CN106257287B - Growth and differentiation factor 15 assesses the new opplication of the starting cerebral apoplexy of hyperpietic - Google Patents
Growth and differentiation factor 15 assesses the new opplication of the starting cerebral apoplexy of hyperpietic Download PDFInfo
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Abstract
The present invention is the new opplication on growth and differentiation factor 15 (growth differential factor 15, GDF15) the assessment starting cerebral apoplexy of hyperpietic.Specifically, the present invention provides application of the growth and differentiation factor 15 as the marker of the assessment starting cerebral apoplexy risk of test individual, application of the horizontal reagent of detection growth and differentiation factor 15 in the detection agent for being used for assessing the starting cerebral apoplexy risk of test individual or detecting system is prepared is additionally provided, additionally provides a kind of detecting system for being used to assess the starting cerebral apoplexy risk of test individual.The present invention has found that cerebral apoplexy occurs first for the elevated hyperpietics of Baseline plasma GDF15, the risk of especially generation cerebral arterial thrombosis significantly raises by the perspective study to hypertension cohort crowd.
Description
Technical field
The present invention be on a kind of new opplication of endogenic secreted protein, more specifically to Growth and Differentiation because
15 (growth-differential factor 15, GDF15) of son assess the new opplication of the starting cerebral apoplexy of hyperpietic, belong to
In the prevention area of cardiovascular and cerebrovascular diseases.
Background technology
China is cerebral apoplexy country occurred frequently, and annual new cases are more than 2,500,000 (China Health statistical yearbook 2002-
2012).Cerebral apoplexy has become national first cause of death in China and first reason that disables of being grown up, every year because of Stroke Death
Number more than 1,700,000, existing post-stroke Survivor about 10,000,000, disability rate is up to 75%, and severe disability is more than 40%
(Lancet, 2013:381(9882)：1987-2015).The Hospitalization expenses that China is used to treat cerebral apoplexy every year are more than 45,000,000,000
Member (Chinese cardiovascular disease report, 2013).The characteristics of cerebral apoplexy high incidence, high mortality and high disability rate, is to social band
Carry out heavy financial burden, but China's resident living mode fast transition at present, aging of population accelerate, and smoking state is also without bright
Aobvious to improve, China's Cerebral Haemorrhage Invasion Rate is risen with the speed for being often close on 9%, the prevention and control situation very severe of cerebral apoplexy.
Hypertension is the most important hazards of cerebral apoplexy.In China, the patients with cerebral apoplexy more than 70% has high blood pressure
History, about 44% compatriots' acute apoplexy are attributed to hypertension (CHINESE JOURNAL OF INTERNAL MEDICINE, 2004,43 (10), 730-734.).No matter
Systolic pressure or diastolic pressure, blood pressure rise are closely related with the generation of cerebral apoplexy.Baseline systolic pressure often increases 10mmHg, brain soldier
Middle morbidity relative risk increase by 49%, diastolic pressure often increase 5mmHg, and (Chinese hypertension prevention and control refers to for Stroke risk increase by 46%
South is 2010).In the crowd of west, the Hazard ratio normotensive that cerebral apoplexy occurs for hyperpietic increases by 4~7 times
(Circulation.2008；118:1558-1566), in population of China, hypertension influences intensity to stroke onset and is far above
West crowd, (Chinese hypertension prevention and control refers to for 13~24 times of the risk rise of Northern Part of China hyperpietic generation cerebral apoplexy
South is 2010).
Hypertension is in China's increased popularity, and four times extensive national Prevalence of Hypertension investigation result show, hypertension trouble
Sick rate raises year by year, by 1958 5% rise to 2002 18.80%, the current China's Hypertension crowd of conservative estimation
Already exceed 200,000,000.Research shows, in Hypertensive Population, the annual morbidity of cerebral apoplexy is about 1~2% (Stroke 2010；41；
2108-2129), i.e., patients with cerebral apoplexy about 2,000,000 is increased newly every year.Cerebral apoplexy onset is anxious, and invisible strong, many patient's appearances are good for
Health, happen suddenly cerebral apoplexy when without any sign.Further, since the pathophysiological process of most apoplexy patients can not reverse, soldier
In the influence that disables can not eradicate.Therefore, the optimal path for reducing palsy Disease Spectrum still prevents that (angiocardiopathy level-one is pre-
Anti- China's Consensus of experts, 2012).In hyperpietic strengthen cerebral apoplexy primary prevention, identify high-risk patient, " curing the disease " in
When " not sick ", individuation is instructed to prevent and treat, this generation to preventing brain stroke, reduce social economical burden to closing weight
Will.The primary prevention of hypertensive cerebral palsy more targetedly should find out the height that 1~2% real hypertension easily sends out cerebral apoplexy
Danger crowd, carries out positive intervention and prevention and control, benefits the nation and the people, significant.
Clinically mainly there are two kinds to cerebral apoplexy early warning scheme at present：1) Sonography arteria carotis is utilized
Media thickness and stenosis, while investigate the cerebral apoplexy conventional risk factors such as hypertension, diabetes, smoking, comprehensive grading；2)
Risk of stroke is assessed by Genetic Detection.Although early warning of the both approaches for cerebral apoplexy has certain suggesting effect, but
All there are larger limitation.First, the specificity of carotid ultrasonography and sensitiveness are undesirable, while to operator's technology
It is more demanding, it is difficult to popularize；Secondly, for Genetic Detection method, existing cerebral apoplexy hereditary variation is minor effect variation, with brain
The correlation of palsy is very weak, adds up and is only capable of explaining the stroke onset risk less than 10%, and hereditary variation is unchangeable,
The process of cerebral apoplexy active development cannot be reacted completely.Therefore, the early warning of Chinese hypertensive cerebral palsy is complete there is an urgent need for one
It is based on Chinese population, with cerebral apoplexy occurrence and development are closely related, the molecular marker of high specific and sensitiveness.
Growth and differentiation factor 15 (growth-differential factor 15, GDF15) is TGF-β
(transforming growth factor β) superfamily member, is a new angiocardiopathy protective factors.Normal
Under physiological conditions, body is not expressed or low expression GDF15, but works as the Various Tissues such as heart, brain, blood vessel and be in pathological state,
When such as pressure rise, ischemic, anoxic state, the expression of GDF15 raises rapidly.Ripe GDF15 albumen is secreted into cell
After outer, combined with cell surface TGF-β family receptors, the downstream signaling pathway such as activation Akt, SMAD, feedback inhibition tissue damage
(Circ Res.2006；98:351-360).There are document report GDF15 and cerebral apoplexy in close relations, in brain injury animal model
In brain tissue, in the blood plasma of Ischemic Stroke, GDF15 expression dramatically increases (Cell Tissue Res.2011；
343:399-409；Cerebrovasc Dis.2011；32:72-78), elevated GDF15 levels are Acute Stroke patient's prognosis
Undesirable independent hazard factor (J Neurol.2012；259:1574-1579).These prior art researchs are mostly to have sent out
The patient of raw cerebral apoplexy or animal model are research object, lack perspective research.And whether can predict brain for GDF15
The generation of palsy, there is no relevant clearly study at present.
The content of the invention
The technical problems to be solved by the invention are to overcome the shortcomings of existing theory and technology, are that prediction of hypertension patient is first
Send out risk of stroke and new biomarkers are provided.
The present invention has found the elevated hypertension of Baseline plasma GDF15 by the perspective study to hypertension cohort crowd
Cerebral apoplexy occurs first for patient, the risk of especially generation cerebral arterial thrombosis significantly raises.This means can will be described
A New Sets of the GDF15 as the starting cerebral apoplexy of prediction of hypertension patient, by the expression of GDF15 in test individual sample or
Expression, new foundation is provided to judge that the risk of cerebral apoplexy occurs first for hyperpietic.
In the present invention, the GDF15 includes GDF15 genes or GDF15 albumen etc..The GDF15 genes are code book
The polynucleotide sequence of the GDF15 albumen of invention.
On the one hand, the present invention provides growth and differentiation factor 15 as the assessment starting cerebral apoplexy risk of test individual
The application of marker.
On the other hand, the horizontal reagent present invention also offers detection growth and differentiation factor 15 is treated in preparation for assessment
Application in the detection agent or detecting system of the starting cerebral apoplexy risk of survey individual.
Specific embodiment according to the present invention, in of the invention, the test individual is hyperpietic.
Specific embodiment according to the present invention, in of the invention, the horizontal rises of GDF15 in the sample from test individual,
The starting cerebral apoplexy of the test individual particularly cerebral arterial thrombosis risk raises.
Specific embodiment according to the present invention, in of the invention, the level of the growth and differentiation factor 15 is Growth and Differentiation
The serum or blood plasma level of the factor 15.
Specific embodiment according to the present invention, in of the invention, the level of the growth and differentiation factor 15 is Growth and Differentiation
The gene expression dose or protein expression level of the factor 15.The horizontal method for detecting growth and differentiation factor 15 can be this area
In known any feasible method, for example, this hair can be detected in protein level using any method known in the art
The expression of bright GDF15, including radioimmunoassay, competitive binding method, Western footprinting assays, enzyme-linked exempt from
The methods of epidemic disease absorption method (ELISA), mass spectrum.So as to, the horizontal reagent for detecting growth and differentiation factor 15 can be based on it is following
Reagent of the method in the expression of protein level detection GDF15：Radioimmunoassay, competitive binding method, Western
Footprinting assays, enzyme linked immunosorbent assay (ELISA) and/or mass spectrometry method.
More specifically, the present invention determines that GDF15 albumen most preferably prejudges concentration (cut- in one embodiment
Off) it is 1008pg/ml.The individual of baseline GDF15 protein levels >=1008pg/ml, relative to GDF15<Of 1008pg/ml
For body, the risk of starting cerebral apoplexy rises 3.7 times, and the risk of starting cerebral arterial thrombosis rises 10.8 times.
On the other hand, present invention also offers a kind of detection system for being used to assess the starting cerebral apoplexy risk of test individual
Unite (detection device), which includes：
Detection unit, the detection unit include the horizontal reagent of detection growth and differentiation factor 15；
Analytic unit, the analytic unit are used to analyze the testing result of detection unit, and assessment test individual is starting
Cerebral apoplexy risk.
Specific embodiment according to the present invention, it is of the invention to be used to assess the starting cerebral apoplexy risk of test individual
Detecting system, is according to the height of GDF15 levels in the sample from test individual, brain is suffered from first to assess the test individual
The height of the risk of palsy particularly cerebral arterial thrombosis.Wherein, the horizontal rises of GDF15 in the sample from test individual, should
The starting cerebral apoplexy of test individual particularly cerebral arterial thrombosis risk raises.
It is of the invention to be used to assess the starting cerebral apoplexy risk of test individual in the specific embodiment of the present invention
Detecting system in, carried out when the analytic unit carries out analysis and evaluation according to following operation (assessment principle)：
By the testing result GDF15 values (protein level) of detection unit compared with prejudging concentration；
It is more than or equal to the individual of anticipation concentration for baseline GDF15, the individual of anticipation concentration is less than relative to GDF15, its
Risk with higher starting cerebral apoplexy particularly cerebral arterial thrombosis.
For example, it is 1008pg/ml that the GDF15 albumen determined in a specific embodiment of the invention, which most preferably prejudges concentration,
Carried out when the analytic unit carries out analysis and evaluation according to following operation：
Judge detection unit testing result GDF15 values (protein level) whether >=1008pg/ml；
For the individual of baseline GDF15 >=1008pg/ml, relative to GDF15<1008pg/ml, it has higher starting
The risk of cerebral apoplexy particularly cerebral arterial thrombosis.More particularly, for the individual of baseline GDF15 >=1008pg/ml,
Relative to GDF15<1008pg/ml, the risk for assessing its starting cerebral apoplexy rise 3.7 times, the risk of starting cerebral arterial thrombosis
Rise 10.8 times.
The detecting system of the present invention for being used to assess the starting cerebral apoplexy risk of test individual, can virtually fill
Put, as long as the detection unit and the function of analytic unit can be realized.The detection unit can be include it is various
Detection reagent, kit or detecting instrument；The data analysis unit can be any inspection that can be realized to detection unit
Survey result to be analyzed and processed and draw computing instrument, module or the virtual unit of starting cerebral apoplexy risk situation, example
Such as can be that GDF15 values height is corresponded into individual starting cerebral apoplexy and/or starting ischemic brain according to above-mentioned assessment principle in advance
Palsy risk height is formulated to the data drawing list consulted easy to control, and the testing result GDF15 values of detection unit are compareed
The data drawing list can show that individual suffers from the risk height of cerebral apoplexy and/or cerebral arterial thrombosis first.
On the other hand, present invention also offers one kind assessment individual particularly starting cerebral apoplexy risk of hyperpietic
Method, this method includes：The level of individual (can be the sample from the test individual) growth and differentiation factor 15 of detection；According to
The height of individual GDF15 levels, to assess the height that the individual suffers from the risk of cerebral apoplexy particularly cerebral arterial thrombosis first.
Specific detection process is referred to any feasible method in fields and carries out, and can be detected in gene level or protein level
The expression of the growth and differentiation factor 15.It is special that the starting cerebral apoplexy of the individual is specifically assessed according to the height of GDF15 levels
It is the process of cerebral arterial thrombosis risk height, is referred to the progress of aforementioned evaluations principle.Wherein, individual GDF15 water
Flat rise, the starting cerebral apoplexy of the individual particularly cerebral arterial thrombosis risk raise.
In conclusion present invention demonstrates GDF15 can as a New Set of the starting cerebral apoplexy of prediction of hypertension patient,
Expression or expression by GDF15 in test individual sample, to judge that the risk of cerebral apoplexy occurs first for hyperpietic
New foundation is provided.
Brief description of the drawings
Fig. 1：Patients serum and the horizontal comparing results of blood plasma GDF15.
Fig. 2：The horizontal ROC curve analysis results of hyperpietic's Baseline plasma GDF15.
Fig. 3：Hyperpietic is divided into two groups (GDF15 >=1008pg/ml and GDF15 ＜ 1008pg/ml) according to ROC curve
The result of the further analysis starting palsy situation of patient afterwards.Wherein, picture A, overall cerebral apoplexy；Picture B, hemorrhagic apoplexy.
Embodiment
With reference to specific embodiment and attached drawing, the present invention is furture elucidated.It is to be understood that these embodiments are only exemplary
, any restrictions are not formed to the scope that is claimed of the present invention.The experiment side of actual conditions is not specified in the following example
Method, usually according to normal condition known to fields, or according to the condition proposed by manufacturer.
Embodiment
1st, study population
In March, 2010 to August, the high blood from Fu Wai cardiovascular diseases hospital of the Chinese Academy of Medical Sciences in Xinyang City, Henan Province
Community study base is pressed, is selected in 271 adult hyperpietics without palsy medical history.The diagnosis basis world health group of hypertension
Knit the standard of office hypertension, i.e., under the conditions of quiet, double Upper extremity blood pressures of different time measurement three times in 2 months, systolic pressure >=
140mmHg and/or diastolic pressure >=90mmHg；Or the past Definite Hypertension, taking antihypertensive drugs.Survey process includes：①
Questionnaire survey basic condition and medical history, smoking and the conventional risk factors situation such as drink；2. the double upper limb seat blood pressures of measurement；3. take out
Limosis vein blood sample；4. leave and take urine sample；5. measure height, weight, waistline, hip circumference；6. internal medicine auscultation and physical inspection；7. 12 lead
ECG examination；8. echocardiography.Each respondent is by by training and examining the investigator of qualification to apply
The scheme that standard mercury column sphygmomanometer is recommended according to American Heart Association measures 3 blood pressures, and according to the right upper arm of respondent
Enclose and select appropriate cuff (adult number, large size, extra large size).30min before blood pressure measurement, respondent cannot drink, smoking, drink
Coffee/tea carries out more violent activity, seat measurement blood pressure after at least 5min that rests.3 average blood pressures are taken as base
Line pressure value.Selected hyperpietic's ordinary circumstance is good, no stroke history, excludes cardiomyopathy, valve disease, congenital
Heart disease, gout and hepatic and kidney function obstacle person.All cases that present study is included all endorsed informed consent form, this research is
Obtain the approval of Ethics Committee of Fuwai Hospital.
2nd, clinical indices define
Diabetes are fasting blood-glucose >=7.0mmol/L, or have diabetes medical history person.Body mass index (BMI)=weight (kg)/
Height (m)2." once smoking " is defined as：Smoking ever since one's birth is more than 20 bags, or continues daily smoking at least one in 1 year；
" once drinking " is defined as：Drink lasting 1 year, averagely at least once a week.
3rd, blood sample collection
Every patient extracts limosis vein blood 8mL overnight (when empty stomach 12~14 is small), is respectively charged into containing 0.5M second two
The anticoagulant blood-collecting pipe of amine tetraacethyl dipotassium (EDTA-K2) and contain serum separation gel and promote solidifying heparin tube, head and the tail are reverse to be mixed, room temperature
Stand after ten minutes, centrifuge 10min, rotating speed 2000g/min.Blood plasma and serum are distributed into cryopreservation tube, -70 DEG C freeze.It is all
Blood specimen operation is completed after venous blood is in vitro in 30 minutes.
4th, main agents and material
All original materials and reagent are commercially available in following embodiments, and main agents and material are：
4.1 reagent：
(1) it is horizontal with enzyme-linked immunosorbent assay (ELISA) detection GDF15.GDF15 antibody and standard items are bought certainly
R＆D system companies.
(2) antibody is captured：In the anti-human GDF15 captures antibody (article No. of 360 μ g mouse：841832, R＆D system) in add
1mL PBS, are dissolved into 360 μ g/mL storage liquid.2~8 DEG C preserve 60 days, can be preserved 6 months for -20 DEG C or -70 DEG C after packing.It is real
When testing, liquid 1 will be stored with PBS:180 are diluted to working solution (2 μ g/mL of concentration).
(3) antibody is detected：Antibody (article No. is detected in the goat-anti people GDF15 of 9 μ g biotin labelings：841833, R＆D
System add 1mL reagent dilutions (referring to " preparation of 4.2 solution ") in), be formulated as 9 μ g/mL storage liquid.2~8 DEG C preserve 60
My god, it can be preserved 6 months for -20 DEG C or -70 DEG C after packing.During experiment, liquid 1 will be stored with PBS:180 are diluted to working solution (concentration
50ng/mL)。
(4) standard items：In 50ng recombined human GDF15 albumen (article No.s：841834, R＆D system) in add 0.5mL examination
Dilution agent liquid, is configured to 100ng/mL standard stock liquid.Gently rock at least 15min.- 70 DEG C can preserve 2 months.
(5) substrate working solution：Streptavidin-horseradish peroxidase (Streptavidin-HRP), just
It can be preserved 6 months for 2~8 DEG C after secondary use.Working solution is prepared with reagent dilutions.
4.2 solution are prepared：
(1)PBS：137mM NaCl, 2.7mM KCl, 8.1mM Na2HPO4, 1.5mM KH2PO4, pH7.2~7.4,0.2 μ
M membrane filtrations.
(2) cleaning solution：0.05% soil temperature 20 (Tween-20), PBS are prepared, pH7.2~7.4.
(3) reagent dilutions：1g bovine serum albumin(BSA)s (BSA) are dissolved in 1L PBS, concentration 1%, pH7.2~7.4.
0.2 μm of membrane filtration.
(4) terminate liquid：2N H2SO4。
4.3 key instruments and equipment：
(1) balance：Shanghai balance equipment, JA5003.
(2) low-temperature and high-speed centrifuge：German Eppendorf companies, 5804R.
(3) low temperature knockout plate centrifuge：German Eppendorf companies, 5402R.
(4) spectrophotometer：Beckman companies of the U.S., 640 types of DUR (U.S., California).
(5) ultrapure water purification installation：U.S. Bio-rad, CFB-320.
(6) microplate reader：Tecan companies of Switzerland, Infinite, M200Pro.
5th, it is horizontal to detect plasma/serum GDF15
5.1 96 orifice plates of pretreatment：
(1) it is pre-coated：Diluting stock solutions by capture antibody are working solution (2 μ g/mL), in 96 orifice plates per 100 μ of Kong Zhongjia
L, incubation at room temperature is overnight.
(2) clean：Liquid is discarded, is dried.400 μ L of board-washing liquid are added per hole, are soaked 1~2 minute, drying.Repeat board-washing 3
It is secondary.
(3) close：Add 300 μ L reagent dilutions per hole.Be incubated at room temperature 1 it is small when.
(4) clean：Repeat step 2, after the completion of cleaning, by 96 orifice plates be placed on 4 DEG C it is stand-by.
5.2 formal experiments：
(1) before experiment starts, from pre-coated 96 good holes from 4 DEG C of taking-ups, and each reagent is balanced to room temperature.
(2) it is loaded：If blank control wells, standard sample wells, sample to be tested hole.It is dilute that reagent is added in 2 blank control wells
Release 100 μ L of liquid.By standard stock liquid doubling dilutions, 7 concentration gradients are set, are followed successively by 1000pg/mL, 500pg/mL,
250pg/mL, 125pg/mL, 62.5pg/mL, 31.25pg/mL, 15.63pg/mL.Above-mentioned standard product dilution is sequentially added 7
A standard sample wells, 100 μ L are added per hole.100 μ L serum or blood plasma are added in sample to be tested hole.Each sample to be tested and standard items
Two parallel repetitions are respectively provided with, pays attention to that during sample-adding hole wall cannot be contacted, there cannot be bubble after sample-adding.Gently rock mixing, enzyme mark
Plate overlay film, be stored at room temperature 2 it is small when.
(3) liquid is discarded, is dried.400 μ L board-washing liquid are added per hole, are soaked 1~2 minute, drying.Repeat board-washing 3 times.
(4) 100 μ L detection antibody working solutions, overlay film, when incubation at room temperature 1 is small are added per hole.
(5) liquid in hole is discarded, is dried, 400 μ L board-washing liquid are added per hole, is soaked 1~2 minute, drying.Repeat board-washing 3
It is secondary.
(6) 100 μ L substrate working solutions, overlay film, the colour developing of room temperature lucifuge are added per hole.Develop the color situation in observation caliber hole, works as concentration
There is an obvious gradient blueness in highest 3~4 hole, rear 3~4 gradient pores still unobvious when, you can terminate.
(7) add 50 μ L terminate liquids per hole, terminate reaction, blueness immediately becomes yellow at this time.The addition sequence of terminate liquid should
It is identical with the addition sequence of substrate solution.
(8) immediately with optical density (OD value) of the microplate reader in each hole of 540nm wavelength measurements.Built by the OD values of standard items
Standard curve, calculates the GDF15 concentration of each sample to be tested.If it find that sample to be tested excessive concentration, be above standard curve
Scope, reply sample be diluted, detect again.
6th, follow-up and endpoints
From in August, 2010 in June, 2013, inventor carries out a follow-up every year to selected hyperpietic.Terminal
Event is starting palsy, and palsy includes Ischemic Stroke, intracerebral hemorrhage, subarachnoid hemorrhage.At the end of research, 254 trouble
Person completes follow-up, and 17 (6.3%) are lost to follow-up.17 patient baseline's data lost to follow-up are with being selected in 254 patients without significant difference.
7th, statistical analysis
Continuous variable is compared with one-way analysis of variance (parametric variable) or Kruskal-Wallis inspection (non-ginsengs
Number variable), classified variable uses Chi-square Test.By the way that by after GDF15 tertiles, the comparison of survival rate uses Kaplan-Meier
Curve, P values calculate and utilize log-rank methods.GDF15 uses multifactor COX regression analyses with starting palsy correlation analysis
Model, and to the age, gender, body mass index, have non-diabetic, whether there is hyperlipidemia, whether smoking, Hypertension stage, whether take
It is corrected with factors such as drug for hypertension, uric acid.Using the method progressively excluded, COX is returned to be divided COX regression analysis models
In analysis, the continuous variable for not meeting normal distribution carries out the conversion (body mass index, uric acid, GDF15) of natural logrithm.Draw
ROC (receiver operating characteristic) curve, examines GDF15 to predict the accuracy of starting palsy.Using
SPSS18.0 carries out statistical analysis, and all inspections are with P<0.05 is statistically significant for difference.
8th, experimental result
In baseline values, 30 patients are randomly selected, with the anticoagulant blood-collecting pipe of EDTAP dipotassium ethylene diamine tetraacetate (EDTA-K2)
Promote solidifying heparin tube with containing serum separation gel, collect the blood plasma and serum sample of same patient respectively.Examined with ELISA kit
It is horizontal to survey GDF15, the results showed that, same person serum is almost consistent with the concentration of GDF15 in blood plasma, does not have between the two
Distinguish (r2=0.98, P<0.001.Referring to Fig. 1).Follow-up study is analyzed using GDF15 blood plasma levels.
This research finally includes 254 hyperpietics, and patient age span was from 40 years old to 75 years old (average age:56.7
± 8.3 years old), masculinity proportion 37%.Baseline plasma GDF15 horizontal extents are 52pg/ml to 2869pg/ml, and median is
650pg/ml.By long term follow-up (follow-up time 3.0 ± 0.6 years), 22 starting palsys, including 12 ischemics occur altogether
Property palsy and 10 intracerebral hemorrhages.Cerebral arterial thrombosis, hemorrhagic apoplexy and the baseline without three groups of hyperpietics of cerebral apoplexy
Data is as shown in table 1, and three groups of patients are in age, systolic pressure, diabetes, uric acid and blood plasma GDF15 etc. significant difference.With
During visit, the baseline GDF15 blood plasma levels that cerebral apoplexy group occurs raise 50% (P than cerebral apoplexy group does not occur<0.001), prompt
Baseline GDF15 is horizontal significantly correlated with hyperpietic's first stroke.ROC curve analysis (Fig. 2) display, Baseline plasma
GDF15 can be very good the starting palsy of prediction of hypertension patient, and area under the curve is 0.73 (95%CI:0.62–0.83,P<
0.001), negative predictive value 95.3%, it is 1008pg/ml most preferably to prejudge concentration (cut-off).
The GDF15 being calculated according to ROC curve most preferably prejudges concentration, by hyperpietic be divided into two groups (GDF15 >=
1008pg/ml and GDF15 ＜ 1008pg/ml), analyze the starting palsy situation of patient.As a result referring to Fig. 3.Baseline GDF15 >=
The hyperpietic of 1008pg/ml, the risk of starting whole palsy rise 5 times of (HR:5.0,95%CI:2.1-11.8,P<
0.001), the risk of starting Ischemic Stroke rises 7.1 times of (HR:7.1,95%CI:2.1-23.4 P=0.001), it is starting go out
The risk of courageous and upright cerebral apoplexy is without significant difference.
Table 1：Hyperpietic's baseline clinical data
Note：Continuous variable is expressed as means standard deviation, and classified variable is expressed as case number or percentage.
Table 2 lists single factor test and multifactor COX Regression Analysis Results after GDF15 is layered by critical value.
Table 2：GDF15 is by single factor test and multifactor COX regression analyses after critical value layering
* multiplicity corrects age, gender, diabetes, hyperlipidemia, Hypertension stage, body mass index, smoking, anti-
Hypertension drug, uric acid
Relative to GDF15<1008pg/ml.
Abbreviation：CI=confidence interval (credibility interval)；GDF15=growth-differentiation
Factor 15 (growth and differentiation factor 15)；HR=hazard ratio (relative risk).
Shown by table 2COX regression analysis models, in correction age, gender, diabetes, hyperlipidemia, Hypertension stage, body
After weight index, smoking, drug for hypertension, a variety of conventional risk factors such as uric acid, baseline GDF15 >=1008pg/ml with it is starting
Palsy (HR:3.7,95%CI:1.4-9.9, P=0.008) and Ischemic Stroke (HR:10.8,95%CI:3.0-39.5,P<
0.001) still obvious related, Baseline plasma GDF15 levels are the independentpredictors of the starting cerebral apoplexy of hyperpietic.Baseline
Blood plasma GDF15 levels often raise 100pg/ml, and the risk of the starting cerebral apoplexy of hyperpietic raises 11% (P=0.01), starting
The risk of cerebral arterial thrombosis raises 18% (P=0.001).
Claims (8)
1. in preparation, for assessing, test individual is starting to be lacked the horizontal reagent of growth and differentiation factor 15 in detection serum or blood plasma
Application in the detection agent or detecting system of courageous and upright cerebral apoplexy risk, the level of the growth and differentiation factor 15 is growth point
Change the protein expression level of the factor 15.
2. application according to claim 1, wherein, the test individual is hyperpietic.
3. application according to claim 1, wherein, the horizontal rises of GDF15 in the sample from test individual, this to be measured
The starting cerebral arterial thrombosis risk rise of body.
4. application according to claim 3, wherein, the individual of baseline GDF15 protein levels >=1008pg/ml, relative to
GDF15<1008pg/ml, the risk of starting cerebral arterial thrombosis rise 10.8 times.
5. application according to claim 1, wherein, the horizontal reagent for detecting growth and differentiation factor 15 is based on lower section
Reagent of the method in the expression of protein level detection GDF15：Radioimmunoassay, competitive binding method, Western prints
Remember analytic approach, enzyme linked immunosorbent assay and/or mass spectrometry method.
6. a kind of detecting system for being used to assess the starting cerebral arterial thrombosis risk of test individual, the detecting system include：
Detection unit, the detection unit include the horizontal examination of growth and differentiation factor 15 in detection test individual serum or blood plasma
Agent；The test individual is hyperpietic；The level of the growth and differentiation factor 15 is the albumen table of growth and differentiation factor 15
Up to level；
Analytic unit, the analytic unit are used to analyze the testing result of detection unit, assess the starting ischemic of test individual
Property cerebral apoplexy risk.
7. detecting system according to claim 6, wherein, the analytic unit is according in the sample from test individual
The height of GDF15 levels, to assess the height that the test individual suffers from the risk of cerebral arterial thrombosis first.
8. detecting system according to claim 7, wherein, according to following operation when the analytic unit carries out analysis and evaluation
Carry out：
Judge detection unit testing result GDF15 protein levels whether >=1008pg/ml；
For the individual of baseline GDF15 >=1008pg/ml, relative to GDF15<1008pg/ml, assesses its starting ischemic cerebral apoplexy
In risk rise 10.8 times.
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