Blood Neutrophil to Lymphocyte Ratio as a Predictor of Hypertension
American Journal of Hypertension
Blood Neutrophil to Lymphocyte Ratio as a Predictor of Hypertension
Xing Liu 1 2
Qing Zhang 0 2
Hongmei Wu 1 2
Huanmin Du 1 2
Li Liu 0 2
Hongbin Shi 0 2
Chongjin Wang 0 2
Yang Xia 1 2
Xiaoyan Guo 1 2
Chunlei Li 1 2
Xue Bao 1 2
Qian Su 1 2
Shaomei Sun 0 2
Xing Wang 0 2
Ming Zhou 0 2
Qiyu Jia 0 2
Honglin Zhao 0 2
Kun Song 0 2
Kaijun Niu 0 1 2
0 Health Management Centre, Tianjin Medical University General Hospital , Tianjin , China
1 Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University , Tianjin , China
2 METHODS Participants were recruited from Tianjin Medical University's General Hospital-Health Management Centre. A total of 28,850 initially hypertension-free subjects were followed from 2007 to 2013. Adjusted Cox proportional hazards regression models were used to assess relationships between NLR categories and incidence of hypertension
BACKGROUND Hypertension is a significant global public health challenge. Low-grade inflammation is known to facilitate the development of essential hypertension and target-organ hypertensive damage. Neutrophil to lymphocyte ratio (NLR) is a simple and reliable indicator of inflammation that may also be useful in the prediction of hypertension.
blood pressure; hypertension; inflammatory markers; neutrophil to lymphocyte ratio
Hypertension is a global public health challenge and often
leads to further complications and severe damage of target
organs, such as the heart, kidney, and brain.1 Worldwide,
hypertension is estimated to affect more than 1 in 3 adults
aged 25 and over, or about 1 billion people.2 It was
demonstrated that there were about 266 million
hypertensive patients in China with more than 10 million patients
Despite extensive study, the precise etiology
underlying most hypertension cases remains unknown; however,
hypertension, like many other chronic diseases, is
characterized by inflammation.4 Low-grade inflammation plays
a crucial pathophysiological role in hypertension,5 as it
facilitates the development of essential hypertension and
target-organ damage.6 Inflammation participates in many
processes that contribute to the development of elevated
blood pressure (BP); for example, several studies have
shown a positive association between hypertension and
elevated white blood cell (WBC),7 C-reactive protein and
The neutrophil to lymphocyte ratio (NLR) is commonly
used as a reliable biomarker of systemic inflammatory
status.9 Blood NLR is a simple marker for chronic low-grade
inflammation that can be easily obtained from a differential
WBC count.10 In addition, NLR is an emerging marker for
both cardiac and noncardiac disorders, and recent
studies have demonstrated the prognostic value of NLR in
stable coronary artery disease,11 acute coronary syndromes,12
heart failure13 as well as patients undergoing percutaneous
coronary interventions14 and coronary artery bypass
grafting.15 Since hypertension can markedly increase the risk
of these diseases, it has been hypothesized that NLR is a
useful predictive factor for the incidence of hypertension;
however, to date, only a few cross-sectional studies have
suggested that NLR is positively related to hypertension.9,16
With this in mind, we designed a ~6-year follow-up cohort
study to investigate how NLR is related to the incidence of
This cohort study was conducted in Tianjin, is a city of
approximately 10.43 million, located in the northeast of the
North China Plain. The Tianjin Chronic Low-grade Systemic
Inflammation and Health cohort study is a large
prospective dynamic study focusing on the relationships between
chronic low-grade systemic inflammation and the health
status of an adult Tianjin population.17 Individuals who had
a routine annual physical examination at the Tianjin Medical
University General Hospital’s Health Management Centre
(the largest and most comprehensive physical examination
center in Tianjin) were recruited. NLR and other blood
indicators, BP measurements and anthropometric parameters
(height and body weight), provided in the annual health
examinations once per year during follow up. All
participants provided written informed consent.
For this analysis, we chose individuals who participated
in the Tianjin Chronic Low-grade Systemic Inflammation
and Health cohort study from 2007 to 2013. During this
period, there were 53,169 participants who received at least
1 health examination, agreed to participate, and provided
informed consent for their data to be analyzed. For each
participant, data of the first examination during follow-up
was used as their baseline information. We excluded
participants who did not undergo WBC counts (n = 4,229)
or who had (at baseline) or developed (during follow up)
inflammatory diseases such as gastritis, chronic
cholecystitis, nephritis, rhinitis, pharyngitis, bronchitis,
myocarditis, rheumatoid arthritis, gout, immune system disorders
and others (n = 1,031), cardiovascular disease (CVD;
n = 2,301) or cancer (n = 314), or if they had hypertension
(n = 12,485) at baseline. A total of 8,189 participants who
did not undergo health examinations during follow-up
were also excluded. After these exclusions, the final cohort
study population comprised 28,850 participants (Figure 1;
follow-up rate: 77.9%; mean ± standard deviation age:
35.4 ± 11.1 years; male: 47.3%). We compared the
baseline data from those 8,198 people to that from the whole
28,850 follow-up people. Compared with subjects who
participated in this study, those subjects who dropped out
had significantly higher age, body mass index (BMI), waist
circumference, triglycerides and diastolic blood pressure,
lower total cholesterol (TC), low-density lipoprotein
cholesterol, high-density lipoprotein cholesterol, and systolic
blood pressure. Additionally, more subjects were male,
or had hyperlipidemia or diabetes, smokers, drinkers or
had a family history of CVD, hypertension, and diabetes.
Otherwise, no significant difference was observed between
groups. The protocol used for this study was approved
by the institutional review board of the Tianjin Medical
Participants who provided informed consent (n = 53,169)
Follow-up participants (n = 37,039)
Participants included in the final follow-up analysis (n = 28,850)
Participants for whom leukocyte data were not available were excluded (n = 4,229)
Participants with a history of inflammatory disease were excluded (n = 1,031)
Participants with a history of cardiovascular disease were excluded (n = 2,301)
Participants with a history of cancer were excluded (n = 314)
Participants who had hypertension at baseline were excluded (n = 12,485)
Participants who did not undergo health examinations during follow up were excluded (n = 8,189)
University and conforms to STROBE guidelines for cohort
Assessment of NLR
After a 12-h fasting period, blood samples were
withdrawn from the cephalic vein using a traumatic
venipuncture and immediately mixed with EDTA. Complete WBC
counts, including neutrophil and lymphocyte counts, were
measured using an automated hematology analyzer and
expressed as ×1,000 cells/mm3, and NLR values were
calculated. In order to investigate how baseline NLR level is related
to incidence of hypertension, we divided participants into
5 categories (quintiles) according to NLR level as follows:
Level 1 (0.24–1.19), Level 2 (1.19–1.45), Level 3 (1.45–1.72),
Level 4 (1.72–2.12), and Level 5 (2.12–16.3). Correlations of
baseline WBC with baseline neutrophils, lymphocytes, and
the NRL were 0.90, 0.60, and 0.37, respectively (all P
values < 0.0001). The correlation of NLR and neutrophils was
extremely high (r = 0.69, P value < 0.0001). Furthermore,
52% of participants had an increasing NLR value during
follow-up. The proportion of participants with increasing NLR
values across NLR quintiles were 74.1, 63.2, 52.5, 42.3, and
Assessment of hypertension
BP was measured at least twice by an experienced
physician using Andon KD-598 BP monitor and an appropriately
sized cuff applied to the sitting subject’s left arm at heart level
after 5 min of rest in a seated position. The mean of these 2
measurements was taken as the BP value. Hypertension was
defined as average systolic blood pressure ≥ 140 mm Hg or
average diastolic blood pressure ≥ 90 mm Hg or use of
Incident cases of hypertension were defined when
subjects were newly diagnosed during follow-up exams and a
doctor confirmed the diagnosis. Subjects with secondary
hypertension were excluded from incident cases. In most
cases, new incidents of hypertension were diagnosed at least
twice during different examination cycles; we assigned the
date of onset of hypertension as the midpoint between the
exam date when hypertension was first noted and the
previous exam date. All participants were followed from the
baseline examination to the date of incident hypertension or, for
those with no hypertension, through the last examination
date in 2013.
Assessment of other variables
Anthropometric parameters (height and body weight)
were recorded using a standard protocol and were measured
without shoes or outer clothing. BMI was calculated as body
weight divided by the square of standing height (kg/m2).
Socio-demographic variables, including gender and age,
were also assessed. A detailed personal and family history of
physical illness and current medications, as well as
information on smoking and drinking status, was noted from “yes”
or “no” responses to relevant questions from a questionnaire
Blood samples for the analysis of fasting blood sugar and
lipids were collected in siliconized vacuum plastic tubes.
Fasting blood sugar was measured by the glucose oxidase
method, TC and triglycerides were measured by enzymatic
methods, low-density lipoprotein cholesterol was measured
by the polyvinyl sulfuric acid precipitation method, and
high-density lipoprotein cholesterol was measured by the
chemical precipitation method using appropriate kits on a
Cobas 8000 analyzer (Roche, Mannheim, Germany).
Data were analyzed using the Statistical Analysis System
version 9.3 for Windows (SAS Institute, Cary, NC).
Descriptive data are presented as the mean (95%
confidence interval, CI) for adjusted continuous variables and
as percent ages for categorical variables. As for all of the
continuous variables, as being non-normally distributed,
they were logarithmically transformed to obtain
substantially normal distributions before analysis and the
geometric means (95% CI) were shown. For analysis, incidences
of hypertension were used as dependent variables and we
categorized baseline NLR into quintiles that were then used
as independent variables. For baseline characteristics
analysis, differences among NLR levels were examined using
analysis of covariance for continuous variables, or
multiple logistic regression analysis for proportional variables,
after adjustment for age and sex. Bonferroni-corrected
P-values were used for comparisons between NLR
quintiles. Model fit of multiple logistic regression analysis was
evaluated using the Hosmer–Lemeshow goodness-of-fit
statistic. For all models, the test was not significant (P ≥
0.25). The Cox proportional hazards model was used to
evaluate the independent effect of NLR on risk of
hypertension incidence. We used 4 models in our Cox analysis:
a crude model, an age- and sex-adjusted model, an
ageand sex- and BMI-adjusted model, and a
multivariateadjusted model. The latter of these models adjusted for age
at baseline, sex, BMI, baseline systolic blood pressure and
diastolic blood pressure, smoking status, drinking status,
diabetes (fasting blood glucose ≥ 7.0 mmol/L or history of
diabetes), hyperlipidemia (TC ≥ 5.17 mmol/L or
triglycerides ≥ 1.7 mmol/L or low-density lipoprotein cholesterol
≥ 3.37 mmol/L or history of hyperlipidemia) and as well
as family history of CVD, hypertension, hyperlipidemia,
and diabetes. The Cox proportional-hazard regression
model with age as the timescale was used to examine the
relationship between NLR categories and the incidence
of hypertension. The assumption of proportional hazards
was checked by examining the interaction term between
the NLR categories and logarithm of the follow-up time.
The result supported the proportional hazards
assumption (P = 0.78). Interactions between the quintiles of NLR
and potential confounders were tested by the addition
of the cross product terms in the regression model. The
tests for interactions between the quintiles of NLR and
these potential confounders in the final models were not
found to be significant (all P values for interaction > 0.12).
Furthermore, as NLR and covariates such as BMI and TC
level change over time, we also conducted a time-varying
American Journal of Hypertension 28(
) November 2015 1341
Cox regression model. In all models, age was the
underlying timescale with entry time defined as the subject’s age in
years at recruitment and exit time defined as the subject’s
age in years at the diagnosis of hypertension or end of
follow-up at 2013 or lost to follow-up. A hazard ratio (HR)
and 95% CI were calculated. The median value of each
NLR quintile was used to calculate the P values for the
linear trends. A Pearson’s correlation coefficient (r) was
calculated to evaluate the correlation of WBC with
neutrophils, lymphocytes, and the NRL. All tests were 2-tailed
and P < 0.05 was defined as statistically significant.
During the 6-year follow-up period between 2007 and
2013, 1,824 individuals developed hypertension. The
median duration of follow-up (interquartile range) was
2.63 (2.58–2.68). Age- and sex-adjusted participant
characteristics relative to NLR levels for follow-up analysis are
presented in Table 1. Compared with participants in the
lowest quintile, those in the top 4 NLR quintiles tended to
be older and to have higher waist circumference,
triglycerides, diastolic blood pressure, but lower TC and
highdensity lipoprotein cholesterol. A higher proportion of
participants in the top 4 quintiles were female, overweight
and obesity, were more likely to be current smokers and
alcohol consumers, and a higher proportion had a
family history of CVD, hypertension and diabetes (P for all
trends ≤ 0.02). Other than these results, no significant
differences were observed between participants among NLR
Incidence of hypertension was evaluated across the
~6-year follow-up period. During this period, a total of
1,824 participants received a new diagnosis of
hypertension. The incidence of hypertension was 23 per 1,000
person-years. In the 5 NLR quintiles, the respective rates of
hypertension were 19, 22, 22, 24, and 29 per 1,000
personyears. Table 2 shows the HRs of hypertension incidence by
NLR quintiles. In the final multivariate model, adjusted
HRs (95% CI) of hypertension were related to the gradual
increase of NLR levels, compared with participants with
the lowest NLR levels and were as follows: 1.08 (0.92,
1.26), 0.97 (0.83, 1.14), 1.10 (0.94, 1.28), 1.23 (1.06, 1.43),
respectively (P for trend < 0.01). A sensitivity analysis was
carried out in the participants (n = 28,114) without type
2 diabetes (n = 736). After final multiple adjustments, the
HRs (95% CI) of hypertension were 1.00 (reference), 1.07
(0.92, 1.26), 0.97 (0.83, 1.14), 1.07 (0.91, 1.25), and 1.23
(1.05, 1.43), respectively (P for trend < 0.01), for
participants with NLR in the 1st, 2nd, 3rd, 4th, and 5th quintiles
(P for trend < 0.01). Moreover, after adjustment for
potential of confounders, the HRs (95% CI) of hypertension for
increasing quintiles of WBC, neutrophil, and lymphocyte
counts were 1.00, 1.00 (0.85, 1.18), 1.11 (0.94, 1.29), 1.17
(1.02, 1.36), and 1.23 (1.06, 1.43; P for trend < 0.01), and
1.00, 1.02 (0.87, 1.21), 1.15 (0.98, 1.35), 1.13 (0.97, 1.33),
and 1.36 (1.17, 1.59; P for trend < 0.0001), and 1.00, 0.87
(0.75, 1.01), 0.87 (0.75, 1.01), 0.89 (0.76, 1.04), and 1.01
(0.87, 1.16; P for trend = 0.34), respectively (Figure 2).
1342 American Journal of Hypertension 28(
) November 2015
The dynamic cohort study examined the relationship
between NLR quintiles and the incidence of hypertension
in an adult population. To our knowledge, this is the first
cohort study to demonstrate that elevated levels of NLR
are significantly correlated with the incidence of
hypertension. In 2008, Tatsukawa et al. have made a cohort study and
demonstrated that elevated WBC count was significantly
associated with an increased risk of developing
hypertension among Japanese,18 but did not mention the relationship
between NLR and hypertension. In Figure 2, we also show
the relationship between the quintiles of WBC, neutrophil
and lymphocyte counts, and hypertension, make our study
Oral antihypertensive drugs, lifestyle changes (such as
exercise and dietary modifications), and traditional
medicines (such as Chinese herbal medicines) are used for
hypertension therapy, but none achieves complete reversal of
symptoms.19 Novel therapeutics or interventions are needed
for the prevention and treatment of hypertension. Since
inflammation plays an important role in the pathogenesis of
hypertension and elevated BP, therapeutic approaches aimed
at low-grade inflammation could be effective at controlling
hypertension and minimizing hypertensive damage.20 In
the vasculature, inflammation can increase proliferation of
smooth muscle cells and participates in vascular
remodeling.5 In the kidney, inflammation is involved in many
hypertensive models, such as salt-sensitive hypertension.21
Several inflammatory markers such as WBC,7,18 C-reactive
protein, or interleukin-6 levels8 have been used to predict
hypertension; however, most of these are time consuming
and expensive.9 NLR has emerged as a straightforward and
reliable indicator of the inflammatory status, and has been
used to predict prognosis and survival in patients with
cancers22 or coronary artery disease.23 Here, we show that the
NLR is also an effective predictor of hypertension.
Neutrophils secrete mediators that are responsible for
the inflammatory response including elastase,24
myeloperoxidase,25 oxygen-free radicals,26 and various hydrolytic
enzymes. Such mediators are associated with tissue
damage and plaque disruption, and can lead to increased risk
of hypertension.27 In addition, neutrophils can lead to the
release of reactive oxygen species, which contribute to
oxidative stress.28 Oxidative stress has been shown to be a
factor in the pathogenesis of hypertension,29 in the vasculature,
reactive oxygen species induce vasoconstriction and in the
kidney, they cause sodium and water retention.30 In mice
experimental models of hypertension, neutrophil counts rise
prior to the development of hypertension.31
The immune system plays a fundamental roles in the
development of hypertension and its complications.20
Several studies have shown that the adaptive immune
response in particular contributes significantly to the
pathophysiology of hypertension.30 Lymphocytes,
particularly the CD4+ T cells, represent the regulatory arm
of the immune system.32 Infusion of alloactivated T cells
for treatment of cancer, increases BP in humans,33
preeclampsia (a life-threatening complication of pregnancy
associated with high BP) involves activation of both
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Abbreviations: BMI, body mass index; NLR, neutrophil/lymphocyte ratio.
aAnalysis by Cox proportional hazards model.
bAdjusted hazard ratios (95% confidence interval; all such values).
cAdjusted for age, sex, BMI, baseline systolic blood pressure and diastolic blood pressure, smoking status, drinking status, diabetes (fasting
blood glucose ≥7.0 mmol/L or history of diabetes), hyperlipidemia (total cholesterol ≥ 5.17 mmol/L or triglycerides ≥1.7 mmol/L or low-density
lipoprotein cholesterol ≥ 3.37 mmol/L or history of hyperlipidemia), and family history of cardiovascular disease, hypertension, hyperlipidemia,
humoral and cellular immunity.34 Conversely,
suppression of the adaptive immune system can inhibit
hypertension. During adaptive immunity, T cells play a crucial role
in the BP elevation caused by angiotensin II (a hormone
increases thirst, promotes salt retention by the kidney,
causes vasoconstriction, and enhances catecholamine
release35) response to sodium and volume challenges.36 In
recent years, experimental evidence has strongly supported
a previously undefined role of T cells in hypertension. For
example, human T lymphocytes have been shown to be
endowed with a functional active renin–angiotensin
system,6 and, a famous experiment by Guzik et al.37 showed
that mice-lacking T cells (RAG-1/mice) have blunted
hypertension and are protected from target-organ damage
during angiotensin II infusion.
NLR has been associated with worse outcomes in
various diseases, including hypertension, as we demonstrate
here. High levels of circulating von Willebrand factor and
increased NLR might reflect vascular inflammation in
hypertensive patients.38 Exercise and catecholamine release
can cause increases in both the individual neutrophil and
lymphocyte count,39 but will affect the NLR to a lesser extent;
as NLR uses counts of both neutrophils and lymphocytes,
the result will be more accurate. In addition, the short life of
neutrophils (around 7 h) and their brief steady kinetic state
might warrant repeated measurements and utilization of a
mean NLR for better prognostication.40
As with any novel prognostic indicator, many unknowns
remain. First, the normal reference range for NLR has not
been systematically explored and established. The reference
ranges for absolute neutrophil and lymphocyte counts are
wide, making it difficult to establish a “normal” NLR range
for our study population. Second, whether the NLR is merely
a marker of poor prognosis or whether it plays a substantial
part in the pathogenesis of the adverse outcomes remains to
be seen. Finally, the 5th quintile had an enormous effect on
hypertension; the significant P for trend across quintiles is
fully driven by the 5th quintile in this study. Further studies
are needed to explore whether there is a useful cutoff NLR
value of NLR that might accurately predict the incidence of
One limitation of this study warrants noting, namely, it is
observational in design and thus further intervention trials
will be required in order to determine a causal relationship
between NLR levels and hypertension. Although the
followup rate is relatively high in this study (77.9%), as many
participants are relatively healthy compared with subjects who
drop out, these results might not accurately reflect the true
physical examination status of the cohort.
In conclusion, this large-scale epidemiological study
demonstrates that elevated NLR levels are significantly
correlated with an increased risk of developing hypertension in
an adult population. Our results indicate that inflammation
may play an important role in the development of
hypertension, and that neutrophils and lymphocytes may be involved.
These findings may be useful for clarifying the mechanism
underlying the pathogenesis of hypertension, and in the
development of new therapeutic approaches aimed at
lowgrade inflammation for the control of hypertension and
This work was supported by grants from the key
technologies R&D program of Tianjin (key project: 11ZCGYSY05700,
12ZCZDSY20400, and 13ZCZDSY20200), the Technologies
development program of Beichen District of Tianjin
(bcws2013-21 and bc2014-05), the technologies project of
Tianjin Binhai New Area (2013-02-04 and 2013-02-06),
and the Science Foundation of Tianjin Medical University
We gratefully acknowledge all of the people who
participated in the study and Tianjin Medical University General
Hospital-Health Management Centre for creating the
possibility to perform the study.
The authors declared no conflict of interest.
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