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Kantor ED, Udumyan R, Giovannucci EL, et al. Association of Blood Marker of Inflammation in Late Adolescence With Premature Mortality. JAMA Pediatr. Published online September 03, 2019. doi:10.1001/jamapediatrics.2019.2835
Inflammation is implicated in various diseases, including cancer and cardiovascular disease (CVD). Despite increasing interest in the role of childhood and adolescent exposures in later-life disease, little is known about the long-term implications of early inflammation. Here, we evaluate the association of inflammation in late adolescence as measured by erythrocyte sedimentation rate (ESR) with cause-specific mortality among ostensibly healthy men assessed for conscription in the Swedish military.
This study is drawn from a cohort of 248 488 men born between 1952 and 1956 who were assessed for compulsory military conscription at age 16 to 20 years, at which time physical and psychological examinations were completed and blood samples were collected. Analyses were restricted to adolescents with no known health conditions or marked physical weakness (n = 108 443) and excluded men missing ESR data or covariates, resulting in a final sample of 106 120 men. Permissions for this study were granted by Regional Ethical Review Board in Uppsala, Sweden, and the Harvard T. H. Chan School of Public Health Institutional Review Board. Informed consent was waived because we used deidentified national register data and had no contact with study participants.
Inflammation was measured by ESR, a nonspecific marker of inflammation.1 Erythrocyte sedimentation rate was categorized as low (≤10 mm/h), moderate (>10-<15 mm/h), and high (≥15 mm/h); the threshold from moderate to high ESR corresponds to the clinical cutoff for normal ESR among adolescents and men in this age group.1,2 Men were observed for death until January 1, 2010, unless censored because of emigration. Cox regression was used to estimate hazard ratios (HRs) and 95% CIs. Statistical significance was assessed at an α less than .05 using a 2-sided test; all P values presented were calculated using the Wald test. Sensitivity analyses were conducted allowing inclusion of adolescents with health conditions deemed minor by the military (n = 203 204).
Of the 106 120 Swedish men included in the analysis, 105 460 (99.4%) were aged 18 to 20 years at the time of examination. Men were observed for a mean of 35 years up to a maximum age of 57 years, over which time 4835 deaths occurred, including deaths due to cancer (n = 1105), CVD (n = 874), alcohol or drugs (n = 280), and suicide, traffic collisions, or falls (n = 1502). Selected covariates, by ESR, are shown in Table 1. The full list of covariates is provided in the footnote of Table 2.
Erythrocyte sedimentation rate was associated with overall mortality (high vs low ESR: multivariable-adjusted HR, 1.36; 95% CI, 1.11-1.67; P for trend < .001) (Table 2). Similar patterns were observed for cancer mortality (HR, 1.78; 95% CI, 1.23-2.59; P for trend = .002) and CVD mortality (HR, 1.54; 95% CI, 0.97-2.43; P for trend = .006). No statistically significant associations were observed for death due to alcohol or drugs (high vs low ESR: HR, 1.17; 95% CI, 0.48-2.86; P for trend = .61) or suicide, traffic collisions, or falls (high vs low ESR: HR, 0.96; 95% CI, 0.63-1.47; P for trend = .89).
To address potential occult disease, sensitivity analyses were conducted excluding the first 5 years of follow-up; results were unchanged (data not shown). Similarly, sensitivity analyses including adolescents with minor health conditions did not differ in interpretation (data not shown). Excluding cancers with an established smoking etiology3 yielded results similar to overall cancer mortality (HR, 1.66; 95% CI, 1.03-2.65; P for trend = .02). Lastly, given heterogeneity of CVD, myocardial infarction–specific mortality was examined, yielding stronger associations between inflammation and mortality due to myocardial infarction (HR, 2.50; 95% CI, 1.32-4.73; P for trend = .001) than for overall CVD mortality (Table 2).
In this large study, we observed inflammation during late adolescence to be positively associated with premature mortality due to cancer and CVD. While the exact underlying mechanisms are unclear, inflammation has been implicated in the development of both cancer and atherosclerosis,4,5 and these data highlight the existence of detectable markers of premature mortality at an early stage of life.
Inflammation was measured at a single time; thus, we could not evaluate the role of earlier or subsequent inflammation. We were also unable to adjust for smoking. However, smoking is not strongly associated with ESR,2 cancer mortality findings were robust after excluding sites with known smoking etiology, and prior research found the association of adolescent ESR with myocardial infarction risk robust after adjusting for smoking.2 Lastly, analyses may not be generalizable to women.6
Results suggest that ESR among ostensibly healthy men in late adolescence marks something beyond that captured by manifested adolescent health conditions. Results demonstrate the need to better understand the role of subclinical early-life inflammation in relation to later-life health outcomes.
Accepted for Publication: April 12, 2019.
Corresponding Author: Elizabeth D. Kantor, PhD, MPH, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 485 Lexington Ave, 2nd Floor, New York, NY 10017 (email@example.com).
Published Online: September 3, 2019. doi:10.1001/jamapediatrics.2019.2835
Author Contributions: Dr Kantor and Ms Udumyan had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr Kantor and Ms Udumyan are co–first authors.
Study concept and design: Kantor, Giovannucci, Montgomery, Fall.
Acquisition, analysis, or interpretation of data: Kantor, Udumyan, Valdimarsdottir, Signorello, Montgomery, Fall.
Drafting of the manuscript: Kantor.
Critical revision of the manuscript for important intellectual content: Udumyan, Giovannucci, Valdimarsdottir, Signorello, Montgomery, Fall.
Statistical analysis: Kantor, Udumyan, Giovannucci, Valdimarsdottir.
Obtained funding: Kantor, Montgomery.
Administrative, technical, or material support: Montgomery, Fall.
Study supervision: Signorello.
Conflict of Interest Disclosures: None reported.
Funding/Support: Drs Montgomery and Fall are supported by Örebro University Strategic Funding, and the cohort was developed with support from the UK Economic and Social Research Council through grants RES-596-28-0001 and ES/JO19119/1 to the International Centre for Life Course Studies. Dr Kantor was supported by grants T32CA009001 and P30CA008748 from the National Cancer Institute and the Rose Traveling Fellowship from the Harvard T. H. Chan School of Public Health.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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