CN105002286B - The multiple mononucleotide polymorphism sites related to hypertension and/or cardiovascular disease incidence risk and related application - Google Patents
The multiple mononucleotide polymorphism sites related to hypertension and/or cardiovascular disease incidence risk and related application Download PDFInfo
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Abstract
The invention provides the multiple mononucleotide polymorphism sites related to hypertension and/or cardiovascular disease incidence risk and related application.Specifically, the invention provides a kind of application of reagent for detecting multiple mononucleotide polymorphism sites in preparing for the detection means of prediction of hypertension and/or cardiovascular disease incidence risk, additionally provide a kind of detection means for being used for prediction of hypertension and/or cardiovascular disease incidence risk, in the present invention, prediction of hypertension and cardiovascular disease incidence risk are detected by multiple SNPs, integrating influences 22 related mononucleotide polymorphism sites of asian population Variation of Blood Pressure, Genotyping is carried out in 26262 research objects, and follow-up investigation is carried out to research object, in the model of conventional risk factors, add genetic risk scoring GRS, it can improve to hypertension and the predictive ability of risk of cardiovascular diseases.
Description
Technical field
The present invention relates to the multiple mononucleotide polymorphism sites related to hypertension and/or cardiovascular disease incidence risk
And related application, and in particular to detect the reagents of multiple mononucleotide polymorphism sites preparing for prediction of hypertension and/or
Application in the detection means of cardiovascular disease incidence risk, further relate to one kind and be used for prediction of hypertension and/or angiocardiopathy
The detection means of onset risk, detected in advance by influenceing 22 related mononucleotide polymorphism sites of asian population Variation of Blood Pressure
Survey hypertension and cardiovascular disease incidence risk.
Background technology
Angiocardiopathy is the primary Disease Spectrum of global human health.The morbidity and mortality of China's cardiovascular disease are in
Rapid increase trend.It is estimated that China's cardiovascular disease number of patients at least 2.3 hundred million, about 3,500,000 people die from angiocarpy every year
Disease.Hypertension is one of most common angiocardiopathy, and the Major Risk Factors of cardiovascular disease.China is cardiovascular within 2013
Disease report display, the generation of about 70% cerebral apoplexy and 50% myocardial infarction is relevant with blood pressure rise, at least half of painstaking effort
Pipe die of illness die it is relevant with hypertension.According to all previous national extensive Prevalence of Hypertension investigation, from the sixties in last century five
To 2007-2009, Prevalence of Hypertension rises to 26.6% by 5.1%, and ascendant trend is obvious, it has also become the important disease in China
Disease burden.Therefore, the preventing and treating of hypertension has become prevention of cardiovascular disease, ensures the important need of national health.
Hypertension and angiocardiopathy are complex diseases, are interacted for a long time institute by multiple minor genes and environmental factor
Cause.The tumor susceptibility gene and/or Disease-causing gene related to hypertension and/or blood pressure rise are identified, the screening increase disease in crowd
The tumor susceptibility gene of sick risk determines susceptible individual, it will help hypertension and cardiovascular disease event (coronary heart disease and cerebral apoplexy)
Onset risk prediction, new drug development, diagnosis and individualized treatment.
Genetic risk scoring (genetic risk score, GRS) is to establish Personal wind based on inheritance susceptible gene
The prediction Rating Model of danger, carrying out model prediction using individual inheritance risk score combination conventional risk factors in individual level is
Identify hypertension and the effective ways of cardiovascular disease incidence people at highest risk.EARLY RECOGNITION people at highest risk, takes and targetedly gives birth to
Mode living is intervened, and can efficiently reduce the generation of hypertension and angiocardiopathy, and containment medical expense increases, extends the national phase
Hope the life-span.
The content of the invention
It is an object of the present invention to provide one kind by multiple SNPs detect prediction of hypertension and/or
The method of cardiovascular disease incidence risk.
Another object of the present invention is to provide the reagent for detecting multiple mononucleotide polymorphism sites in preparation for pre-
The application surveyed in the detection means of hypertension and/or cardiovascular disease incidence risk.
Another object of the present invention is to provide a kind of inspection for prediction of hypertension and/or cardiovascular disease incidence risk
Survey device.
In the present invention, the related multiple mononucleotide polymorphism sites of asian population Variation of Blood Pressure are influenceed by integrating,
Genotyping is carried out in the research object of great amount of samples, and follow-up investigation for many years is carried out to research object, calculates genetic risk
Score (GRS).In the model of conventional risk factors, genetic risk scoring is added, is improved to hypertension and cardiovascular event wind
The predictive ability of danger.
According to specific embodiments of the present invention, related multiple mononucleotide polymorphics of the asian population Variation of Blood Pressure
Property site includes following 22 mononucleotide polymorphism sites：The rs10745332 in CASZ1 regions rs880315, MOV10 region
With rs17030613, FIGN region rs16849225, SLC4A7 region rs820430, ULK4 region rs9815354, CACNA1D
Region rs9810888, FGF5 region rs1902859, ENPEP region rs6825911, GUCY1A3 region rs13143871, NPR3
Region rs1173766, HFE region rs1799945, HLA-B region rs9266359, CYP21A2 region rs2021783,
CYP17A1 regions rs4409766, SOX6 region rs4757391, ATP2B1 region rs17249754, ALDH2 region
Rs11066280, TBX3-TBX5 region rs1991391, TBX3 region rs35444, MED13L region rs11067763 and JAG1
Region rs1887320.By detecting these mononucleotide polymorphism sites, can be sent out with prediction of hypertension and/or angiocardiopathy
Sick risk.
So as to, on the one hand, the invention provides the reagent for detecting multiple mononucleotide polymorphism sites to prepare for pre-
The application surveyed in the detection means of hypertension and/or cardiovascular disease incidence risk, wherein, the multiple SNP
Site includes following 22 mononucleotide polymorphism sites：
The rs10745332 in CASZ1 regions rs880315, MOV10 region and rs17030613, FIGN region
Rs16849225, SLC4A7 region rs820430, ULK4 region rs9815354, CACNA1D region rs9810888, FGF5 region
Rs1902859, ENPEP region rs6825911, GUCY1A3 region rs13143871, NPR3 region rs1173766, HFE region
Rs1799945, HLA-B region rs9266359, CYP21A2 region rs2021783, CYP17A1 region rs4409766, SOX6 area
Domain rs4757391, ATP2B1 region rs17249754, ALDH2 region rs11066280, TBX3-TBX5 region rs1991391,
TBX3 regions rs35444, MED13L region rs11067763 and JAG1 regions rs1887320.
The present invention abundant experimental results on the basis of, it is of the invention further study show that, these SNPs danger etc.
Position gene be respectively：Rs880315 pleomorphism sites are C；Rs17030613 pleomorphism sites are C；Rs10745332 polymorphic positions
Point is A；Rs16849225 pleomorphism sites are C；Rs820430 pleomorphism sites are A；Rs9815354 pleomorphism sites are A；
Rs9810888 pleomorphism sites are G；Rs1902859 pleomorphism sites are C；Rs6825911 pleomorphism sites are C；
Rs13143871 pleomorphism sites are T；Rs1173766 pleomorphism sites are C；Rs1799945 pleomorphism sites are G；
Rs9266359 pleomorphism sites are C；Rs2021783 pleomorphism sites are C；Rs4409766 pleomorphism sites are T；
Rs4757391 pleomorphism sites are C；Rs17249754 pleomorphism sites are G；S11066280 pleomorphism sites are T；
Rs1991391 pleomorphism sites are G；Rs35444 pleomorphism sites are A；Rs11067763 pleomorphism sites are A；rs1887320
Pleomorphism site is A.
Possible technique any in this area can be used to detect multiple monokaryon glycosides of the present invention in DNA level, rna level
Sour pleomorphism site.Such as：The method that direct Sequencing can be used, crt gene can be directly disclosed by DNA direct Sequencings
And the sequence difference between mutator is carried, can be specifically traditional use business sequencing kit or automatic sequencer pair
DNA is directly sequenced, or develop in recent years pyrosequencing (Pyrosequencing), micro sequence (SNaPshot)
Deng.The method based on hybridization can also be used, specifically includes Taqman sonde methods, DNA chip method etc..It can also use and be based on drawing
The method of thing extension, such as Matrix Assisted Laser Desorption ion flight time mass spectrum (MALDI-Tof-MS).It can also use and be based on
The method of conformation, specifically for example RFLP (RFLP) analysis, single-strand conformation polymorphism (single-
Strand conformational polymorphism, SSCP) analyze, denaturing gradient gel electrophoresis (denaturing
Gradient gel electrophoresis, DGGE) analyze, Denaturing high performance liquid chromatography (denaturing high
Performance liquid chromatography, dHPLC) etc. analytical technology.High-resolution solubility curve can also be used
Analytical technology (HRM).In the specific implementation, those skilled in the art can select above-mentioned any skill according to actual conditions
Art vitro detection multiple mononucleotide polymorphism sites of the present invention, can also be using the combination of multiple technologies come vitro detection
The multiple mononucleotide polymorphism site.The reagent of the heretofore described multiple mononucleotide polymorphism sites of detection can be with
It is reagent material and/or instrument used in these any feasible technologies for detecting the multiple mononucleotide polymorphism sites
Device equipment etc..In the specific embodiment of the present invention, application is iPLEX Sequenom MassARRAY partings system
System detects to the multiple mononucleotide polymorphism site, wherein the extension products MassARRAY after PCR is expanded
Nanodispenser RS1000 point sample instruments (Sequenom) are moved on SpectroCHIP (Sequenom) chip, are used
MALDI-TOP (matrix-assisted laser desorption/ionization-time of fligh, Matrix-assisted
Flight time mass spectrum) analysis, and use the softwares of TYPER 4.0 (Sequnom) parting and output result.
According to specific embodiments of the present invention, described test individual can be asian population, preferably Chinese Han nationality
Crowd.During specific detection, testing sample may be from blood, urine, saliva, gastric juice, hair or the biopsy of test individual.
In specific embodiments of the present invention, the present invention chooses 26262 normal populations in Chinese han population and ground
Study carefully object, follwing-up in average is observed 6.9 years, is gathered fasting blood and is collected sex, age, blood pressure level, blood lipid level, height, body
Weight, smoking, drink and the relevant information such as history of disease.Using iPLEX Sequenom MassARRAY classification systems, to 22 blood
Press related SNP (SNP) site carry out Genotyping experiment (CASZ1 regions rs880315, MOV10 region
Rs10745332 and rs17030613, FIGN region rs16849225, SLC4A7 region rs820430, ULK4 region
Rs9815354, CACNA1D region rs9810888, FGF5 region rs1902859, ENPEP region rs6825911, GUCY1A3 area
Domain rs13143871, NPR3 region rs1173766, HFE region rs1799945, HLA-B region rs9266359, CYP21A2 area
Domain rs2021783, CYP17A1 region rs4409766, SOX6 region rs4757391, ATP2B1 region rs17249754, ALDH2
Region rs11066280, TBX3-TBX5 region rs1991391, TBX3 region rs35444, MED13L region rs11067763 and
JAG1 region rs1887320).Increased using each SNP site of logistic and cox regression analyses assessment with annual blood pressure,
The relation of (coronary heart disease and cerebral apoplexy) occurs for hypertension incidence and cardiovascular disease event, calculates the effect value of dangerous allele
(β), relative risk (Odds ratio, OR) or Hazard ratio (Hazard ratio, HR).Comprehensive each individual carries 22
The dangerous allele situation of SNP site, genetic risk scoring is carried out to each research object, and methods of marking is to utilize blood early stage
The risk allele effect value (β) for pressing full-length genome research to obtain.By research object carry the number of dangerous allele with
Dangerous allele effect value (β), which is multiplied, obtains each SNP site hereditary effect.Then 22 SNP hereditary effect is summed
Obtain the genetic risk scoring (GRS) of the research object, calculation formula：Genetic risk scoring (GRS)=∑ βi×Ni, wherein βi
Refer to i-th SNP systolic pressure and the average value of diastolic pressure effect value, NiRefer to the dangerous equipotential of i-th of SNP entrained by research object
Number gene.Using genetic risk scoring as continuous variable, the standard deviation (SD) that genetic risk scores is calculated.Meanwhile according to
Research object is divided into 5 groups by all research object genetic risk scorings.Respectively the 1st group 7.765~13.465 (G1), the 2nd
13.466~14.616 (G2) of group, the 3rd group 14.617~15.545 (G3), the 4th group 15.545~16.654 (G4) and the 5th group
16.655~22.125 (G5).Compared with genetic risk scores minimum 1 group, the height of other each group onset risks is calculated.Knot
Fruit shows that genetic risk scoring is the independent hazard factor that blood pressure rise, hypertension and cardiovascular event occur.
In specific embodiments of the present invention, the present invention further established the morbidity wind of hypertension and angiocardiopathy
Dangerous forecast model.Hypertension forecast model, which includes genotype information (genetic risk scoring packet) and conventional risk factors, to be included
Sex, age, body mass index, smoking, drink, pulse, systolic pressure and diastolic pressure.In cardiovascular disease incidence risk forecast model
Include sex, age, body mass index, smoking, drink including genotype information (genetic risk scoring packet) and conventional risk factors
Wine situation, diabetes, T-CHOL, HDL-C, angiocardiopathy family history, systolic pressure and take depressor
Situation.Summary h and E factor establishes hypertension and cardiovascular disease incidence risk forecast model：
Hypertension incidence risk=1/ (1+exp (- Z)).Z=-14.808+0.142 × G2+0.193 × G3+0.265 ×
G4+0.339 × G5+0.165 × sex+0.034 × age+0.063 × body mass index+(- 0.013) × whether smoking+0.159
×+0.01 × pulse+0.061 × systolic pressure+0.04 × diastolic pressure of whether drinking.Wherein, sex：Man=1, female=0；Whether inhale
Cigarette：Smoking=1, non-smoking=0；Whether drink：Drink=1, no drinking=0；Pulse item：Beat/min；Systolic pressure：mmHg；Diastole
Pressure：mmHg.
Cardiovascular disease incidence risk=1/ (1+exp (- Z)).Z=-8.558+0.126 × G2+0.159 × G3+0.297
× G4+0.256 × G5+ (- 0.273) × sex+0.056 × age+0.035 × body mass index+0.19 × whether smoking+(-
0.475) whether × drink+0.358 × has non-diabetic+0.006 × T-CHOL+(- 0.028) × HDL courage to consolidate
Whether alcohol+0.643 × whether having+0.015 × systolic pressure of angiocardiopathy family history+0.309 × takes depressor.Wherein, property
Not：Man=1, female=0；Whether smoking：Smoking=1, non-smoking=0；Whether drink：Drink=1, no drinking=0；There is aglycosuria
Disease：Have=1, without=0；T-CHOL：mg/dl；HDL-C：mg/dl；Whether cardiovascular disease family history is had：
Have=1, without=0；Systolic pressure：mmHg；Whether depressor is taken：It is=1, no=0.
In above-mentioned model, G2, G3, G4, G5 be it is foregoing according to research object genetic risk score packet, the 1st group 7.765
~13.465 (G1), the 2nd group 13.466~14.616 (G2), the 3rd group 14.617~15.545 (G3), the 4th group 15.545~
16.654 (G4) and the 5th group 16.655~22.125 (G5).When the scoring of test individual genetic risk, to fall into G2, G3, G4, G5 any
During group, its corresponding group G value is 1, and remaining value is 0.For example, when the scoring of test individual genetic risk falls into G2 groups, G2 takes
It is worth for 1, the equal value 0 of G3, G4, G5 (when the scoring of test individual genetic risk factors falls into G1 groups, the equal value 0 of G2, G3, G4, G5).
In specific embodiments of the present invention, the present invention puts genetic risk scoring packet and environmental factor exposure information
Enter risk forecast model and calculate the hypertension of every research object and the onset risk of angiocardiopathy.Using making subject's work
Make indicatrix (ROC) and models fitting curve (Calibration) assesses hypertension and the prediction of angiocardiopathy occurrence risk
Model.The value of the Forecasting Methodology is evaluated according to area under ROC curve.As a result show, what hypertension and angiocardiopathy occurred
Area is respectively 0.776 and 0.813 under ROC, shows that the model prediction is functional, can be very good to identify people at highest risk.
Models fitting curve shows that the predicted value of hypertension and cardiovascular event occurrence risk and observed value are distinguished without significant difference, P values
It is good for 0.882 and 0.24, models fitting.
So as to which on the other hand, present invention also offers one kind to be used for prediction of hypertension and/or cardiovascular disease incidence risk
Detection means, the detection means includes detection unit and data analysis unit；
The detection unit includes being used to detect the dangerous equipotential that test individual carries multiple mononucleotide polymorphism sites
The detection unit (may include to detect reagent material used and/or instrument and equipment etc.) of genetic profile, obtain testing result；Its
In, the multiple mononucleotide polymorphism site includes following 22 mononucleotide polymorphism sites：CASZ1 regions
The rs10745332 in rs880315, MOV10 region and rs17030613, FIGN region rs16849225, SLC4A7 region
Rs820430, ULK4 region rs9815354, CACNA1D region rs9810888, FGF5 region rs1902859, ENPEP region
Rs6825911, GUCY1A3 region rs13143871, NPR3 region rs1173766, HFE region rs1799945, HLA-B region
Rs9266359, CYP21A2 region rs2021783, CYP17A1 region rs4409766, SOX6 region rs4757391, ATP2B1
Region rs17249754, ALDH2 region rs11066280, TBX3-TBX5 region rs1991391, TBX3 region rs35444,
MED13L regions rs11067763 and JAG1 regions rs1887320；
The data analysis unit includes being used for the processing unit for analyzing and processing the testing result of detection unit, obtains
Obtain genetic risk scoring；Wherein, the height of genetic risk scoring suffers from hypertension and/or cardiovascular disease incidence wind with test individual
The height of danger is into positive correlation.
According to specific embodiments of the present invention, of the invention is used for prediction of hypertension and/or cardiovascular disease incidence wind
The detection means of danger, wherein：
Detection unit that the detection unit also includes being used for detecting test individual conventional risk factors (including detection
Reagent material and/or instrument and equipment etc.)；Wherein, hypertension correlation conventional risk factors include sex, age, body mass index, suction
Cigarette, drink, pulse, systolic pressure and diastolic pressure；Angiocardiopathy correlation conventional risk factors include sex, age, body mass index,
Smoking, Alcohol Consumption Status, diabetes, T-CHOL, HDL-C, angiocardiopathy family history, systolic pressure kimonos
With depressor situation；
The data analysis unit also includes being used to carry out at analysis the conventional risk factors testing result of detection unit
The processing unit of reason, obtain the hypertension and/or cardiovascular disease incidence wind of complex inheritance risk score and conventional risk factors
Danger prediction scoring.
The detection means of the present invention for being used for prediction of hypertension and/or cardiovascular disease incidence risk, can be empty
Intend device, as long as the function of the detection unit and data analysis unit can be realized.Described detection unit can be
Including various detection reagent materials and/or detecting instrument equipment etc.；Described data analysis unit can any can be realized
The testing result of detection unit is analyzed and processed and draws test individual genetic risk scoring (or complex inheritance risk score
With the result of conventional risk factors) computing instrument, module or virtual unit, such as can be in advance according to above-mentioned hereditary wind
Danger scoring formula and the data drawing list formulated, the testing result of detection unit is compareed into the data drawing list can draw genetic risk
Score value.
According to specific embodiments of the present invention, of the invention is used for prediction of hypertension and/or cardiovascular disease incidence wind
The detection means of danger, wherein, hypertension and/or the angiocardiopathy hair of the complex inheritance risk score and conventional risk factors
Sick risk profile scoring meets according to the numerical value being calculated with drag：
Hypertension incidence risk forecast model：
Hypertension incidence risk=1/ (1+exp (- Z)).Z=-14.808+0.142 × G2+0.193 × G3+0.265 ×
G4+0.339 × G5+0.165 × sex+0.034 × age+0.063 × body mass index+(- 0.013) × whether smoking+0.159
×+0.01 × pulse+0.061 × systolic pressure+0.04 × diastolic pressure of whether drinking.Wherein, sex：Man=1, female=0；Whether inhale
Cigarette：Smoking=1, non-smoking=0；Whether drink：Drink=1, no drinking=0；Pulse：Beat/min；Systolic pressure：mmHg；Diastole
Pressure：mmHg.
Cardiovascular disease incidence risk forecast model：
Cardiovascular disease incidence risk=1/ (1+exp (- Z)).Z=-8.558+0.126 × G2+0.159 × G3+0.297
× G4+0.256 × G5+ (- 0.273) × sex+0.056 × age+0.035 × body mass index+0.19 × whether smoking+(-
0.475) whether × drink+0.358 × has non-diabetic+0.006 × T-CHOL+(- 0.028) × HDL courage to consolidate
Whether alcohol+0.643 × whether having+0.015 × systolic pressure of angiocardiopathy family history+0.309 × takes depressor.Wherein, property
Not：Man=1, female=0；Whether smoking：Smoking=1, non-smoking=0；Whether drink：Drink=1, no drinking=0；There is aglycosuria
Disease：Have=1, without=0；T-CHOL：mg/dl；HDL-C：mg/dl；Whether cardiovascular disease family history is had：
Have=1, without=0；Systolic pressure：mmHg；Whether depressor is taken：It is=1, no=0.
G2, G3, G4, G5 value are with reference to foregoing in above-mentioned model.
Using the technology of the present invention, calculated according to model and obtain the research object hypertension and/or cardiovascular event generation
Risk, it can be determined that whether the research object is people at highest risk.The report of individuation health guidance is completed, reports hypertension and the heart
The height of vascular diseases event occurrence risk.The report of individuation health guidance is on the basis of genotype results, with reference to life
The risk that mode hazard factor assessment research object hypertension and cardiovascular disease event occur, and make for research object
Individuation health action scheme.It can be seen that technology of the invention has in the prediction and prevention of hypertension and/or angiocardiopathy
Important application prospect.
Brief description of the drawings
Fig. 1-Fig. 9：rs4757391、rs9810888、rs1902859、rs4409766、rs10745332、
Rs17249754, rs 880315, rs 9815354 and rs11066280 genotypic results scatter diagram (each 2 piece of 384 plate).
Figure 10：Genetic risk scoring packet and environmental factor exposure information prediction hypertension and cardiovascular disease onset risk
ROC curve.
Figure 11：Genetic risk scoring packet and environmental factor exposure information prediction hypertension and cardiovascular disease onset risk
Models fitting curve.
Figure 12：Blood pressure related locus danger allele hereditary effect checks chart quickly.
Figure 13：Genetic risk scoring quick checking chart.
Embodiment
In order to be more clearly understood that the present invention, the present invention is further described referring now to the following example and accompanying drawing.Embodiment
It is only used for explaining without limiting the invention in any way.The experimental method of unreceipted actual conditions is art in embodiment
Well known conventional method and normal condition, or according to the condition proposed by manufacturer.
The foundation of the onset risk forecast model of embodiment one, hypertension and angiocardiopathy
First, case-control sample inclusion criteria
Normal population research object is chosen first in Chinese han population, during research object comes from Chinese cardiovascular disease more
Heart cooperating research (InterAsia in China) and Chinese cardiovascular health study multiple northern research centers, research approach warp
Each investigation center locality Ethics Committee of research institution approval, all participants endorsed informed consent form.It is Chinese cardiovascular
Sick multicenter cooperating research has carried out follow-up in 2008 in 2000-2001.Chinese cardiovascular health research is 2006-
Institute an inquiry within 2007,2013-2014 has carried out follow-up.Follwing-up in average observe 6.9 years, gather fasting blood and collect sex,
Age, blood pressure level, blood lipid level, height, body weight, smoking, drink and the relevant information such as history of disease.
Blood pressure measuring method：Research object blood pressure recommends blood pressure by training qualified investigator according to American Society of Cardiology
Measurement standard measures three times.Sat quietly before blood pressure measurement 5 minutes；And avoid drinking in 30 minutes before blood pressure measurement, smoking, drink
Coffee or tea beverage and physical exertion.Patient for taking antihypertensive drugs, blood pressure are each by systolic pressure, diastolic pressure gauger respectively
Increase by 10 and 5mmHg to calculate.Hypertension is defined as：Systolic pressure >=140mm Hg and/or diastolic pressure DBP >=90mm Hg or self
Depressor is taken in report for the purpose for the treatment of hypertension.Normal arterial pressure is defined as not taking any depressor, and systolic pressure<
140mm Hg while diastolic pressure<90mm Hg.
Smoking is defined as：Whether number of smoking (is 1/ no 0) more than 100 in life.
Drink and be defined as：It (is 1/ no 0) that past 1 year, which examined whether more than 12 times,.
Diabetes are defined as：Hospital clinical diagnosis (has 1/ without 0).
Body mass index (BMI) calculation formula：Body mass index (kg/m2)=body weight (kg)/height (m)2
Follow-up period：Cardiovascular endpoints event is defined as occurring myocardial infarction, angina pectoris, revascularization, palsy and dead
Die and be attributed to coronary artery disease and palsy.Follow-up content is entered with including follow-up investigation object and its guardian's current resident
Investigate to determine the important informations such as morbid state at family.If respondent has in hospital or emergency treatment attention during being reported in follow-up,
Trained investigator uses standard survey table, extracts its medical history, physical examination result, laboratory examination results by questionnaire and goes out
The information such as institute's diagnosis.Death report during all follow-ups from local hygiene department or public security organ all by obtaining death certificate
Examined.It is made up of the cardiologist in the Chinese Academy of Medical Sciences (Beijing), neurologist and clinical epidemiology man
The end-point assessment committee is dead to determine to investigate endpoints or last diagnostic by looking back all hospital records and death certificate
Reason.Cardiovascular endpoints event by two committeemans independent clinical diagnosis, as diagnostic result is different, then by more entrusting
Member can member's discussion determination.
In the present invention, analysis, which have chosen Follow-up Data and inherent cause scoring, the participant of partial data, and excludes
Cardiovascular disease event individual occurs for baseline period, and totally 26262 individuals include analysis (table 1), 378 coronary diseases during follow-up
Disease and 749 cerebral apoplexies occur, altogether 1078 cardiovascular disease events.7724 baseline blood pressures are normal and have follow-up blood pressure data
Respondent include blood pressure rise and hypertension occur analysis.
The essential characteristic of the study population of table 1.
| Total sample size | 26262 |
| Male/female (% male) | 11736/14526(44.69) |
| Age (standard deviation) | 50.86(8.92) |
| BMI(kg/m2) (standard deviation) | 24.24(3.65) |
| Systolic pressure (SBP, mmHg) (standard deviation) | 130.69(22.78) |
| Diastolic pressure (DBP, mmHg) (standard deviation) | 81.68(12.57) |
| Prevalence of Hypertension (%) | 37.79 |
| T-CHOL (TC, mmol/l) (standard deviation) | 4.71(0.97) |
| High density matter protein cholesterol (HDL, mmol/l) (standard deviation) | 1.35(0.40) |
| Triglyceride (TG, mmol/l) (standard deviation) | 1.60(1.20) |
| Drink (%) | 20.99 |
| Smoking (%) | 31.02 |
| Angiocardiopathy family history (%) | 9.69 |
2nd, SNP selections, Genotyping
In the present invention, have selected in East Asia crowd and Chinese population genome-wide association study with systolic pressure or diastole
22 related SNP (SNP) sites are pressed, gene is carried out using iPLEX Sequenom Mass ARRAY platforms
Parting.22 SNP are：The rs10745332 in CASZ1 regions rs880315, MOV10 region and rs17030613, FIGN area
Domain rs16849225, SLC4A7 region rs820430, ULK4 region rs9815354, CACNA1D region rs9810888, FGF5 area
Domain rs1902859, ENPEP region rs6825911, GUCY1A3 region rs13143871, NPR3 region rs1173766, HFE area
Domain rs1799945, HLA-B region rs9266359, CYP21A2 region rs2021783, CYP17A1 region rs4409766, SOX6
Region rs4757391, ATP2B1 region rs17249754, ALDH2 region rs11066280, TBX3-TBX5 region
Rs1991391, TBX3 region rs35444, MED13L region rs11067763 and JAG1 regions rs1887320.
Genotyping application iPLEX Sequenom MassARRAY classification systems (Complete i Gold
Genotyping Reagent Set 384；Sequenom；Cat No.10148-2) complete.Its principle is：SNP positions will be included
The DNA technique amplification in point region, using MassARRAY iPLEX Single base extension technologies, special extension primer and PCR are produced
Thing carries out single base extension.The different terminal bases of extension products will cause the poor polymorphism of the molecular weight of product after extending
Caused base difference is embodied by the difference of molecular weight, passes through substance assistant laser desorpted detection extension products molecular weight
Size, the analysis software of application specific, lead to the detection of SNP partings.
The specific experiment step of Genotyping：
1) treated using Sequenom companies Genotyping Tools and MassARRAY Assay Design Software for Design
Survey the pcr amplification primer thing and Single base extension primer of SNP site.
2) subject's peripheral blood is gathered, extracts DNA sample, and DNA concentration is adjusted to 55 μ g/ μ l (± 5 μ g/ μ l).
3) PCR reacts：
Instrument：Gene Amp PCR System 9700 (Dural 384), Amplied Biosystems
Reaction system (5/ μ l)：
PCR conditions：
4) PCR primer alkaline phosphatase treatment：After PCR reactions terminate, by PCR primer SAP (shrimp
Alkaline phosphatase, shrimp alkaline phosphotase) processing, with remove system middle reaches from dNTPs.
Reaction system：
Reaction condition：37℃40min；85℃5min；4℃∞.
5) Single base extension
By the μ l of single base extension liquid 2, add 4) corresponding in 384 holes, in being reacted as follows in PCR instrument：
Single base extension liquid matches (2 μ l)：
6) purifying resin
By the tiling of Clean Resin resins into 6mg resin plate, add 16 μ l water in the corresponding aperture of extension products；Will
Dried resin is poured into extension products plate, sealer；Slow speed vertical rotation 30 answers thing fully to contact；Centrifugation makes resin sink to hole
Bottom.
7) chip point sample
Start MassARRAY Nanodispenser RS1000 point sample instruments (Sequenom), by the extension after purifying resin
Product is moved on 384 hole SpectroCHIP (Sequenom) chips.
8) Mass Spectrometer Method
SpectroCHIP chips after point sample are used into MALDI-TOP (matrix-assisted laser
Desorption/ionization-time of fligh, Matrix-assisted flight time mass spectrum) analysis, testing result use
The softwares of TYPER 4.0 (Sequnom) parting and output result.
9) genotyping result
Fig. 1 to Fig. 9 be respectively rs4757391, rs9810888, rs1902859, rs4409766, rs10745332,
Rs17249754, rs 880315, rs 9815354 and rs11066280 genotypic results scatter diagram (each 2 piece of 384 plate).
3rd, genetic risk scores
22 SNP cumulative effect is evaluated using the genetic risk scoring (GRS) of blood pressure, according to genome-wide association study
As a result, it is determined that for evaluating each SNP to systolic pressure (SBP) and the average effect size of diastolic pressure (DBP) (β weight coefficients).
22 site informations are shown in Table 2.The dangerous number of alleles in the site is multiplied by with each SNP β weight coefficients and by results added,
Calculate genetic risk scoring (GRS), calculation formula：Genetic risk scoring=∑ βi×Ni, wherein βiRefer to i-th of SNP systolic pressure
With the average value of diastolic pressure effect value, NiRefer to the dangerous allele number of i-th of SNP entrained by research object.By hereditary wind
Danger scoring is as continuous variable or carries out 5 points of position packets, the relation that analysis occurs with hypertension and cardiovascular disease event.
Application of Statistic Methods Logistic return and the single SNPs of Cox Proportional hazards regression analyses and they form
GRS increases with blood pressure, hypertension occur and cardiovascular disease event occur correlation, and in a model correction tradition it is dangerous because
Element.Compare the C indexes (C-indice) in GRS model is whether there is, scored with evaluation using genetic risk to hypertension and the heart
The improvement of vascular events occurrence risk prediction.Hypertension and cardiovascular disease are assessed using models fitting curve (Calibration)
Whether sick occurrence risk forecast model fitting is good.
The related site of 2. 22 blood pressures of table and its effect
* the hypertension genome-wide association study (Nat that effect value is carried out from East Asia crowd and Chinese population
Genet.2011；43:531-538,Hum Mol Genet.2015；24:865-874).
22 blood pressure sites in addition to rs6825911, it is annual raise the-0.11mm Hg of systolic pressure 0.01 and diastolic pressure 0.004-
0.07mm Hg.Wherein generation (the P=6.06 10 of 20 SNPs increase hypertension and cardiovascular disease event-5) (table 3).6
SNP (rs17030613, rs10745332, rs9810888, rs1902859, rs11066280, rs35444 and blood pressure or
Hypertension incidence correlation reaches the level of signifiance (P<0.05).5 SNP (rs880315, rs820430, rs13143871,
Rs11066280 and rs1887320) with cardiovascular disease event occur correlation reach the level of signifiance (P<0.05).
The influence that blood pressure, hypertension and cardiovascular disease event occur in the site of table 3. 22
From the above, it is seen that the effect of single genetic locus is relatively weak, the present invention incorporates the accumulation in 22 sites
Effect, the predictive ability of inherent cause can be dramatically increased.The period in arithmetric of research object 5 is divided into 5 according to genetic risk score value
Group, respectively the 1st group 7.765~13.465 (G1), the 2nd group 13.47~14.616 (G2), the 3rd group 14.62~15.545
(G3), the 4th group 15.545~16.654 (G4) and the 5th group 16.655~22.125 (G5).Minimum 1 group with genetic risk scoring
Compare, calculate the height of other each group onset risks.With the increase of genetic risk scoring score value, systolic pressure and diastolic pressure level
Also dramatically increase.(being shown in Table 4).Genetic risk scoring score value each group hypertension cumulative life-incidence from low to high is respectively
29.4%th, 31.6%, 32.4%, 36.2% and 36.8%.Sex, age, body mass index are added in a model, smoking, are drunk
Situation, pulse, systolic pressure and diastolic pressure, compared with genetic risk scores minimum packet individual, be in second and third, four and the
Risk of hypertension occurs for five five period in arithmetrics packet individuals increases by 15%, 21%, 30%, and 40% (trend test P=respectively
3.82×10-5).Genetic risk scoring from low to high each group angiocardiopathy cumulative life-incidence be respectively 3.1%, 3.5%,
3.7%th, 4.2% and 4.4%.Sex, age, body mass index are added in a model, and smoking, Alcohol Consumption Status, diabetes, total courage are consolidated
Alcohol, HDL-C, cardiovascular disease family history, systolic pressure and depressor situation is taken, with genetic risk scoring most
Low packet individual is compared, be in second and third, four and the 5th five period in arithmetrics packet individual cardiovascular disease event occurs
Risk increases by 11%, 15%, 32% and 26% (trend test P=4.57 × 10 respectively-3).The display heredity of the studies above result
Risk score is the independent hazard factor that blood pressure rise, hypertension and cardiovascular disease event occur.The hereditary wind of the present invention
Danger scoring can be used for pre- measuring blood pressure rise, hypertension and cardiovascular disease event and occur.
The genetic risk of table 4. scores causes danger with blood pressure rise, hypertension and cardiovascular event
Hypertension correction sex, age, body mass index, smoking, Alcohol Consumption Status, pulse, systolic pressure and diastolic pressure.
Cardiovascular disease event occur correction sex, the age, body mass index, smoking, Alcohol Consumption Status, diabetes, T-CHOL,
HDL-C, cardiovascular disease family history, systolic pressure and take depressor.
Genetic risk scores in the effect assessment of hypertension and cardiovascular event occurrence risk forecast model：
In the model of conventional risk factors, genetic risk scoring GRS is added, can be improved to hypertension and cardiovascular event
The predictive ability of occurrence risk, C- index variations are that 0.2%, P values are all equal<0.05 (table 5).
The forecast model that the conventional risk factors of table 5. are added after genetic risk scoring is assessed
4th, the onset risk forecast model of hypertension and angiocardiopathy is established
Hypertension forecast model, which includes genotype information (genetic risk scoring packet) and conventional risk factors, includes year
Age, sex, body mass index, smoking, drink, pulse, systolic pressure and diastolic pressure, correlation effect are shown in Table 6.Cardiovascular disease incidence wind
Dangerous forecast model, which includes genotype information (genetic risk scoring packet) and conventional risk factors, includes sex, age, body weight
Index, smoking, Alcohol Consumption Status, diabetes, T-CHOL, HDL-C, angiocardiopathy family history, systolic pressure
With take depressor situation, the effect of each variable is shown in Table 7.Summary h and E factor establishes hypertension and angiocarpy
Disease incidence risk forecast model：
Hypertension incidence risk forecast model
Hypertension incidence risk=1/ (1+exp (- Z)).Z=-14.808+0.142 × G2+0.193 × G3+0.265 ×
G4+0.339 × G5+0.165 × sex+0.034 × age+0.063 × body mass index+(- 0.013) × whether smoking+0.159
×+0.01 × pulse+0.061 × systolic pressure+0.04 × diastolic pressure of whether drinking.
Cardiovascular disease incidence risk forecast model：
Cardiovascular disease incidence risk=1/ (1+exp (- Z)).Z=-8.558+0.126 × G2+0.159 × G3+0.297
× G4+0.256 × G5+ (- 0.273) × sex+0.056 × age+0.035 × body mass index+0.19 × whether smoking+(-
0.475) whether × drink+0.358 × has non-diabetic+0.006 × T-CHOL+(- 0.028) × HDL courage to consolidate
Whether alcohol+0.643 × whether having+0.015 × systolic pressure of angiocardiopathy family history+0.309 × takes depressor.
The hypertension occurrence risk forecast model variable of table 6.
The cardiovascular disease event occurrence risk forecast model variable of table 7.
Genetic risk scoring packet and environmental factor exposure information are put into risk forecast model and calculate every research pair
The hypertension of elephant and the onset risk of angiocardiopathy.Using making Receiver operating curve (ROC) and models fitting curve
(Calibration) hypertension and angiocardiopathy occurrence risk forecast model are assessed.It is pre- that this is evaluated according to area under ROC curve
The value of survey method.As shown in Figure 10, area is respectively 0.776 He under the ROC that hypertension and angiocardiopathy occur
0.813, show that the model prediction is functional, can be very good to identify people at highest risk.Models fitting curve show hypertension and
The predicted value and observed value of cardiovascular event occurrence risk are respectively 0.882 and 0.24 without significant difference, P values, and models fitting is good
It is good, see Figure 11.
Embodiment two, test individual hypertension and cardiovascular disease incidence risk evaluation contents
The risk for obtaining the research object hypertension and cardiovascular disease event generation is calculated according to model, judges the research
Whether object is people at highest risk.The report of individuation health guidance is completed, reports hypertension and cardiovascular disease event occurrence risk
Height.The report of individuation health guidance is on the basis of genotype results, is studied with reference to life style hazard factor assessment
The risk that object hypertension and cardiovascular disease event occur, and make the healthy action side of individuation for research object
Case.
According to 22 pleomorphism sites of the 26262 of the detection detected in embodiment one individuals (rs880315,
rs17030613、rs10745332、rs16849225、rs820430、rs9815354、rs9810888、rs1902859、
rs6825911、rs13143871、rs1173766、rs1799945、rs9266359、rs2021783、rs4409766、
Rs4757391, rs17249754, rs11066280, rs1991391, rs35444, rs11067763 and rs1887320) situation,
The follow-up observation result of average 6.9 years, formulate blood pressure related locus danger allele hereditary effect quick checking chart (Figure 12) with
And genetic risk scoring quick checking chart (Figure 13).Genetic risk, which scores minimum group, arrives highest group, hypertension and angiocardiopathy hair
Sick risk gradually rises, and obvious dose-effect relationship be present.
Test individual Mr. Wang, Chinese han population, male, 73 years old, using the present invention for assessing test individual hypertension
And/or the detection means of cardiovascular disease incidence risk assesses it and suffers from hypertension and/or cardiovascular disease incidence risk height, institute
Be used to assess the test individual hypertension and/or the detection means of cardiovascular disease incidence risk stated include detection unit, data
Analytic unit, assessment unit, carried out essentially according to following steps：
(1) gather fasting blood and collect sex, the age, blood pressure level, blood lipid level, height, body weight, smoking, drink and
The relevant informations such as history of disease, insert following table (table 8).
The test individual information registration form of table 8
(2) DNA in test individual anticoagulation is separated, the genotype in 22 sites, the embodiment are detected using detection unit
In, detection unit mainly includes iPLEX Sequenom MassARRAY classification systems, record of the concrete operations with reference to specification
Carry out.
After testing, the genotype in 22 sites of Mr. Wang is respectively：Rs880315 is CC；Rs17030613 is AC；
Rs10745332 is AG；Rs16849225 is CC；Rs820430 is AG；Rs9815354 is AG；Rs9810888 is TT；
Rs1902859 is CT；Rs6825911 is CC；Rs13143871 is CC；Rs1173766 is CC；Rs1799945 is CC；
Rs9266359 is CC；Rs2021783 is CC；Rs4409766 is TT；Rs4757391 is TT；Rs17249754 is GA；
Rs11066280 is AT；Rs1991391 is GG；Rs35444 is AA；Rs11067763 is AG；Rs1887320 is AG；Its risk
The number of allele is respectively：2nd, 1,1,2,1,1,0,1,2,0,2,0,2,2,2,0,1,1,2,2,1 and 1.
(3) testing result is analyzed and processed：
(1) testing result is analyzed and processed using data analysis unit, including blood pressure relevant bits shown in Figure 12
The testing result of 22 mononucleotide polymorphism sites is compareed the chart by the dangerous allele hereditary effect zoom table of point,
Each site dangerous allele Genetic Contributions accordingly are found out, are added, obtain genetic risk scoring, it is specific as follows：
Genetic risk scoring=∑ β i × Ni, wherein β i refer to i-th of SNP systolic pressure and being averaged for diastolic pressure effect value
Value, Ni refer to the dangerous allele number of i-th of SNP entrained by research object.
The scoring of Mr. Wang's hypertension incidence genetic risk is 15.505, consults Figure 13, is scored the 3rd group in genetic risk.
(2) hypertension incidence forecast model is utilized, calculates hypertension incidence risk：
Hypertension incidence risk=1/ (1+exp (- Z)).Z=-14.808+0.142 × G2+0.193 × G3+0.265 ×
G4+0.339 × G5+0.165 × sex+0.034 × age+0.063 × body mass index+(- 0.013) × whether smoking+0.159
×+0.01 × pulse+0.061 × systolic pressure+0.04 × diastolic pressure of whether drinking.Specially：
Z=-14.808+0.142 × 0+0.193 × 1+0.265 × 0+0.339 × 0+0.165 × 1+0.034 × 73+
0.063 × 28+ (- 0.013) × 0+0.159 × 0+0.01 × 70+0.061 × 135+0.04 × 80=1.931.
Hypertension incidence risk=1/ (1+exp (- Z))=0.87.
Mr. Wang's hypertension incidence risk is 0.87, i.e., 87%.
(3) cardiovascular disease incidence risk forecast model is utilized, calculates cardiovascular disease incidence risk：
Cardiovascular disease incidence risk=1/ (1+exp (- Z)).Z=-8.558+0.126 × G2+0.159 × G3+0.297
× G4+0.256 × G5+ (- 0.273) × sex+0.056 × age+0.035 × body mass index+0.19 × whether smoking+(-
0.475) whether × drink+0.358 × has non-diabetic+0.006 × T-CHOL+(- 0.028) × HDL courage to consolidate
Whether alcohol+0.643 × whether having+0.015 × systolic pressure of angiocardiopathy family history+0.309 × takes depressor.Specially：
Z=-8.558+0.126 × 0+0.159 × 1+0.297 × 0+0.256 × 0+ (- 0.273) × 1+0.056 × 73+
0.035×28+0.19×0+(-0.475)×0+0.358×1+0.006×299+(-0.028)×48+0.643×0+0.015
× 135+0.309 × 0=-0.771. cardiovascular disease incidence risk=1/ (1+exp (- Z))=0.31.
Mr. Wang's cardiovascular disease incidence risk is 0.31, i.e., 31%.
(3) hypertension is carried out to Mr. Wang and cardiovascular disease incidence risk is assessed：
By the analyzing and processing of testing result, Mr. Wang's hypertension incidence risk is 87%.
According to Framingham researchs to the classification of angiocardiopathy occurrence risk (be low danger between 0-10%, 10-20%
Between be poor risk, be people at highest risk more than 20%), Mr. Wang's cardiovascular disease incidence risk be 31%, belong to people at highest risk.
Predicted by h and E factor and determine that the hypertension of Mr. Wang and angiocardiopathy occurrence risk are higher, it is proposed that its
In addition to healthy Lifestyle is taken, pay attention to controlling blood glucose, blood fat, periodically carry out health examination, seen a doctor in time if any abnormal.This hair
The bright one kind that provides predicts individual hypertension and/or cardiovascular disease incidence risk according to multiple SNP polymorphisms
Model, can be good at identifying hypertension and angiocardiopathy people at highest risk, so as to targetedly be intervened, reach early stage
It was found that, the purpose that occurs of early prevention hypertension and/or angiocardiopathy.Research on utilization subject gene type result calculates hereditary wind
Danger scoring, genetic risk scoring is added in conventional risk factors model, complete the report of test individual genotype detection and individual
Change health guidance report, and report that the height of hypertension and/or risk of cardiovascular diseases occurs in it.
Claims (7)
1. the reagent for detecting multiple mononucleotide polymorphism sites is used for prediction of hypertension and/or cardiovascular disease incidence in preparation
Application in the detection means of risk, wherein, it is more that the multiple mononucleotide polymorphism site includes following 22 mononucleotides
State property site：
The rs10745332 and rs17030613, FIGN region rs16849225 in CASZ1 regions rs880315, MOV10 region,
SLC4A7 regions rs820430, ULK4 region rs9815354, CACNA1D region rs9810888, FGF5 region rs1902859,
ENPEP regions rs6825911, GUCY1A3 region rs13143871, NPR3 region rs1173766, HFE region rs1799945,
HLA-B regions rs9266359, CYP21A2 region rs2021783, CYP17A1 region rs4409766, SOX6 region
Rs4757391, ATP2B1 region rs17249754, ALDH2 region rs11066280, TBX3-TBX5 region rs1991391,
TBX3 regions rs35444, MED13L region rs11067763 and JAG1 regions rs1887320；
Wherein, detection unit and data are included for the detection means of prediction of hypertension and/or cardiovascular disease incidence risk
Analytic unit；The detection unit is for detecting danger of test individual carrying 22 mononucleotide polymorphism sites etc.
Position genetic profile and detection test individual conventional risk factors, obtain testing result；The data analysis unit includes being used for
The processing unit analyzed and processed to the testing result of detection unit, obtain complex inheritance risk score and conventional risk factors
Hypertension and/or cardiovascular disease incidence risk prediction scoring；
Wherein, the genetic risk scoring meets the numerical value being calculated in accordance with the following methods：
Genetic risk scoring G=∑s βi×Ni, wherein βiRefer to i-th SNP systolic pressure and the average value of diastolic pressure effect value, NiRefer to
I-th of SNP dangerous allele number entrained by research object；
Hypertension and/or cardiovascular disease incidence risk the prediction scoring of the complex inheritance risk score and conventional risk factors
Meet according to the numerical value being calculated with drag：
Hypertension incidence forecast model：
Hypertension incidence risk=1/ (1+exp (- Z))；Z=-14.808+0.142 × G2+0.193 × G3+0.265 × G4+
0.339 × G5+0.165 × sex+0.034 × age+0.063 × body mass index+(- 0.013) × whether smoking+0.159 ×
Whether drink+0.01 × pulse+0.061 × systolic pressure+0.04 × diastolic pressure；
Cardiovascular disease event Occurrence forecast model：
Cardiovascular disease incidence risk=1/ (1+exp (- Z))；Z=-8.558+0.126 × G2+0.159 × G3+0.297 × G4
+ 0.256 × G5+ (- 0.273) × sex+0.056 × age+0.035 × body mass index+0.19 × whether smoking+(- 0.475)
× whether drink+0.358 × have non-diabetic+0.006 × T-CHOL+(- 0.028) × HDL-C+
Whether 0.643 × whether having+0.015 × systolic pressure of angiocardiopathy family history+0.309 × takes depressor；
In above-mentioned model, G2, G3, G4, G5 be it is foregoing according to research object genetic risk score G packet, the 1st group 7.765~
13.465 be G1 groups, the 2nd group 13.466~14.616 be G2 groups, the 3rd group 14.617~15.545 be G3 groups, the 4th group 15.545
~16.654 are G4 groups and the 5th group 16.655~22.125 is G5 groups；When test individual genetic risk scoring fall into G2, G3, G4,
During any group of G5, its corresponding group G value is 1, and remaining value is 0；G1 groups are fallen into when test individual genetic risk factors score,
The equal value 0 of G2, G3, G4, G5.
2. application according to claim 1, wherein, the dangerous allele point of 22 mononucleotide polymorphism sites
It is not：Rs880315 pleomorphism sites are C；Rs17030613 pleomorphism sites are C；Rs10745332 pleomorphism sites are A；
Rs16849225 pleomorphism sites are C；Rs820430 pleomorphism sites are A；Rs9815354 pleomorphism sites are A；
Rs9810888 pleomorphism sites are G；Rs1902859 pleomorphism sites are C；Rs6825911 pleomorphism sites are C；
Rs13143871 pleomorphism sites are T；Rs1173766 pleomorphism sites are C；Rs1799945 pleomorphism sites are G；
Rs9266359 pleomorphism sites are C；Rs2021783 pleomorphism sites are C；Rs4409766 pleomorphism sites are T；
Rs4757391 pleomorphism sites are C；Rs17249754 pleomorphism sites are G；S11066280 pleomorphism sites are T；
Rs1991391 pleomorphism sites are G；Rs35444 pleomorphism sites are A；Rs11067763 pleomorphism sites are A；rs1887320
Pleomorphism site is A.
3. application according to claim 1 or 2, wherein, described test individual is Chinese han population.
4. application according to claim 1 or 2, wherein, blood of the testing sample from test individual, urine, saliva, stomach
Liquid, hair or biopsy.
5. a kind of detection means for being used for prediction of hypertension and/or cardiovascular disease incidence risk, the detection means include detection
Unit and data analysis unit；
The detection unit includes being used to detect the dangerous allele that test individual carries multiple mononucleotide polymorphism sites
Situation and the detection unit for detecting test individual conventional risk factors, obtain testing result；Wherein, the multiple monokaryon
Nucleotide polymorphism site includes following 22 mononucleotide polymorphism sites：CASZ1 regions rs880315, MOV10 region
Rs10745332 and rs17030613, FIGN region rs16849225, SLC4A7 region rs820430, ULK4 region
Rs9815354, CACNA1D region rs9810888, FGF5 region rs1902859, ENPEP region rs6825911, GUCY1A3 area
Domain rs13143871, NPR3 region rs1173766, HFE region rs1799945, HLA-B region rs9266359, CYP21A2 area
Domain rs2021783, CYP17A1 region rs4409766, SOX6 region rs4757391, ATP2B1 region rs17249754, ALDH2
Region rs11066280, TBX3-TBX5 region rs1991391, TBX3 region rs35444, MED13L region rs11067763 and
JAG1 regions rs1887320；
The data analysis unit includes being used for the processing unit for analyzing and processing the testing result of detection unit, obtains comprehensive
Close genetic risk scoring and hypertension and/or cardiovascular disease incidence risk the prediction scoring of conventional risk factors；
Wherein, the genetic risk scoring meets the numerical value being calculated in accordance with the following methods：
Genetic risk scoring G=∑s βi×Ni, wherein βiRefer to i-th SNP systolic pressure and the average value of diastolic pressure effect value, NiRefer to
I-th of SNP dangerous allele number entrained by research object；
Hypertension and/or cardiovascular disease incidence risk the prediction scoring of the complex inheritance risk score and conventional risk factors
Meet according to the numerical value being calculated with drag：
Hypertension incidence forecast model：
Hypertension incidence risk=1/ (1+exp (- Z))；Z=-14.808+0.142 × G2+0.193 × G3+0.265 × G4+
0.339 × G5+0.165 × sex+0.034 × age+0.063 × body mass index+(- 0.013) × whether smoking+0.159 ×
Whether drink+0.01 × pulse+0.061 × systolic pressure+0.04 × diastolic pressure；
Cardiovascular disease event Occurrence forecast model：
Cardiovascular disease incidence risk=1/ (1+exp (- Z))；Z=-8.558+0.126 × G2+0.159 × G3+0.297 × G4
+ 0.256 × G5+ (- 0.273) × sex+0.056 × age+0.035 × body mass index+0.19 × whether smoking+(- 0.475)
× whether drink+0.358 × have non-diabetic+0.006 × T-CHOL+(- 0.028) × HDL-C+
Whether 0.643 × whether having+0.015 × systolic pressure of angiocardiopathy family history+0.309 × takes depressor；
In above-mentioned model, G2, G3, G4, G5 be it is foregoing according to research object genetic risk score G packet, the 1st group 7.765~
13.465 be G1 groups, the 2nd group 13.466~14.616 be G2 groups, the 3rd group 14.617~15.545 be G3 groups, the 4th group 15.545
~16.654 are G4 groups and the 5th group 16.655~22.125 is G5 groups；When test individual genetic risk scoring fall into G2, G3, G4,
During any group of G5, its corresponding group G value is 1, and remaining value is 0；G1 groups are fallen into when test individual genetic risk factors score,
The equal value 0 of G2, G3, G4, G5.
6. detection means according to claim 5, wherein, the dangerous equipotential base of 22 mononucleotide polymorphism sites
Because being respectively：Rs880315 pleomorphism sites are C；Rs17030613 pleomorphism sites are C；Rs10745332 pleomorphism sites are
A；Rs16849225 pleomorphism sites are C；Rs820430 pleomorphism sites are A；Rs9815354 pleomorphism sites are A；
Rs9810888 pleomorphism sites are G；Rs1902859 pleomorphism sites are C；Rs6825911 pleomorphism sites are C；
Rs13143871 pleomorphism sites are T；Rs1173766 pleomorphism sites are C；Rs1799945 pleomorphism sites are G；
Rs9266359 pleomorphism sites are C；Rs2021783 pleomorphism sites are C；Rs4409766 pleomorphism sites are T；
Rs4757391 pleomorphism sites are C；Rs17249754 pleomorphism sites are G；S11066280 pleomorphism sites are T；
Rs1991391 pleomorphism sites are G；Rs35444 pleomorphism sites are A；Rs11067763 pleomorphism sites are A；rs1887320
Pleomorphism site is A.
7. the detection means according to claim 5 or 6, wherein：
Hypertension correlation conventional risk factors include age, sex, body mass index, smoking, drunk, pulse, systolic pressure and diastole
Pressure；Angiocardiopathy correlation conventional risk factors include sex, age, body mass index, smoking, Alcohol Consumption Status, diabetes, total courage
Sterol, HDL-C, cardiovascular disease family history, systolic pressure and take depressor situation.
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