not measured, including immune status, antioxidant supplements and liver function. These variables may explain part of the observed effect, but it is unlikely that unmeasured positive confounders account for the full observed magnitude of effect. Finally, a limitation of this study is a lack of the measurements of serum levels of TNF, to correlate with circulating sTNFR1 levels. It may be that unbound TNF and not sTNFR1 is aetiologically responsible for increased mortality risk, but this does not preclude the prognostic value of sTNFR1 in clinical settings. The increased stability of sTNFR1 measurements compared with TNF may also make it a better assay for population-based studies.
Conclusion
In conclusion, sTNFR1 levels predict 10-year risk of mortality in this urban, community-dwelling population—particularly in individuals without health insurance or with Medicaid. If these findings can be replicated in other studies, sTNFR1 may improve mortality risk assessment in clinical practice.
Key points.
Identify early mortality risk.
Measuring underlying inflammation.
Interaction with an insurance status.
Conflicts of interest
None declared.
Funding
This study was supported by R37 NS29993 from the National Institute of Neurological Disorders and Stroke.
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