Risk assessment for cardiovascular disease

A method for identifying a human subject in need of cardiovascular therapy or in need of preventive cardiovascular therapy/measurements for a cardiovascular event, comprising steps of:

• a) determining in a sample isolated from said human subject a presence in at least one allele of a polymorphism at position 27 within each nucleic acid sequence set forth in SEQ ID NOs:
• 2, 3, 4, 5, 7, 8, 9, 10, 11 or 16, 12, and 35, wherein presence at position 27 of a C in SEQ ID NO:
• 2, T in SEQ ID NO:
• 3, C in SEQ ID NO:
• 4, C in SEQ ID NO:
• 5, T in SEQ ID NO:
• 7, G in SEQ ID NO:
• 8, A in SEQ ID NO:
• 9, A in SEQ ID NO:
• 10, A in SEQ ID NO:
• 11 or A in SEQ ID NO:
• 16, G in SEQ ID NO:
• 12, and T in SEQ ID NO:
• 35 is indicative of having a decreased response to a cardiovascular therapy, being in need of an early and aggressive cardiovascular therapy, or in need of a prophylactic cardiovascular treatment;
• b) based on the presence of the polymorphisms determined in step a), selecting the human subject as being in need of cardiovascular therapy or in need of preventive cardiovascular therapy/measurements for a cardiovascular event;
• and
• c) administering to the selected human subject an agent with hypolipemic capabilities, an anticoagulant, an antiplatelet agent, a thrombolytic agent, an antithrombotic, an antiarrhythmic agent, an agent that prolongs repolarization, an antihypertensive agent, a vasodilator, a diuretic, an inotropic agent, and/or an antianginal agent.

A method to establish therapeutical objectives of preventive treatments and/or therapeutical treatments for a human subject having a cardiovascular event or suspected of having a predisposition for a cardiovascular event, comprising steps of:

• a) determining in a sample isolated from said human subject a presence of a polymorphism at position 27 within each nucleic acid sequence set forth in SEQ ID NOs:
• 2, 3, 4, 5, 7, 8, 9, 10, 11 or 16, 12, and 35, wherein presence at position 27 of a C in SEQ ID NO:
• 2, T in SEQ ID NO:
• 3, C in SEQ ID NO:
• 4, C in SEQ ID NO:
• 5, T in SEQ ID NO:
• 7, G in SEQ ID NO:
• 8, A in SEQ ID NO:
• 9, A in SEQ ID NO:
• 10, A in SEQ ID NO:
• 11 or A in SEQ ID NO:
• 16, G in SEQ ID NO:
• 12, and T in SEQ ID NO:
• 35 is indicative of the human subject being in need of the preventive treatments and/or the therapeutical treatments;
• b) based on the presence of the polymorphisms determined in step a), selecting the human subject as being in need of cardiovascular therapy or in need of preventive cardiovascular therapy/measurements for a cardiovascular event;
• and
• c) administering to the selected human subject an agent with hypolipemic capabilities, an anticoagulant, an antiplatelet agent, a thrombolytic agent, an antithrombotic, an antiarrhythmic agent, an agent that prolongs repolarization, an antihypertensive agent, a vasodilator, a diuretic, an inotropic agent, and/or an antianginal agent.

A method of determining a probability of a human subject presenting a fatal or non-fatal myocardial infarction or angina in a 10 year period based on a presence of 1 to P classical risk factors and 1 to J polymorphism at position 27 within each nucleic acid sequence set forth in SEQ ID NOs:

• 2, 3, 4, 5, 7, 8, 9, 10, 11 or 16, 12, and 35, wherein said polymorphism at said position 27 is C in SEQ ID NO:
• 2, T in SEQ ID NO:
• 3, C in SEQ ID NO:
• 4, C in SEQ ID NO:
• 5, T in SEQ ID NO:
• 7, G in SEQ ID NO:
• 8, A in SEQ ID NO:
• 9, A in SEQ ID NO:
• 10, A in SEQ ID NO:
• 11 or A in SEQ ID NO:
• 16, G in SEQ ID NO:
• 12, and T in SEQ ID NO:
• 35, the method comprising:
• a) determining the probability using the formula:
• 1
• -
• S
• ⋒
• e
• ⁢
• ⁢
• xp
• [
• ∑
• p
• =
• 1
• P
• ⁢
• β
• CRF
• p
• *
• ⁢
• CRF
• p
• ,
• i
• +
• ∑
• j
• =
• 1
• J
• ⁢
• β
• SNP
• j
• *
• ⁢
• SNP
• j
• ,
• i
• -
• ∑
• p
• =
• 1
• P
• ⁢
• β
• CRF
• p
• *
• ⁢
• CR
• ⁢
• F
• P
• _
• -
• ∑
• j
• =
• 1
• J
• ⁢
• β
• SNP
• j
• *
• ⁢
• SNP
• j
• _
• ]
• wherein,
• S is a mean survival free of coronary events in a population,
• ∑
• p
• =
• 1
• P
• is a summatory function along the P classical risk factors,
• βCRFp is a logarithm of hazard ratio corresponding to classical risk factor “p”,
• CRFp,i is a value of each classical risk factor “p” included in the equation for the human subject “i”,
• ∑
• j
• =
• 1
• J
• is a summatory function along the J genetic variants,
• βSNP j is a logarithm of hazard ratio corresponding to genetic variant “j”,
• SNPj,i is a number of risk alleles (0,1,2) for genetic variant “j” included in the formula for the human subject “i”,
• CRFP is an average value for the classical risk factor “p” in the population, and
• SNPj is an average risk allele number of copies for genetic variant “j” in the population;
• b) based on the probability determined in step a), selecting the human subject as having an elevated probability of presenting a fatal or non-fatal myocardial infarction or angina in a 10 year period;
• and
• c) administering to the selected human subject an agent with hypolipemic capabilities, an anticoagulant, an antiplatelet agent, a thrombolytic agent, an antithrombotic, an antiarrhythmic agent, an agent that prolongs repolarization, an antihypertensive agent, a vasodilator, a diuretic, an inotropic agent, and/or an antianginal agent.

A method of determining a probability of an individual “i” presenting a fatal or non-fatal myocardial infarction or angina in a 10 year period based on a presence of 1 to P different classical risk factors and 1 to Q different genetic variants, wherein said genetic variants is comprised of a polymorphism at position 27 within each nucleic acid sequence set forth in SEQ ID NOs:

• 2, 3, 4, 5, 7, 8, 9, 10, 11 or 16, 12, and 35, wherein presence at position 27 of a C in SEQ ID NO:
• 2, T in SEQ ID NO:
• 3, C in SEQ ID NO:
• 4, C in SEQ ID NO:
• 5, T in SEQ ID NO:
• 7, G in SEQ ID NO:
• 8, A in SEQ ID NO:
• 9, A in SEQ ID NO:
• 10, A in SEQ ID NO:
• 11 or A in SEQ ID NO:
• 16, G in SEQ ID NO:
• 12, and T in SEQ ID NO:
• 35 wherein the method comprises steps of:
• a) determining the probability using the formula:
• 1
• -
• S
• ⋒
• e
• ⁢
• ⁢
• xp
• [
• ∑
• p
• =
• 1
• P
• ⁢
• β
• CRF
• p
• *
• ⁢
• CRF
• p
• ,
• i
• +
• β
• GRS
• *
• ⁢
• GRS
• i
• -
• ∑
• p
• =
• 1
• P
• ⁢
• β
• CRF
• p
• *
• ⁢
• CR
• ⁢
• F
• P
• _
• -
• β
• GRS
• *
• ⁢
• GRS
• _
• ]
• wherein
• Ŝ is a mean survival free of coronary events in a population,
• GRSi is a genetic risk score defined as a weighted number of risk alleles for the J genetic variants included in the formula for the individual “i”,
• Exp is natural exponentiation,
• ∑
• p
• =
• 1
• P
• is a summatory function along the P classical risk factors,
• βCRFp is a logarithm of hazard ratio corresponding to classical coronary risk factor “p”,
• CRFp,i is a value of each coronary risk factor “p” included in the formula for the individual “i”,
• βGRS is a logarithm of hazard ratio corresponding to one unit increase in the value of the genetic risk score,
• CRFP is an average value for classical risk factor “p” in the population, and
• GRS is a mean value of the genetic risk score in the population;
• b) based on the probability determined in step a), selecting the individual as having an elevated probability of presenting a fatal or non-fatal myocardial infarction or angina in a 10 year period;
• and
• c) administering to the selected individual an agent with hypolipemic capabilities, an anticoagulant, an antiplatelet agent, a thrombolytic agent, an antithrombotic, an antiarrhythmic agent, an agent that prolongs repolarization, an antihypertensive agent, a vasodilator, a diuretic, an inotropic agent, and/or an antianginal agent.

A method of determining a probability of an individual “i” presenting a fatal or non-fatal myocardial infarction or angina in a 10 year period based on a presence of 1 to P different classical risk factors and 1 to J different genetic variants, wherein said genetic variants is comprised of a polymorphism at position 27 within each nucleic acid sequence set forth in SEQ ID NOs:

• 2, 3, 4, 5, 7, 8, 9, 10, 11 or 16, 12, and 35, wherein presence at position 27 of a C in SEQ ID NO:
• 2, T in SEQ ID NO:
• 3, C in SEQ ID NO:
• 4, C in SEQ ID NO:
• 5, T in SEQ ID NO:
• 7, G in SEQ ID NO:
• 8, A in SEQ ID NO:
• 9, A in SEQ ID NO:
• 10, A in SEQ ID NO:
• 11 or A in SEQ ID NO:
• 16, G in SEQ ID NO:
• 12, and T in SEQ ID NO:
• 35 wherein the method comprises:
• a) determining the probability using steps of:
• (i) computing a linear combination of risk factors wi using the function
• w
• i
• =
• β
• chol
• *
• ⁡
• (
• cholesterol
• i
• -
• 6
• )
• +
• β
• SPB
• *
• ⁡
• (
• SBP
• i
• -
• 120
• )
• +
• β
• smoker
• *
• ⁢
• current
• i
• +
• ∑
• j
• =
• 1
• J
• ⁢
• β
• SNP
• j
• *
• ⁡
• (
• SNP
• i
• ,
• j
• -
• SNP
• i
• ,
• j
• _
• )
• wherein
• cholesterol is a cholesterol level for the individual “i”,
• βchol is a logarithm of hazard ratio corresponding to the cholesterol,
• SBPi is a systolic blood pressure for the individual “i”,
• βSBP is a logarithm of hazard ratio corresponding to systolic blood pressure,
• currenti is a current smoking status for the individual “i”,
• βsmoker:
• is a logarithm of hazard ratio corresponding to current smoking status,
• ∑
• j
• =
• 1
• J
• is a summatory function along the J genetic variants,
• βSNP j is a logarithm of hazard ratio corresponding to genetic variant “j”,
• SNPj,i is a number of risk alleles (0,1,2) of genetic variant “j” included in the formula for the individual “i”,
• SNPj is an average risk allele number of copies for genetic variant “j” in a population,
• (ii) computing the baseline survival SO for a given age using the function
• S0(age)=exp{−exp(α)*(age−20)p}
• S0(age+10)=exp{−exp(α)*(age−10)p}
• wherein
• α, p are shape and scale parameters of the weibull distribution, and
• exp is natural exponentiation,
• (iii) computing 10 years survival S10(age) using the function
• S(age)={S0(age)}exp(w)
• S(age+10)={S0(age+10)}exp(w)
• S10(age)=S(age+10)/S(age)
• (iv) computing the probability of having an event during the 10 years follow-up Risk10 (age) using the function,
• Risk10(age)=1−S10(age)
• and
• (v) computing the probability of having a cardiovascular event during the 10 years follow-up as the sum of coronary and non-coronary cardiovascular risk using the function
• CVDRisk10=[CHDRisk10(age)]+[Non-CHDRisk10(age)];
• b) based on the probability determined in step a), selecting the individual as having an elevated probability of presenting a fatal or non-fatal myocardial infarction or angina in a 10 year period;
• and
• c) administering to the selected individual an agent with hypolipemic capabilities, an anticoagulant, an antiplatelet agent, a thrombolytic agent, an antithrombotic, an antiarrhythmic agent, an agent that prolongs repolarization, an antihypertensive agent, a vasodilator, a diuretic, an inotropic agent, and/or an antianginal agent.