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2. (WO2010142713) RISK MARKERS FOR CARDIOVASCULAR DISEASE
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Claims

1. A method of determining whether a subject has an increased risk of having an adverse cardiovascular disease or disorder or of determining the response to a cardiovascular therapy in a subject comprising the steps of determining in a sample isolated from said subject the presence of polymorphisms at positions 27 within the nucleic acid sequences of SEQ ID N0:1 to 11, wherein the presence at position 27 of a C in SEQ ID N0:1, A in SEQ ID N0:2, C in SEQ ID N0:3, T in SEQ ID N0:4, C in SEQ ID N0:5, A in SEQ ID N0:6, T in SEQ ID N0:7, C in SEQ ID N0:8, C in SEQ ID N0:9, T in SEQ ID NO:10 and T in SEQ ID N0:11 is indicative of an increased risk of having an adverse cardiovascular disease or disorder or of a low response to a cardiovascular therapy.

2. A method of determining whether a subject has an increased risk of having an adverse cardiovascular disease or disorder or of determining the response to a cardiovascular therapy in a subject comprising the steps of determining in a sample isolated from said subject the presence of one or more polymorphisms as defined in table 1A as indicative of an increased risk of having an adverse cardiovascular disease or disorder or of a low response to a cardiovascular therapy.

3. A method as defined in claim 1 or 2 wherein the cardiovascular disease is selected from the group of myocardial infarction, stroke, angina pectoris, transient ischemic attacks, congestive heart failure, aortic aneurysm or a combination thereof.

4. A method for identifying a subject in need of early and/or aggressive cardiovascular therapy or in need of prophylactic cardiovascular therapy comprising the steps of determining in a sample isolated from said subject the presence in at least one allele of polymorphisms at positions 27 within a nucleic acid sequences of SEQ ID N0:1 to 11, wherein the presence at position 27 of a C in SEQ ID N0:1, A in SEQ ID N0:2, C in SEQ ID N0:3, T in SEQ ID N0:4, C in SEQ ID N0:5, A in SEQ ID N0:6, T in SEQ ID N0:7, C in SEQ ID N0:8, C in SEQ ID N0:9, T in SEQ ID NO:10 and T in SEQ ID N0:11 or the presence of one or more polymorphisms as defined in Table 1A is indicative of having a decreased response to a cardiovascular therapy or of being in need of early and aggressive cardiovascular therapy or in need of prophylactic cardiovascular treatment.

5. A method as defined in any of claims 1 or 3 further comprising determining one or more of a cardiovascular disease or disorder risk factor selected from the group consisting of age, race, sex, body mass index, blood pressure, smoking status, low density lipoprotein (LDL)- or high density lipoprotein (HDL)-cholesterol level, systolic blood pressure, diastolic blood pressure, history of heart failure, diabetes, renal insufficiency, left ventricular hypertrophy, alcohol consumption history, smoking history, exercise history, diet, and family history of cardiovascular disease or disorder.

6. The method according to any one of claims 1 to 5 wherein the sample is an oral tissue sample, scraping, or wash or a biological fluid sample, preferably saliva, urine or blood.

7. The method according to any one or more of claims 1 to 6 wherein the presence or absence of the polynucleotide is identified by amplifying or failing to amplify an amplification product from the sample, wherein the amplification product is preferably digested with a restriction enzyme before analysis and/or wherein the SNP is identified by hybridizing the nucleic acid sample with a primer label which is a detectable moiety.

8. A method of treatment of a patient suffering from a cardiovascular disease with a cardiovascular therapy wherein the patient is selected for said therapy based on the presence in a sample isolated from said subject of a polymorphism at position 27 in the nucleotide sequences of SEQ ID N0:1 to 11, wherein said polymorphism at said position 27 is C in SEQ ID N0:1, A in SEQ ID N0:2, C in SEQ ID N0:3, T in SEQ ID N0:4, C in SEQ ID N0:5, A in SEQ ID N0:6, T in SEQ ID N0:7, C in SEQ ID N0:8, C in SEQ ID N0:9, T in SEQ ID NO:10 and T in SEQ ID N0:11.

9. A method of treatment of a patient suffering from a cardiovascular disease with a cardiovascular therapy wherein the patient is selected for said therapy based on the presence in a sample isolated from said subject of one or more polymorphisms as defined in Table 1A.

10. A method as defined in claim 8 or 9 wherein the cardiovascular disease is selected from the group of myocardial infarction, stroke, angina pectoris, transient ischemic attacks, congestive heart failure, aortic aneurysm or a combination thereof.

11. A method of determining the probability of an individual of presenting a fatal or non-fatal myocardial infarction or angina in a 10 year period based on the presence of 1 to P classical risk factors and 1 to J polymorphisms at positions 27 in the nucleotide sequences of SEQ ID NO:1 to 11, wherein said polymorphisms at said positions 27 are selected from the group of C in SEQ ID NO:1, A in SEQ ID NO:2, C in SEQ ID NO:3, T in SEQ ID NO:4, C in SEQ ID NO:5, A in SEQ ID NO:6, T in SEQ ID NO:7, C in SEQ ID NO:8, C in SEQ ID NO:9, T in SEQ ID NO:10 and T in SEQ ID NO:11 using the formula:

wherein, *SNPj
is the mean survival free of coronary events at the population,

p ' is the summatory function along the P classical risk factors, βCRF p is the logarithm of hazard ratio corresponding to the classical coronary risk factor "p" as shown in table A,

CRFp.i is the value of each coronary risk factor "p" included in the equation for an individual Y1

Σ j ' is the summatory function along the J genetic variants.

SNPy is the logarithm of hazard ratio corresponding to the genetic variant Y as shown in table B.

SNPj.i is the number of risk alleles (0,1,2) for a specific genetic variant "j" included in the equation for an individual "i". p is the average value for the classical risk factor "p" in the population.

SNP

J is the average risk allele number of copies for genetic variant "j" in the population.

12. A method of determining the probability of an individual of presenting a fatal or non-fatal myocardial infarction or angina in a 10 year period based on the presence of 1 to P classical risk factors and 1 to J polymorphisms as defined in Table 1A1 using the formula:

wherein, — j

.exp ∑βCRF *CRFP)) + ∑/?SNP *SNPJ;1 - ∑βCRF *CRFP - ∑/3SNP *SNPj

1 -S p=l μ j=l J p=l v j=l J

^ is the mean survival free of coronary events at the population, p

Σ p ' is the summatory function along the P classical risk factors,

p is the logaπthm of hazard ratio corresponding to the classical coronary πsk factor "p" as shown in table A, CRFp.i is the value of each coronary risk factor "p" included in the equation for an individual "f ,

Σ

J ' is the summatory function along the J genetic variants.

SN?J is the logarithm of hazard ratio corresponding to the genetic variant "j" as shown in table B. SNPj, i is the number of risk alleles (0,1,2) for a specific genetic variant "j" included in the equation for an individual "ι".

CRF p is the average value for the classical risk factor "p" in the population.

SNP

J is the average πsk allele number of copies for genetic vaπant "j" in the population. 13. A method of determining the probability of an individual of presenting a fatal or non-fatal myocardial infarction or angina in a 10 year period based on the presence of 1 to P different classical risk factors and 1 to Q different genetic variants wherein said genetic variant is a polymorphism at positions 27 in the nucleotide sequences of SEQ ID NO: 1 to 11 , wherein said polymorphism at said position 27 are selected from the group of C in SEQ ID NO.1, A in SEQ ID NO.2, C in SEQ ID NO.3, T in SEQ ID NO.4, C in SEQ ID NO.5, A in SEQ ID NO:6, T in SEQ ID NO:7, C in SEQ ID NO:8, C in SEQ ID NO:9, T in SEQ ID NO:10 and T in SEQ ID NO 11 using the formula"

SQ *GSQQ


wherein

is the mean survival free of coronary events at the population. This survival will be adapted to the regional or national rates.

P

Σ p"' is the summatory function along the P classical risk factors, βCRF p is the logarithm of hazard ratio corresponding to the classical coronary risk factor "p" as shown in table C.

CRFpj is the value of each coronary risk factor "p" included in the equation for an individual "i".

Q

Σ q ' is the summatory function along the Q (5) quintiles. βGSQq is the logarithm of hazard ratio corresponding to different genetic score quintiles (GSQ) "q" as shown in table D,

GSQq, i is the genetic score quintile "q" according to the distribution of the number of risk alleles (0,1,2) for the genetic variants included in the equation at the population level for an individual "i built according to the allele frequencies of the genetic variants, p is the average value for the classical risk factor "p" in the population.

Q is the values from 1 to 5 of the different quintiles for the genetic score quintile "q" in the population.

14. A method of determining the probability of an individual of presenting a fatal or non-fatal myocardial infarction or angina in a 10 year period based on the presence of 1 to P different classical risk factors and 1 to Q different genetic variants wherein said genetic variant is a polymorphism as defined in Table 1A, using the formula:


is the mechr 'ssuurrvvii'val free of coronary events at the population. This survival or national rates.

P

Σ

M is the summatory function along the P classical risk factors,

0, CKP p is the logarithm of hazard ratio corresponding to the classical coronary risk factor "p" as shown in table C.

CRFp.i is the value of each coronary risk factor "p" included in the equation for an individual Y Q Σ q ' is the summatory function along the Q (5) quintiles. βGSQq is the logarithm of hazard ratio corresponding to different genetic score quintiles (GSQ) "q" as shown in table D,

GSQq.i is the genetic score quintile "q" according to the distribution of the number of risk alleles (0,1,2) for the genetic variants included in the equation at the population level for an individual 1 built according to the allele frequencies of the genetic variants, p is the average value for the classical risk factor "p" in the population.

Q is the values from 1 to 5 of the different quintiles for the genetic score quintile "q" in the population.

15. A method of determining the probability of an individual of presenting a fatal or non-fatal myocardial infarction or angina in a 10 year period based on the presence of 1 to P different classical risk factors and 1 to Q different genetic variants wherein said genetic variant is a polymorphism at positions 27 in the nucleotide sequences of SEQ ID NO:1 to 11 , wherein said polymorphism at said position 27 is selected from the group of C in SEQ ID NO:1, A in SEQ ID NO:2, C in SEQ ID NO:3, T in SEQ ID NO:4, C in SEQ ID NO:5, A in SEQ ID NO:6, T in SEQ ID NO:7, C in SEQ ID NO:8, C in SEQ ID NO:9, T in SEQ ID NO:10 and T in SEQ ID NO:11 using the steps of: compute the linear combination of risk factors wi using the function w, = PcHo1 * [cholesterol, - 6)+ βSPB * {SBP, - 12θ) + βsmoka * current, + ∑βSNPj * (sNP,j - SNP^) wherein cholesteroli: cholesterol level for the individual "i" in mmol/L. βchol: logarithm of hazard ratio corresponding to the cholesterol (Table E).

SBPi: systolic blood pressure for the individual "i" in mmHg. βSBP: logarithm of hazard ratio corresponding to systolic blood pressure (Table E). currenti: current smoking status for the individual "i" (1: current, 0: former/never). βsmoker: logarithm of hazard ratio corresponding to systolic blood pressure (Table E).

∑β^ iβNPij - SNP.j)

J=I

Σ j ' summatory function along the J genetic variants. β SNPy logarithm of hazard ratio corresponding to the genetic variant "j". The possible range of values of the β for each genetic variant "j" is shown in table B.

SNPj.i: number of risk alleles (0,1,2) for a specific genetic variant "j" included in the equation for an individual "i".

SNP- 1 : average risk allele number of copies for genetic variant "j" in the population. This average value will be adapted to the regional or national prevalence. compute the baseline survival So for a given age using the function

S0 (age) = exp{- exp(α) * (age - 20)" }

S0 (age + 10) = exp{- exp(α) * (age -10)"} wherein α, p: shape and scale parameters of the weibull distribution. Their values are shown in Table F (parameters) exp: natural exponentiation compute 10 years survival S10(age) using the function

S(age) = {Sϋ(age)}M

S(age + \0) = {SQ(age + \0)}np(w)

Si0(age) = S(age + 10) I S (age)

compute the probability of having the event during the 10 years follow-up ιs 10 ^a&e' using the function . Riskλ0 (age) = \ -Sλ0(age) and compute the probability of having a cardiovascular event during the 10 years follow-up CVDRiskiO as the sum of coronary and non-coronary cardiovascular risk using the function

CVDRiSk10 = [CHDRisk^0(age)]+ [Non - CHDRis^age)]

16. A method of determining the probability of an individual of presenting a fatal or non-fatal myocardial infarction or angina in a 10 year period based on the presence of 1 to P different classical risk factors and 1 to Q different genetic variants wherein said genetic variant is a polymorphism as defined in Table 1A, using the steps of : compute the linear combination of risk factors wi using the function w. = PcHo, * {cholesterol, - 6)+ βSPB * {SBP, - 12θ)+ βsmotø ^ current, + ∑βSNPj * (sNPltJ - SNϊQ wherein cholesteroli: cholesterol level for the individual "i" in mmol/L βchol: logarithm of hazard ratio corresponding to the cholesterol (Table E).

SBPi: systolic blood pressure for the individual "i" in mmHg. βSBP: logarithm of hazard ratio corresponding to systolic blood pressure (Table E).

currenti: current smoking status for the individual "i" (1: current, O: former/never), βsmoker: logarithm of hazard ratio corresponding to systolic blood pressure (Table E).


Σ

J"' summatory function along the J genetic variants.

SNPy' logarithm of hazard ratio corresponding to the genetic variant "j". The possible range of values of the β for each genetic variant "j" is shown in table B. SNPjJ: number of risk alleles (0,1 ,2) for a specific genetic variant "j" included in the equation for an individual "i".

SNP- ' : average risk allele number of copies for genetic variant "j" in the population. This average value will be adapted to the regional or national prevalence, compute the baseline survival So for a given age using the function

S0 (age) = exp{- exp(α) * (age - 20)' }

S0 (age + 10) = exp{- exp(α) * (age -10)'} wherein α, p: shape and scale parameters of the weibull distribution. Their values are shown in Table F (parameters) exp: natural exponentiation compute 10 years survival S10(age) using the function

S(age) = {S0(age)f*p(w)

S(age + \0) = {S0(age + \0)}exp(w)

Sι0(age) = S(age + \0)/S(age)

compute the probability of having the event during the 10 years follow-up 1S 10 ^a^e' using the function . Risk10(age) = l - Si0 (age) and compute the probability of having a cardiovascular event during the 10 years follow-up CVDRiski 0 as the sum of coronary and non-coronary cardiovascular risk using the function

CVDRiSk10 = [CHDRisk,0(age)] + [Non - CHDRisk,0 (age)]

17. A method as defined in claims 13 to 16 wherein a plurality of classical risk factors "p" are used being said plurality being selected from the group of:

Sex, age, Total cholesterol, HDL-cholesterol, blood pressure, diabetes and smoking,

Age, LDL-cholesterol, HDL-cholesterol, triglycerides, systolic blood pressure, family story of myocardial infarction and diabetes,

Sex, Log(age/10), total cholesterol/HDL-cholesterol, body mass index, family story of premature CVD, smoking,

Townsend score of output area, systolic blood pressure, treatment for hypertension and interaction SBPΗTN treatment.

18. A computer program or a computer-readable media containing means for carrying out a method as defined in any of claims 1 to 17.

19. A kit comprising reagents for detecting the identity of the nucleotide at position 27 within a nucleic acid sequence selected from the group of SEQ ID N0:1 to 11 or for detecting the identity of polymorphisms as defined in Table 1A.

20. A kit as defined in claim 19 which comprises one or more primer pairs specific for the amplification of a region comprising at least position 27 within a nucleic acid sequence of SEQ ID N0:1 to 12, or specific for the polymoφhisms as defined in Table 1 A.