CN102758010A - Combination of multiple genetic single nucleotide polymorphisms and environmental factors related to coronary heart disease and application of combination - Google Patents
Combination of multiple genetic single nucleotide polymorphisms and environmental factors related to coronary heart disease and application of combination Download PDFInfo
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Abstract
The invention relates to a combination of multiple genetic single nucleotide polymorphisms and environmental factors related to a coronary heart disease and application of the combination. The genetic single nucleotide polymorphisms comprise the following locus: rs2123536, rs18422896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280; and the environmental factors comprise individual smoking, drinking and body mass index information, and blood gloucose and high density lipoprotein cholesterol value in venous blood. Based on the combination factors, a prediction model for individual level coronary heart disease is established, and the combination of the multiple genetic single nucleotide polymorphisms and the environmental factors related to the coronary heart disease has an important application prospect in assessing the coronary heart disease risk for people.
Description
Technical field
The present invention relates to combination of a plurality of gene mononucleotide polymorphisms site relevant and environmental factors and application thereof with coronary heart disease; The combination that inherited genetic factors and the individual environmental exposure factor to be measured that is specifically related to comprise the mononucleotide polymorphism site of rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280 comprise smoking, drink etc., and based on the application of such blocking factor in the ill risk of assessment crowd's coronary heart disease.
Background technology
The atherosclerotic cardiovascular and cerebrovascular disease have become the main health problem that world wide is paid close attention to.The World Health Organization's report in 2004 shows that the annual cardiovascular disorder in the whole world is taken the death toll Da Gaoda 1,720 ten thousand that causes as the leading factor with coronary heart disease and apoplexy, accounts for 1/3rd of all death tolls.Estimate that this numeral of the year two thousand twenty will further increase by 50%, up to 2,500 ten thousand, cardiovascular disorder is global human " No.1 killer ".An extensive perspective study of carrying out in China shows that also heart disease has become the major causes of death of Chinese population, apportion man, women's cause of death the 2nd and the 1st.China annual New Development myocardial infarction 500,000 people, the Hazard Factor of being correlated with along with the change and the atherosclerosis of mode of life continue to increase, and coronary heart disease and myocardial infarction morbidity yet will be lasting ascendant trend.
Present confirmed coronary heart disease environmental risk factor comprises: smoking, drink, obesity and hyperlipemia etc.A large amount of research datas show that coronary heart disease is a kind of complex disease, are by due to a plurality of minor genes and the long-term interaction of environmental factors.Therefore identify tumor susceptibility gene relevant or Disease-causing gene and combine with the environmental risk factor with coronary heart disease; Further the tumor susceptibility gene of screening increase disease risks is confirmed susceptible individual in the crowd, will help cause of coronary heart disease risk profile, new drug development, diagnosis and individualized treatment.From the basis to clinical; People have carried out a large amount of research to this; And accumulating a large amount of knowledge aspect the Hazard Factor of coronary heart disease and the pathogenetic physiopathology of coronary disease; But the definite genetic molecule mechanism about coronary heart disease and myocardial infarction generation is but known little about it, and for how to identify inheritance susceptible gene and the coronary heart disease genetic predisposition of identifying the experimenter, lacks comprehensive system effective recognition method always.
EARLY RECOGNITION coronary heart disease high risk population takes mode of life intervention targetedly, be to reduce coronary heart disease to take place, thereby the containment medical expense increases, prolongs the key of life expectancy.At present, everybody generally believes that adopting the individual conventional risk factors level of model method utilization in individual level is identification coronary heart disease high risk population's effective ways.Risk prediction is intervened the scheme effect assessment for disease prevention, government decision and health, simultaneously also can for clinical treatment provide can reference information.The biological study that is integrated into human complex disease or proterties of full genomics technology and epidemiological method has brought new angle.The individual risk assessment is an important component part of its clinical decision, if take more morning or stronger intervening measure in view of the above, the patient might benefit from it.Find that at present the genetic predisposition locus that coronary heart disease is relevant can be to incidence of coronary heart disease risk performance independent effect, the effect of these heritable variations in the disease risks prediction of therefore should reappraising.With the ability of effective raising disease risks prediction, thereby on the basis of conventional risk factors, further strengthen understanding to disease risks.
Summary of the invention
To the problems referred to above, an object of the present invention is to provide the combination of a kind of a plurality of gene mononucleotide polymorphisms site and environmental factors; Another object of the present invention provides the application of described a plurality of gene mononucleotide polymorphisms site and environmental factors combination, specifically is that it is used for assessing individual application of suffering from the proofing unit of coronary heart disease risk to be measured in preparation; Another object of the present invention provides a kind of method that detects a plurality of gene mononucleotide polymorphisms site of the present invention and environmental factors; Another object of the present invention provides the method for relevant a plurality of gene mononucleotide polymorphisms site of a kind of vitro detection coronary heart disease and environmental factors; Another object of the present invention provides a kind of agent combination that detects a plurality of gene mononucleotide polymorphisms site of the present invention and environmental factors and is used for preparation, test kit or the proofing unit of vitro detection coronary heart disease correlative factor or the application of model in preparation; The agent combination that another object of the present invention provides a plurality of gene mononucleotide polymorphisms site and environmental factors in the sample of a kind of vitro detection from individuality to be measured is in preparation, test kit or the proofing unit of the preparation prediction individual danger of suffering from coronary heart disease to be measured or the application in the model; Another object of the present invention provides a kind of external prediction individual method of suffering from the danger of coronary heart disease to be measured.
Another object of the present invention provides a kind of individual proofing unit of suffering from coronary heart disease risk to be measured that is used to assess; According to gene pleiomorphism and the individual incidence of coronary heart disease risk of The Environmental Factor Prediction; Can be good at discerning the high risk population of coronary heart disease; Thereby intervene targetedly, reach and delay and prevent the pathogenetic purpose of coronary disease.
At first; The invention provides the combination of a kind of a plurality of gene mononucleotide polymorphisms site and environmental factors; Wherein, described a plurality of gene mononucleotide polymorphisms site comprises following site: rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280; Described environmental factors comprises individual smoking, drinks, blood glucose value and high density lipoprotein cholesterol value in weight index information and the venous blood.
Among the present invention; Described a plurality of gene mononucleotide polymorphisms site: rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280; And described environmental factors: whether smoking of individuality, whether drink, information such as blood glucose value and high density lipoprotein cholesterol value in weight index information and the venous blood, be on the bases of a large amount of experiments, to draw.In embodiment of the present invention, utilize FludigmEP1
TMGENETIC ANALYSIS system; Taqman MGB probe method is carried out the gene type experiment to 7012 routine patients with coronary heart disease and 8579 routine check samples; Data are carried out the lot of experiments analysis; Draw above-mentioned 9 SNP sites (rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280) and coronary disease susceptibility significant correlation first, and propose environmental factors: individual whether smoking, whether drink, the dependency of information such as blood glucose value and high density lipoprotein cholesterol value and coronary disease susceptibility in weight index information and the venous blood.
On a large amount of experimental results of the present invention basis; Of the present inventionly discover that further the dangerous allelotrope of these SNPs is respectively: the rs2123536 pleomorphism site is that T, rs1842896 pleomorphism site are that T, rs9349379 pleomorphism site are that G, rs9268402 pleomorphism site are that G, rs12524865 pleomorphism site are that C, rs10757274 pleomorphism site are that G, rs1333042 pleomorphism site are that G, rs7136259 pleomorphism site are that T, rs11066280 pleomorphism site are A.Carrying these dangerous allelic individual relative risks that coronary heart disease take place and being does not have 1.13 to 1.36 times of the carrier.On the other hand, in said environmental factors, individual smoking, drink, blood glucose value is all relevant with coronary disease susceptibility with high density lipoprotein cholesterol value etc. in weight index information and the venous blood.
Thereby on the one hand, the present invention provides a kind of method that detects a plurality of mononucleotide polymorphism site of the present invention and environmental factors.Wherein, detect that said environmental factors comprises individual smoking, drinks, the method for blood glucose value and high density lipoprotein cholesterol value all is the ordinary methods in affiliated field in weight index information and the venous blood, the present invention repeats no more.Detect the also available multiple technologies known in the art of a plurality of mononucleotide polymorphism site of the present invention and detect a plurality of mononucleotide polymorphism site of the present invention at dna level, rna level.For example:
Can adopt the method for direct order-checking; Can directly disclose crt gene and carry the sequence difference between the mutator gene through the dna direct order-checking; Specifically can be that traditional commercial sequencing kit of use or automatic DNA sequencer DNA checks order to dna direct, or the tetra-sodium of development in recent years order-checking (Pyrosequencing), micrometering preface (SNaPshot) etc.The tetra-sodium sequencing technologies is suitable for the sequencing analysis to known short sequence; After its principle is primer and template DNA annealing; Under the synergy of archaeal dna polymerase (DNA polymerase), ATP sulfurylase (ATP sulfurytase), luciferase (luciferase) and 4 kinds of enzymes of apyrase (Apyrase); The polymerization of each dNTP on the primer and the release coupling of first order fluorescence signal are got up; Through detecting the release and the intensity of fluorescence, reach the purpose of The real time measure dna sequence dna.The SnaPshot technology platform is Applied Biosystems; ABI company has released to aim at detects SNP analysis of design software and test kit; Can carry out gene type simultaneously to a plurality of SNP site, also be called as minisequencing, after the primer SNaPshot reaction of this method to different mutational site design different lengthss; Product is analyzed through electrophoretic separation, multicolored fluoroscopic examination, Gene mapper, can in a running gel, detect a plurality of SNP site.
Also can adopt method, specifically comprise the Taqman probe method, DNA chip method etc. based on hybridization.TaqMan SNP gene type principle: utilize exonuclease that the excision of 5 ' the special allelotrope dye marker is produced the check signal that continues, reaction system comprises: with genomic dna or PCR product is template; One couple of PCR primers, and two types of 2 MGB probe in detecting SNP of using FAM and VIC mark respectively; Read the somatotype data at the PCR reaction end.The DNA chip technology: testing gene is after extracting; Be cut into fragment different in size; Behind fluorescence chemical material mark, be expelled on the slide glass that is embedded with chip, because the degree of DNA and probe hybridization is relevant with fluorescence intensity; Therefore through laser scanning, can measure the variation of sequence to be detected according to the fluorescence power.
Can also adopt method, resolve ion flight time mass spectrum (MALDI-Tof-MS) like ground substance assistant laser based on primer extension.Ground substance assistant laser is resolved the ion flight time mass spectrum and is detected principle: one section probe of adjacent SNP site design; In reaction system, substitute dNTP, make probe only extend a base and promptly stop, according to the difference in SNP site in the SNP site with ddNTP; Probe will combine different ddNTP; Thereby have different molecular weight, mass spectrograph can detect this molecular weight difference, thereby realizes the purpose of SNP somatotype.
Can also adopt method based on conformation; Concrete example such as restriction fragment length polymorphism (RFLP) are analyzed, single strand conformation polymorphism (single-strand conformational polymorphism; SSCP) analysis, denaturing gradient gel electrophoresis (denauring gradient gel electrophoresis; DGGE) (denaturing high performance liquid chromatography dHPLC) waits the technology of analysis for analysis, sex change high-efficient liquid phase chromatogram technology.Wherein, The principle of RFLP: some SNP polymorphic site just in time is in the recognition site place of restriction enzyme; Wherein a kind of pcr amplification segment of polymorphic correspondence can be cut by corresponding restriction endonuclease; And another kind can not, therefore can know through the fragment length analysis behind the PCR product electrophoresis after enzyme is cut and detect the genotype of sample in this site; There is not proper restriction site if detect the SNP site; Often can introduce restriction enzyme digestion sites, can realize that through this primer method of modifying the somatotype in most SNP site can both realize with rflp analysis through changing indivedual bases at PCR primer 3 ' end.SSCP: under the condition of non-sex change, single stranded DNA has certain pleated sheet structure, and this pleated sheet structure is by its nucleotide sequence decision; The susceptibility of SSCP depends on SNP to folding influence and the folding electrophoretic mobility that how to influence aim sequence; Its strategy is, the fragment to be measured of pcr amplification is mixed with deionized formamide, and then 95 ℃ of sex change are unwind; Be quenched to again in the ice, separate through native polyacrylamide gel electrophoresis then; Under the stable ideal conditions, the isolating result of gel electrophoresis is that heterozygote comprises two very near bands of separation in a certain position range, and normal dna fragmentation occupy a wherein band, and the dna fragmentation of homozygous mutation SNP occupy another band.DGGE: utilize double chain DNA molecule in the gel of certain gradient sex change agent concentration, during electrophoresis, can issue first portion in certain denaturing agent concentration and unwind, cause electrophoretic mobility to descend; Even have the difference of having only a base pair between a kind of two kinds of dna moleculars of SNP allelotype respectively, also can part take place at different time and unwind, thereby be separated into two bands.DHPLC: this technology is the mutating technology of a detection SNP who on SSCP and DGGE basis, grows up, and this technology is mixed with the dna fragmentation and the wild-type DNA of the unknown, after heat denatured, makes its cooling reannealing again; If the DNA of sudden change is arranged, this moment, formed duplex had two kinds, was homologous duplex and allos duplex; Different based on homologous duplex and allos duplex melting temperature(Tm); Through the temperature of control DHPLC, it is maintained near the operation down of dna molecular Tm value, carry out wash-out then; The more little dna molecular and the avidity of post are more little, just elute more easily; After DNA expands through PCR because the existence of base mismatch forms heteroduplex because single stranded DNA with charge ratio double-stranded few, eluted earlier, and separated with normal pairing two strands, last peak type or number according to chromatographic peak confirmed having of SNP or do not had.
Can also adopt high resolving power solubility curve analytical technology (HRM).This analytical technology is according in certain TR, the product of pcr amplification being carried out sex change, during fluorescent signal in the detection architecture in real time.Fluorescent value can be drawn solubility curve along with temperature variation.Each segment DNA all has its unique sequence, thereby unique melting curve shape has also just been arranged, and is the same as dna fingerprinting, has very high specificity, stability and repeated.Accurately distinguish wild-type homozygote, heterozygote and mutagenicity homozygote according to curve.
In the specific implementation, those skilled in the art can select any above-mentioned technological vitro detection a plurality of gene label mononucleotide polymorphism sites according to the invention according to practical situation.Also can adopt the combination of multiple technologies to come the said a plurality of gene label mononucleotide polymorphism sites of vitro detection.For example, when the restriction fragment length polymorphism analytical procedure with after PCR combines, detection sensitivity and specificity are higher.When direct sequencing was used in combination with PCR, detection sensitivity improved greatly.In an embodiment of the present invention, application be Taqman MGB method, use be Fludigm
EP1
TMGENETIC ANALYSIS system platform; Because this platform is the gene type platform that belongs to higher flux; When sample number is 96 sites of 96 pattern detection (using 96.96 dynamic chips) or 48 sites of 48 pattern detection (using 48.48 dynamic chips), has the advantage of economical and efficient.And when being applied to the analyzing and testing of a small amount of testing sample, adopt Fludigm specific to scheme of the present invention
EP1
TMGENETIC ANALYSIS system platform does not just possess the advantage on economy and the efficient; Can adopt the real-time fluorescence quantitative PCR system this moment; Like 7900HT (Fast) the real time PCR system of Applied Biosystems, 7500real time PCR system etc., use the Taqman-MGB probe method gene type is carried out in single site; Also can PCR RFLP, other methods of genotyping such as HRM.
In addition, the present invention also can further comprise the detected result of said a plurality of mononucleotide polymorphism sites is carried out statistical study.For example; In an embodiment of the invention; Result to by tagged single-nucleotide polymorphic loci of the present invention carries out statistical study; And set up the model that is used to assess individual trouble coronary heart disease risk to be measured, and then a kind of individual proofing unit of suffering from coronary heart disease risk to be measured that is used to assess is provided.
According to the proofing unit that is used to assess individual trouble coronary heart disease risk to be measured provided by the present invention, comprise detecting unit and data analysis unit, wherein:
Said detecting unit is to be used to detect idiogenetics information to be measured and environmental factors, obtains detected result; Wherein detect the dangerous allelotrope situation that the genetic information situation comprises that detection individuality to be measured carries said 9 mononucleotide polymorphism sites, the dangerous allelotrope of said 9 mononucleotide polymorphism sites is respectively: the rs2123536 pleomorphism site is that T, rs1842896 pleomorphism site are that T, rs9349379 pleomorphism site are that G, rs9268402 pleomorphism site are that G, rs12524865 pleomorphism site are that C, rs10757274 pleomorphism site are that G, rs1333042 pleomorphism site are that G, rs7136259 pleomorphism site are that T, rs11066280 pleomorphism site are A; Testing environment factor situation comprise detect whether smoking of individuality to be measured, whether drink, blood glucose value and high density lipoprotein cholesterol value in weight index information and the venous blood;
Said data analysis unit is to be used for the detected result of detecting unit is carried out analyzing and processing, comprising:
Calculate individual coronary heart disease genetic risk factor scoring to be measured according to following formula:
Genetic risk factor scoring=∑ log (OR
i) * N
i, OR wherein
iThe relative risk that refers to i mononucleotide polymorphism site, N
iThe dangerous allelotrope number that refers to entrained i the mononucleotide polymorphism site of individuality to be measured;
Judge individual packets to be measured according to score value, the 1st group of G1:0.115～1.200, the 2nd group of G2:1.201～1.473, the 3rd group of G3:1.474～1.737, the 4th group of G4:1.738～2.021, the 5th group of G5:2.022～2.972;
Calculate the ill relatively risk score of trouble coronary heart disease according to following formula:
Suffer from the ill relatively risk score=exp of coronary heart disease (0.220+0.232 * G2+0.403 * G3+0.534 * G4+0.852 * G5+0.178 * drink+1.110 * smoking+0.010 * blood glucose value+0.074 * weight index+(0.080) * high density lipoprotein cholesterol value)/0.222; Smoking, drink and for " being " perhaps " deny ", " being " is 1, and " denying " is 0; Weight index is BMI=body weight/height
2, unit is Kg/m
2Blood sugar, determine cholesterol with high density lipoprotein method are 12 hours on an empty stomach, and unit is mg/dl.
The proofing unit that is used to assess individual trouble coronary heart disease risk to be measured of the present invention can be a virtual bench, as long as can realize the function of said detecting unit and data analysis unit.Described detecting unit can be to comprise various detection reagent, test kit or detecting instrument; Described data analysis unit can be that any can realization carried out analyzing and processing and drawn computing instrument, module or the virtual unit of individual coronary heart disease genetic risk factor scoring to be measured the detected result of detecting unit; For example can be the data drawing list of formulating according to above-mentioned genetic risk factor scoring formula in advance, this data drawing list of detected result contrast of detecting unit can be drawn genetic risk factor score value.
According to specific embodiments of the present invention, among the present invention, the height of the ill relatively risk score of the said trouble coronary heart disease reflection individual dangerous height of coronary heart disease of suffering to be measured.
In embodiment of the present invention; For the individual coronary heart disease risk of suffering to be measured of convenient assessment in the practical application; Detected the dangerous allelotrope situation that 8579 healthy subjects and 7012 patients with coronary heart disease carry said 9 SNP gene mononucleotide polymorphism sites, calculated each research object according to following formula and carry out the scoring of coronary heart disease genetic risk factor: genetic risk factor scoring=∑ log (OR
i) * N
i, OR wherein
iThe relative risk that refers to i SNP, N
iThe dangerous allelotrope number that refers to entrained i the SNP of research object (individuality to be measured); And according to all research object coronary heart disease genetic risk factors scoring is divided into 5 groups with research object, set up the ill risk contrast of coronary heart disease model.In concrete real-time mode of the present invention, described 5 groups are respectively the 1st group 0.115～1.200, the 2nd group 1.201～1.473, the 3rd groups 1.474～1.737, the 4th groups 1.738～2.021 and the 5th groups 2.022～2.972; Coronary heart disease genetic risk factor is marked minimum group to the highest group, and the ill risk of coronary heart disease raises gradually.On this basis; Further combining environmental factor; Set up predictive model, can calculate and suffer from the ill relatively risk score of coronary heart disease: suffer from the ill relatively risk score=exp of coronary heart disease (0.220+0.232 * G2+0.403 * G3+0.534 * G4+0.852 * G5+0.178 * drink+1.110 * smoking+0.010 * blood glucose value+0.074 * weight index+(0.080) * high density lipoprotein cholesterol value)/0.222.
Among the present invention; Said a plurality of gene mononucleotide polymorphism Sites Combination state can provide the individual coronary heart disease risk rate information of suffering to be measured, and said rs2123536 carries T allelotrope, rs1842896 and carries T allelotrope, rs9349379 and carry G allelotrope, rs9268402 and carry G allelotrope, rs12524865 and carry C allelotrope, rs10757274 and carry G allelotrope, rs1333042 and carry G allelotrope, rs7136259 and carry T allelotrope and rs11066280 and carry the allelic individual risk of suffering from coronary heart disease of A and raise 1.13 to 1.36 times.The risk that said environmental factors is suffered from coronary heart disease for individuality also has certain dependency.
Thereby on the other hand, the present invention also provides described a plurality of gene mononucleotide polymorphisms site and environmental factors to be combined in preparation to be used for assessing individual the suffer from proofing unit of coronary heart disease risk and the application of model to be measured.
On the other hand, the present invention's agent combination of the reagent that detects mononucleotide polymorphism site rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280 also being provided and having detected said environmental factors is used for preparation, the test kit of vitro detection coronary heart disease correlative factor (comprising coronary heart disease dependent genes, environmental factors) or is used to assess individual the suffer from proofing unit of coronary heart disease risk or the application of model to be measured in preparation.The reagent that the reagent of wherein said detection mononucleotide polymorphism site rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280 is used in can preceding method for example is: the reagent that is used for direct sequencing; Or be used for the reagent that the polymerase chain reaction combines with the restriction fragment length polymorphism analysis; Or be used for the reagent that the polymerase chain reaction combines with direct sequencing; Or be used for the reagent that the polymerase chain reaction combines with direct sequencing; Or be used for the reagent of following any SNP classifying method: based on the method for hybridization, based on the method for primer extension, based on the method or the high resolving power solubility curve analytical technology of conformation.The reagent that detects said environmental factors can be the conventional reagent in the affiliated field.
On the other hand; The present invention also provides vitro detection from the reagent of mononucleotide polymorphism site: rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280 in the sample of individuality to be measured and the application of agent combination in preparation, test kit or the proofing unit of the danger of preparation prediction individual trouble coronary heart disease to be measured that detects said environmental factors; Wherein, said rs2123536 carries T allelotrope, rs1842896 and carries T allelotrope, rs9349379 and carry G allelotrope, rs9268402 and carry G allelotrope, rs12524865 and carry C allelotrope, rs10757274 and carry G allelotrope, rs1333042 and carry G allelotrope, rs7136259 and carry T allelotrope and rs11066280 and carry allelic individual the dangerous of coronary heart disease of suffering from of A and significantly raise.
The testing sample that contains gene of the present invention can obtain Tathagata autoblood, urine, saliva, gastric juice, hair or examination of living tissue from experimenter's cell.Preferably come autoblood.Can obtain to contain the testing sample of gene of the present invention earlier from experimenter's cell, extract the DNA of gene then according to ordinary method.Said individuality to be measured is preferably Chinese han population.
On the basis of the statistical study of large sample of the present invention; Can use method of the present invention separately; Vitro detection is from the allelotrope situation of carrying and the described environmental factors of mononucleotide polymorphism site rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280 in the sample of individuality to be measured; With the external prediction individual danger of suffering from coronary heart disease to be measured, reach the external prediction individual dangerous purpose of coronary heart disease of suffering to be measured.
According to specific embodiments of the present invention, when utilizing technical evaluation of the present invention individuality to be measured to suffer from coronary heart disease risk, can carry out according to following operation:
(1) collection research object (individuality to be measured) environmental exposure factor comprise smoking, drink, weight index information, wherein weight index equal body weight (Kg) divided by height (m) square.Venous blood samples is measured blood sugar and high density lipoprotein cholesterol.
(2) obtain the scoring of idiogenetics Hazard Factor.(2p24.1 zone rs2123536,4q32.1 zone rs1842896,6p24.1 zone rs9349379,6p21.32 zone rs9268402,6q23.2 zone rs12524865,9p21.3 zone rs10757274,9p21.3 zone rs1333042,12q21.33 zone rs7136259 and 12q24.13 zone rs11066280 carry out gene type to the pleomorphism site (SNP) of 9 ill risks of coronary heart disease.Comprehensive individuality carries the dangerous allelotrope situation in 9 SNP sites; Carry out the scoring of coronary heart disease genetic risk factor; Methods of marking is that research object is carried the allelic number of risk and risk allelotrope effect value (log (OR)) and multiplied each other and obtain each SNP site hereditary effect, then the hereditary effect summation of 9 SNP is obtained the coronary heart disease genetic risk factor scoring of this research object.Judge research object grouping, the 1st group 0.115～1.200 (G1), the 2nd group 1.201～1.473 (G2), the 3rd group 1.474～1.737 (G3), the 4th group 1.738～2.021 (G4) and the 5th group 2.022～2.972 (G5) according to score value.
(3) above-mentioned genetic information and environmental factors exposure information are put into the predictive model of having set up: suffer from the ill relatively risk=exp of coronary heart disease (0.220+0.232 * G2+0.403 * G3+0.534 * G4+0.852 * G5+0.178 * drink+1.110 * smoking+0.010 * blood glucose value+0.074 * weight index+(0.080) * high density lipoprotein cholesterol value)/0.222.
(4) calculate ill risk: obtain the relative risk that this research object is suffered from coronary heart disease according to Model Calculation, judge whether this research object is the high risk population of coronary heart disease.
(5) accomplish the report of individuation health guidance, the height that the report research object is suffered from coronary heart disease risk.The report of individuation health guidance is on genotype result's basis, suffers from the risk of coronary heart disease in conjunction with coronary heart disease mode of life hazard factor assessment research object, and makes to the healthy action scheme of the individuation of research object.
In sum; The present invention has found 9 important variant sites: rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and the rs11066280s relevant with coronary heart disease; The particular combination in these several sites has increased the individual risk of suffering from coronary heart disease greatly, further on this basis combining environmental factor; Be used to assess the individual coronary heart disease risk of suffering to be measured, can be good at discerning the high risk population of coronary heart disease.In view of the above; The doctor can calculate the scoring of coronary heart disease genetic risk factor; Accomplish report of research object genotype detection and the report of individuation health guidance, and the height of report research object trouble coronary heart disease risk, make to the healthy action scheme of the individuation of research object.Further can intervene targetedly, guidance should individuality changes bad life habits, reduces environmental factors to the bringing out of disease, and delays and prevents the pathogenetic purpose of coronary disease thereby reach.It is thus clear that technology of the present invention has important application prospects in the prediction of coronary heart disease and prevention.
Description of drawings
Fig. 1 is the dangerous allelotrope heredity of a coronary heart disease contribution quick checking chart.
Fig. 2 is that the scoring of coronary heart disease genetic risk factor divides into groups to check quickly chart.
Fig. 3 exposes the ROC curve of information prediction coronary heart disease risk for genetic risk factor scoring grouping and environmental factors.
Embodiment
In order more to be expressly understood the present invention, further describe the present invention with reference to the following example and accompanying drawing at present.Embodiment only is used for explaining and does not limit the present invention in any way.The experimental technique of unreceipted actual conditions is ordinary method and the normal condition that affiliated field is known among the embodiment, or the condition of advising according to manufacturers.
Embodiment one
At first in Chinese han population, choose the normal artificial research object of 7012 routine patients with coronary heart disease and 8579 examples; Gather fasting blood and collect age, sex, blood pressure level, lipid level, height, body weight, smoking, drink and relevant information such as history of disease, specific as follows:
Case-control sample inclusion criteria: the coronary heart disease case comprises myocardial infarction patient and patient with angina pectoris.The selected Case definition of myocardial infarction case is Diagnosis of Acute Myocardial Infarction standard (according to WHO a Case definition in 1979): promptly the typical chest pain symptom duration is more than 30 minutes; Continuous 2 the ST sections of leading of electrocardiogram(ECG are raised (limb leads 0.1mv, chest leads 0.2mv) and serial dynamic change are arranged; The serum marker substrate concentration of myocardial necrosis raises, and raises like troponin (TNT/TNI), and myocardium isozyme (CK-MB) raises greater than high 2 times of limitting of normal value.The selected Case definition of stenocardia case surpasses 70% for finding that through coronary angiography at least one main branch of coronary artery is narrow.Valvular heart disease, congenital heart disease, heart failure, serious kidney and hepatic diseases, secondary hypertension, myocardosis, familial hypercholesterolemia and suspicious patients with coronary heart disease except each item inspection.The case that meets above-mentioned diagnosis can be gone into anthology research.The control group inclusion criteria: previously there are not coronary heart disease or other Atheromatosis histories, no pectoralgia, cardiac symptom such as uncomfortable in chest, electrocardiogram(ECG does not have obvious ischemic change.Case group and control group are Chinese han population, and consanguinity-less relation.
The study population comprises 7012 routine patients with coronary heart disease and 8579 routine normal peoples, its essential characteristic such as following table:
| Case | Contrast | |
| Sample size | 7012 | 8579 |
| Male/female | 5887/1125 | 5865/2714 |
| Age | 51.65±8.03 | 55.31±8.80 |
| BMI(kg/m 2) | 26.27±3.64 | 24.65±3.64 |
| Systolic pressure (mmHg) | 124.09±17.80 | 140.23±22.86 |
| Diastolic pressure (mmHg) | 77.33±11.42 | 86.23±12.89 |
| Blood sugar (mg/dL) | 107.02±33.73 | 94.56±30.07 |
| TC(mg/dL) | 173.35±41.65 | 182.53±34.58 |
| TG(mg/dL) | 161.13±101.04 | 145.99±106.07 |
| HDLC(mg/dL) | 39.48±10.05 | 50.74±12.43 |
| LDLC(mg/dL) | 95.10±32.62 | 103.68±29.21 |
| Hypertension (%) | 57.06 | 56.52 |
| Mellitus (%) | 24.57 | 3.76 |
| Smoking (%) | 67.61 | 37.87 |
| (%) drinks | 44.41 | 32.51 |
The Forecasting Methodology of the ill risk of analysis coronary heart disease of present embodiment exposes the comprehensive assessment research object to suffer from the height of coronary heart disease risk in conjunction with research object genetic information and environmental factors, and this Forecasting Methodology may further comprise the steps:
(1) sets up the coronary heart disease information database, comprise that genotype information and environmental factors expose information.
(2) (2p24.1 zone rs2123536,4q32.1 zone rs1842896,6p24.1 zone rs9349379,6p21.32 zone rs9268402,6q23.2 zone rs12524865,9p21.3 zone rs10757274,9p21.3 zone rs1333042,12q21.33 zone rs7136259 and 12q24.13 zone rs11066280 carry out gene type and obtain genotype information through the pleomorphism site (SNP) to 9 ill risks of coronary heart disease.9 mononucleotide polymorphic sites and both wings sequence thereof are following:
rs2123536AAAGAGGGACGGGGAATCAGAAAGTG[T/C]GCGTCGTATTTCAGACATCAAACGT(SEQ?ID?No.1)
rs1842896AGTATTATTTAAAATAGCACCAAAAT[G/T]CATTCCCTTAAAAGCACTAGTTATC(SEQ?ID?No.2)
rs9349379GTCTATGCCCTTGAGATCATATAAAA[G/A]TAGCTTAAAATCATTGGCCATAGTT(SEQ?ID?No.3)
rs9268402aaatcttgagagggatatgaacatcc[A/G]gattgaagacgatcaaagcatccca(SEQ?ID?No.4)rs?12524865GAAGGTGAATGGGAAAAATAACTTAA[A/C]GTCAGTCCCAAAGGCTAAAGTGGTA(SEQ?ID?No.5)
rs10757274GTGGGTCAAATCTAAGCTGAGTGTTG[A/G]GACATAATTGAAATTCACTAGATAG(SEQ?ID?No.6)
rs1333042GGCAAGGGGACATACCAAACACTAAC[A/G]GGCACATTGGGGTTTTCTGGCTATT(SEQ?ID?No.7)
rs7136259aggtttgtgtagtacactgtgtgaat[C/T]tgcacaataacgaaattgcaacgca(SEQ?ID?No.8)
rs11066280GAGAGGTTCTTTCCTTTGAAAACCAT[A/T]CTTCTGTGGAAATAGCTGACAAATT(SEQ?IDNo.9)
Analytical results shows that above-mentioned 9 genotype polymorphism sites (rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280) are significantly related with the ill risk of coronary heart disease.Wherein, Rs2123536 carries T allelotrope, rs1842896 and carries T allelotrope, rs9349379 and carry G allelotrope, rs9268402 and carry G allelotrope, rs12524865 and carry C allelotrope, rs10757274 and carry G allelotrope, rs1333042 and carry G allelotrope, rs7136259 and carry T allelotrope and rs11066280 and carry the allelic individual risk of suffering from coronary heart disease of A and obviously raise, the ill risk of coronary heart disease 1.13 to 1.36 times (the seeing table 1) that raise.
Incidence relation between table 1.9 mononucleotide polymorphic site and coronary heart disease are ill
OR (95%CI) representes to compare with carrying the allelic individuality of reference, carries the allelic individual relative risk that coronary heart disease takes place of risk.
Comprehensive each individuality carries the dangerous allelotrope situation in 9 SNP sites; Each research object is carried out the scoring of coronary heart disease genetic risk factor; Methods of marking is that research object is carried the allelic number of risk and risk allelotrope effect value (log (OR)) and multiplied each other and obtain each SNP site hereditary effect, then the hereditary effect summation of 9 SNP is obtained coronary heart disease genetic risk factor scoring (the genetic risk factor scoring=∑ log (OR of this research object
i) * N
i, OR wherein
iThe relative risk that refers to i mononucleotide polymorphism site, N
iThe dangerous allelotrope number that refers to entrained i the mononucleotide polymorphism site of individuality to be measured).According to all research object coronary heart disease genetic risk factor scorings research object is divided into 5 groups.Be respectively the 1st group 0.115～1.200 (G1), the 2nd group 1.201～1.473 (G2), the 3rd group 1.474～1.737 (G3), the 4th group 1.738～2.021 (G4) and the 5th group 2.022～2.972 (G5).
In the present embodiment; Also according to 8579 healthy subjects that detected and 9 pleomorphism sites of 7012 patients with coronary heart disease (rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280) situation; Formulate hereditary contribution quick checking chart (Fig. 1) of the dangerous allelotrope of coronary heart disease and the scoring of coronary heart disease genetic risk factor and divided into groups to check chart (Fig. 2) quickly, can comparatively promptly draw genetic risk factor score value and grouping according to this data drawing list of detected result contrast when being beneficial to actual detected idiogenetics information.
(3) genotype information (scoring of genetic risk factor is divided into groups) and environmental factors exposure information index are carried out single factor analysis, corresponding statistical procedures method is following: the successive type variable adopts independent sample T check; Two classified variables adopt chi square test or the accurate stochastic method of Fisher; Inspection level is 0.05, and the result filters out the variable index that difference has statistical significance.
(4) with the variable that filters out do the logistic analysis of reaching the same goal; Carry out model testing; Obtain the corresponding β value of each factor, set up the equation of reaching the same goal, ln (p/ (1-p))=-0.220+0.232 * G2+0.403 * G3+0.534 * G4+0.852 * G5+0.178 * drink+1.110 * smoking+0.010 * blood glucose value+0.074 * weight index+(0.080) * high density lipoprotein cholesterol value); Calculate the relative risk of each factor: OR=Exp (β), see table 2.According to the Equation for Calculating of reaching the same goal do not have the heredity ln (p/ (1-p)) individual with the environmental risk factor (the genetic risk factor mark at first group, non-smoking and do not drink, the individuality of BMI, fasting plasma glucose and the normal M.L. of high density lipoprotein cholesterol) be 0.222; Therefore certain individuals is with respect to there not being the heredity risk profile model individual with the environmental risk factor: suffer from the ill relatively risk=exp of coronary heart disease (0.220+0.232 * G2+0.403 * G3+0.534 * G4+0.852 * G5+0.178 * drink+1.110 * smoking+0.010 * blood glucose value+0.074 * weight index+(0.080) * high density lipoprotein cholesterol value)/0.222, the ill relatively value-at-risk of calculating for mark at first group, non-smoking with respect to the genetic risk factor and do not drink, the multiple of the individuality generation coronary heart disease risk of BMI, fasting plasma glucose and the normal M.L. of high density lipoprotein cholesterol.This value shows that more greatly ill risk is high more.
Table 3-table 6 is to calculate and obtain in smoking population, non-smokers, drink crowd and non-drink the crowd relative risk (OR value) of h and E factor accordingly according to smoking and the back of dividing into groups of drinking.
The relative risk of the factor of the ill risk of table 2. coronary heart disease
The relative risk of the factor of the ill risk of table 3. smoking population coronary heart disease
The relative risk of the factor of the ill risk of table 4. non-smokers coronary heart disease
The drink relative risk of factor of the ill risk of crowd's coronary heart disease of table 5.
The relative risk of the factor of the non-ill risk of crowd's coronary heart disease of drinking of table 6.
(5) the ill relatively risk of trouble coronary heart disease that the risk profile Model Calculation goes out every research object is put in genetic risk factor scoring grouping and environmental factors exposure information; To suffer from the ill relatively risk of coronary heart disease is test variable; Whether ill with research object is state variables; Do experimenter's performance curve (ROC) analysis, estimate the value of this Forecasting Methodology according to TG-AUC.The detailed process of ROC tracing analysis is following: according to a series of ill risk truncation points research object is divided into two groups (predicting ill group and prediction normal group); Whether combine the research object actual diseased then; Calculate sensitivity and specific degree; With sensitivity is that ordinate zou is represented True Positive Rate, is that ordinate zou represents false positive rate drafting ROC curve as shown in Figure 3 with (1-specific degree).Area is 0.80 under the ROC.Show that this model prediction is functional, can well discern the coronary heart disease high risk population.
Show through above-mentioned experimental study of the present invention; The invention provides a kind of model according to gene pleiomorphism prediction combination individual level incidence of coronary heart disease risk; Can be good at discerning the high risk population of coronary heart disease; Thereby intervene targetedly, reach and delay and prevent the pathogenetic purpose of coronary disease.Utilize research object genotype result to calculate coronary heart disease danger and mark, accomplish report of research object genotype detection and the report of individuation health guidance, and report the height of research object trouble coronary heart disease risk.The report of individuation health guidance is on genotype result's basis, suffers from the risk of coronary heart disease in conjunction with coronary heart disease mode of life hazard factor assessment research object, and makes to the healthy action scheme of the individuation of research object.
Embodiment two
For example Zhang San seeks advice from its trouble coronary heart disease risk height.To analyze according to following steps:
(1) carries out questionnaire and somatometry
Collect Zhang San's age, sex, smoking and the situation of drinking; Measure and raise and body weight the calculating weight index.Obtain following information: Zhang San, the male sex, 55 years old, non-smoking was drunk, height 172cm, body weight 75KG.The weight index that obtains that calculates is 25.35.
(2) extract venous blood (anti-freezing, non-anti-freezing) on an empty stomach, measure blood sugar, high density lipoprotein cholesterol in the serum
Zhang San's glucose level is 90mg/dl, and high density lipoprotein cholesterol is 45mg/dl.
(3) separate DNA in the anticoagulation, detect the genotype in 9 sites and calculate the scoring of genetic risk factor
The genotype in 9 sites of Zhang San is respectively: rs2123536 is CT, and rs1842896 is GG, and rs9349379 is AA; Rs9268402 is AG, and rs12524865 is AA, and rs10757274 is GG; Rs1333042 is AG; Rs7136259 is CC, and rs11066280 is AT, and the allelic number of its risk is respectively: 1,0,0,1,0,2,1,0 and 1.Contrast the dangerous allelotrope heredity of coronary heart disease shown in Figure 1 contribution quick checking chart; Calculate genetic risk factor scoring=1 * 0.122+0 * 0.140+0 * 0.174+1 * 0.148+0 * 0.122+2 * 0.307+1 * 0.293+0 * 0.131+1 * 0.231=1.41; Contrast coronary heart disease genetic risk factor scoring grouping zoom table shown in Figure 2, belong to G2 and divide into groups.
(4) scoring of genetic risk factor and environmental risk factor are calculated the relative risk of changing coronary heart disease
Relative risk=the exp of Zhang San's coronary heart disease (0.220+0.232 * 1+0.403 * 0+0.534 * 0+0.852 * 0+0.178 * 1+1.110 * 0+0.010 * 90+0.074 * 25.35+ (0.080) * 45)/0.222=2.39; Show Zhang San with respect to the individuality that does not have heredity and environmental risk factor (the genetic risk factor mark at first group, non-smoking and do not drink, BMI, fasting plasma glucose and high density lipoprotein cholesterol be normal M.L.); 2.39 times of coronary heart disease risk take place, and belong to the high risk population.
(5) accomplish report of research object genotype detection and the report of individuation health guidance
Zhang San self has higher genetic predisposition, adds the bad life habits of smoking, and the risk of therefore suffering from coronary heart disease is higher.Should abstinence from alcohol, keep on a diet simultaneously and body weight, reduce the ill risk of coronary heart disease.
Claims (10)
1. many gene mononucleotide polymorphism sites and environmental factors combination, wherein,
Described a plurality of gene mononucleotide polymorphisms site comprises following site: rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280;
Described environmental factors comprises individual smoking, drinks, blood glucose value and high density lipoprotein cholesterol value in weight index information and the venous blood.
2. a plurality of gene mononucleotide polymorphisms site according to claim 1 and environmental factors combination, wherein,
Said rs2123536 carries T allelotrope, rs1842896 and carries T allelotrope, rs9349379 and carry G allelotrope, rs9268402 and carry G allelotrope, rs12524865 and carry C allelotrope, rs10757274 and carry that G allelotrope, rs1333042 carry G allelotrope, rs7136259 carries T allelotrope and rs11066280 carries A allelotrope;
Whether described environmental factors comprises whether smoking of individuality, drinks, blood glucose value and high density lipoprotein cholesterol value in weight index information and the venous blood.
3. claim 1 or a plurality of gene mononucleotide polymorphisms site of 2 and environmental factors are combined in preparation and are used for assessing individual application of suffering from the proofing unit of coronary heart disease risk to be measured.
4. detect the reagent of mononucleotide polymorphism site rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280 and detect the agent combination that individual environmental factors comprises blood glucose value and high density lipoprotein cholesterol value in the venous blood, be used for preparation, the test kit of vitro detection coronary heart disease correlative factor or be used to assess individual application of suffering from the proofing unit of coronary heart disease risk to be measured in preparation.
5. according to claim 3 or 4 described application, wherein, saidly be used to assess individual proofing unit of suffering from coronary heart disease risk to be measured and comprise detecting unit and data analysis unit;
Said detecting unit is to be used to detect idiogenetics information to be measured and environmental factors, obtains detected result; Wherein detect the dangerous allelotrope situation that the genetic information situation comprises that detection individuality to be measured carries said 9 mononucleotide polymorphism sites, the dangerous allelotrope of said 9 mononucleotide polymorphism sites is respectively: the rs2123536 pleomorphism site is that T, rs1842896 pleomorphism site are that T, rs9349379 pleomorphism site are that G, rs9268402 pleomorphism site are that G, rs12524865 pleomorphism site are that C, rs10757274 pleomorphism site are that G, rs1333042 pleomorphism site are that G, rs7136259 pleomorphism site are that T, rs11066280 pleomorphism site are A; Testing environment factor situation comprise detect whether smoking of individuality to be measured, whether drink, blood glucose value and high density lipoprotein cholesterol value in weight index information and the venous blood;
Said data analysis unit is to be used for the detected result of detecting unit is carried out analyzing and processing, comprising:
Calculate individual coronary heart disease genetic risk factor scoring to be measured according to following formula:
Genetic risk factor scoring=∑ log (OR
i) * N
i, OR wherein
iThe relative risk that refers to i mononucleotide polymorphism site, N
iThe dangerous allelotrope number that refers to entrained i the mononucleotide polymorphism site of individuality to be measured;
Judge individual packets to be measured according to score value, the 1st group of G1:0.115～1.200, the 2nd group of G2:1.201～1.473, the 3rd group of G3:1.474～1.737, the 4th group of G4:1.738～2.021, the 5th group of G5:2.022～2.972;
Calculate the ill relatively risk score of trouble coronary heart disease according to following formula:
Suffer from the ill relatively risk score=exp of coronary heart disease (0.220+0.232 * G2+0.403 * G3+0.534 * G4+0.852 * G5+0.178 * drink+1.110 * smoking+0.010 * blood glucose value+0.074 * weight index+(0.080) * high density lipoprotein cholesterol value)/0.222; Smoking, drink and for " being " perhaps " deny ", " being " is 1, and " denying " is 0; Weight index is BMI=body weight/height
2, unit is Kg/m
2Blood sugar, determine cholesterol with high density lipoprotein method are 12 hours on an empty stomach, and unit is mg/dl;
The height reflection individual dangerous height of coronary heart disease of suffering to be measured of wherein, suffering from the ill relatively risk score of coronary heart disease.
6. according to claim 3 or 4 described application; Wherein, Said a plurality of gene mononucleotide polymorphism Sites Combination state provides the individual coronary heart disease risk rate information of suffering to be measured, and said rs2123536 carries T allelotrope, rs1842896 and carries T allelotrope, rs9349379 and carry G allelotrope, rs9268402 and carry G allelotrope, rs12524865 and carry C allelotrope, rs10757274 and carry G allelotrope, rs1333042 and carry G allelotrope, rs7136259 and carry T allelotrope and rs11066280 and carry the allelic individual risk of suffering from coronary heart disease of A and raise 1.13 to 1.36 times.
7. vitro detection is from the reagent of mononucleotide polymorphism site: rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280 in the sample of individuality to be measured and the agent combination that detects blood glucose value and high density lipoprotein cholesterol value in the individual venous blood; Application in preparation, test kit or the proofing unit of the danger for preparing prediction individual trouble coronary heart disease to be measured; Wherein, said rs2123536 carries T allelotrope, rs1842896 and carries T allelotrope, rs9349379 and carry G allelotrope, rs9268402 and carry G allelotrope, rs12524865 and carry C allelotrope, rs10757274 and carry G allelotrope, rs1333042 and carry G allelotrope, rs7136259 and carry T allelotrope and rs11066280 and carry allelic individual the dangerous of coronary heart disease of suffering from of A and significantly raise.
8. according to claim 3,4 or 7 described application, wherein said individuality to be measured is a Chinese han population; Preferably, testing sample is from blood, urine, saliva, gastric juice, hair or the examination of living tissue of individuality to be measured.
9. according to claim 4 or 7 described application, the reagent of wherein said detection mononucleotide polymorphism site rs2123536, rs1842896, rs9349379, rs9268402, rs12524865, rs10757274, rs1333042, rs7136259 and rs11066280 is: the reagent that is used for direct sequencing; Or be used for the reagent that the polymerase chain reaction combines with the restriction fragment length polymorphism analysis; Or be used for the reagent that the polymerase chain reaction combines with direct sequencing; Or be used for the reagent that the polymerase chain reaction combines with direct sequencing; Or be used for the reagent of following any SNP classifying method: based on the method for hybridization, based on the method for primer extension, based on the method or the high resolving power solubility curve analytical technology of conformation.
10. one kind is used to assess individual proofing unit of suffering from coronary heart disease risk to be measured, and this device comprises detecting unit and data analysis unit, wherein:
Said detecting unit is to be used to detect idiogenetics information to be measured and environmental factors, obtains detected result; Wherein detect the dangerous allelotrope situation that the genetic information situation comprises that detection individuality to be measured carries said 9 mononucleotide polymorphism sites, the dangerous allelotrope of said 9 mononucleotide polymorphism sites is respectively: the rs2123536 pleomorphism site is that T, rs1842896 pleomorphism site are that T, rs9349379 pleomorphism site are that G, rs9268402 pleomorphism site are that G, rs12524865 pleomorphism site are that C, rs10757274 pleomorphism site are that G, rs1333042 pleomorphism site are that G, rs7136259 pleomorphism site are that T, rs11066280 pleomorphism site are A; Testing environment factor situation comprise detect whether smoking of individuality to be measured, whether drink, blood glucose value and high density lipoprotein cholesterol value in weight index information and the venous blood;
Said data analysis unit is to be used for the detected result of detecting unit is carried out analyzing and processing, comprising:
Calculate individual coronary heart disease genetic risk factor scoring to be measured according to following formula:
Genetic risk factor scoring=∑ log (OR
i) * N
i, OR wherein
iThe relative risk that refers to i mononucleotide polymorphism site, N
iThe dangerous allelotrope number that refers to entrained i the mononucleotide polymorphism site of individuality to be measured;
Judge individual packets to be measured according to score value, the 1st group of G1:0.115～1.200, the 2nd group of G2:1.201～1.473, the 3rd group of G3:1.474～1.737, the 4th group of G4:1.738～2.021, the 5th group of G5:2.022～2.972;
Calculate the ill relatively risk score of trouble coronary heart disease according to following formula:
Suffer from the ill relatively risk score=exp of coronary heart disease (0.220+0.232 * G2+0.403 * G3+0.534 * G4+0.852 * G5+0.178 * drink+1.110 * smoking+0.010 * blood glucose value+0.074 * weight index+(0.080) * high density lipoprotein cholesterol value)/0.222; Smoking, drink and for " being " perhaps " deny ", " being " is 1, and " denying " is 0; Weight index is BMI=body weight/height
2, unit is Kg/m
2Blood sugar, determine cholesterol with high density lipoprotein method are 12 hours on an empty stomach, and unit is mg/dl.
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| CN108676873A (en) * | 2018-07-25 | 2018-10-19 | 上海海洋大学 | Detect the suspension microballon array system of coronary heart disease susceptibility loci |
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| CN114075599A (en) * | 2020-08-17 | 2022-02-22 | 中国科学院上海营养与健康研究所 | Application of single nucleotide polymorphism sites in preparation of genetic risk scoring system of metabolism-related factors |
| CN113506594A (en) * | 2021-05-26 | 2021-10-15 | 中国医学科学院阜外医院 | Construction method, device and application of multi-gene genetic risk comprehensive score of coronary heart disease |
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| CN113506594B (en) * | 2021-05-26 | 2023-02-03 | 中国医学科学院阜外医院 | Construction method, device and application of polygene genetic risk comprehensive score of coronary heart disease |
| CN114898809A (en) * | 2022-04-11 | 2022-08-12 | 中国科学院数学与***科学研究院 | Analysis method and storage medium for gene-environment interaction suitable for complex traits |
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