Researchers Submit Patent Application, “Polygenic Score for Cardiac Heart Failure”, for Approval (USPTO 20220333169): Henry Ford Health System
2022 NOV 08 (NewsRx) -- By a
The patent’s assignee is
News editors obtained the following quote from the background information supplied by the inventors: “Beta-blockers (BB) are one of the most important therapeutic options for heart failure (HF), especially those with reduced ejection fraction (HFrEF). However, individual responses to BB treatment vary. Improved methods to identify patients that are good candidates for BB treatment are needed. The present disclosure provides methods for identification of patients that are BB responders versus non-responders, and to derive and validate the first polygenic response predictor (PRP) for BB survival benefit in heart failure (HF) patients.
“Beta-blockers (BB) are one of the most important treatments for heart failure. Despite BB importance in the clinic, individual responses to BB treatment vary. The observed variation in response to BB may be due, in part, to genetic variation. However, individual SNPs have not proven clinically useful to target treatment. The present disclosure provides an unbiased robust approach to identify a multi-genetic marker profile of BB effectiveness. The presently disclosed approach provides insights about treatment-specific survival prediction by combining multiple genetic markers identified using a genome-wide (GW) approach.
“The landmark beta-blocker (BB) clinical trials for heart failure with reduced ejection fraction (HFrEF) showed a significant reduction in the risk of death overall, (1-3) but it is important to point out that individual patient responses to BB widely vary. For example, in one randomized clinical trial, the 95% confidence interval for change in left ventricular ejection fraction (LVEF) with carvedilol was -11.1 to +32.9. (4) Despite this well-recognized variability BB response, (5) current guidelines for HF correctly adopt a “one size fits all” approach, whereby all patients are recommended to be treated with the same target doses of BB,6 because clinical characteristics largely did not impact HF patients’ response to BB therapy in terms of survival. (1-3) A relatively recent possible exception to this is atrial fibrillation, which some studies have reported negates BB effectiveness in HF. (7, 8) Since clinical factors are largely unable to identify BB responders vs. non-responders, understandably much research has focused on other factors, such as genetic variation, to support precision medicine approaches for BB treatment decisions. (9-11) These pharmacogenetic studies, mostly employing the candidate gene approach, (12-16) generally support the concept that genetic variation impacts BB response in HF patients but results are inconsistent and no clinically actionable markers are proven to date. (17) Although there are some examples where one or two genetic variants (usually in the setting of altered drug metabolism) have sufficient impact on drug response to generate a clinical action (e.g. CYP2C19 and clopidogrel) (18), it now appears that common complex phenotypes are likely under the influence of many genetic loci, each variant acting with relatively small impact, (19-21) and drug response may be similarly complex and polygenic in nature.
“Polygenic risk scores have emerged as a method to aggregate the small effects of numerous genetic variants into a score that reflects the overall genetic risk of a phenotype of interest. For common complex traits, this appears to often capture enough variation for clinical utility, where a smaller number of genome-wide significant “hits” have failed to do so. (22, 23) Polygenic scores have now been developed for several common diseases, such as coronary disease and others, (23, 24) and these will soon be explored for implementation of targeted population management. Despite this exciting new development, similar analytic methods have largely not yet been successfully adapted to drug response in the setting of prevalent disease.
“There are emerging examples published, (10, 25-34) but to our knowledge, none applied to treatment of HF. Limited adaptation of polygenic scores to drug-response may be due in part to methodologic challenges, such as lack of sufficiently detailed drug exposure data and complexities of analysis. Although cohorts with detailed drug exposure information tend to be smaller in size relative to recent genome-wide association study (GWAS), a polygenic score approach may offer enhanced power and an efficient approach for constructing polygenic drug-response scores could have broad impact on precision medicine and drug development. The present disclosure advances over the existing art, by illustrating a way to derive and validate the first polygenic response predictor (PRP) for BB-associated survival benefit in patients with HF.”
As a supplement to the background information on this patent application, NewsRx correspondents also obtained the inventor’s summary information for this patent application: “In one aspect, provided herein are systems and methods for identifying, diagnosing, and treating heart failure patients of European descent who are likely to respond to beta-blocker treatment. The present invention is based, at least in part on the recognition that many common genetic variants each with modest effect sizes can contribute to a person’s response to beta-blocker treatment within the disease of heart failure, and in aggregate, a polygenic response predictor score can explain and predict the likelihood that a heart failure subject will derive a survival benefit due to beta-blocker administration.
“In one aspect, the invention concerns a method for assessing a human subject’s likelihood to respond to beta-blocker treatment during the subject’s course of heart failure treatment comprising determining in a biological sample from the subject the presence or absence of risk alleles of common allelic variants associated with beta-blocker efficacy at a plurality of independent loci.
“In some embodiments, the method comprises calculating a polygenic response predictor score (PRP) for beta-blocker survival benefit in heart failure subjects. In some embodiments, the PRP defined using a random subset of heart failure patients of European descent. The PRP is constructed from a genome-wide analysis of beta-blocker genotype interaction predicting time to all-cause mortality, adjusted for a MAGGIC score, genotype, level of beta-blocker exposure, and a beta-blocker propensity score as shown in FIGS. 4A, 4B and 4C.
“In some embodiments, identifying the presence of relevant SNPs that are used in the determination of the subject’s PRP comprises measuring the presence of the at least 42 SNPs in the biological sample, of which at least twenty (20) SNPs are used to calculate the PRP. In some embodiments, the method further comprises assigning the subject to a risk group having a specified PRP cutoff score which separates responders from non-responders based on the PRP. In some embodiments, method further comprises an initial step of obtaining a biological sample from the subject. In some embodiments, at least 10,000 SNPs are identified. In some embodiments, at least 5,000 SNPs, or at least 4,500 SNPs, or at least 4,000 SNPs, or at least 3,500 SNPs, or at least 3000 SNPs, or at least 2500 SNPs, or at least 2000 SNPs are identified of which at least 44, or 43, or 42 or 41 of the highest relevant SNPs are counted in accordance with Table 1 in the calculation of the PRP in accordance with the method described in FIGS. 4A, 4B and 4C.
“In some embodiments, the identified SNPs comprise the beta-blocker drug effect SNPs. In some embodiments, the identified SNPs comprise
“In some embodiments, the method further comprises initiating a beta-blocker treatment to the subject having been determined as a likely responder based on the calculated PRP score. In some embodiments, the treatment is determined or adjusted according to the PRP score and determination whether the subject is a likely responder or non-responder. In some embodiments, identifying whether the SNP is present comprises sequencing at least part of a genome of one or more cells from the subject. In some embodiments, the subject is a white or Caucasian human of European descent. In some embodiments, the heart failure is systolic heart failure. In some embodiments, the heart failure is
“In another aspect, the invention relates to a method of determining a beta-blocker polygenic response predictor score (PRP) for beta-blocker survival benefit in a heart failure subject of European descent, the method comprising selecting at least 20 single nucleotide polymorphisms (SNPs) from Table 1; identifying whether the at least 20 SNPs are present in a biological sample from the subject; and calculating the polygenic response predictor score (PRP) based on the presence of the SNPs.
“In another embodiment, the subject has been diagnosed with early stage heart failure.
“In yet another embodiment, the subject has been diagnosed with intermediate heart failure.
“In a still further embodiment, determining the presence of absence of one or more risk alleles is achieved by amplification of nucleic acid from said sample.
“In various embodiments, amplification may comprise PCR, amplification may be located on a chip, where primers for amplification are specific for alleles of the common genetic variants tested.
“In a particular embodiment, the amplification comprises: (i) admixing an amplification primer or amplification primer pair with a nucleic acid template isolated from the biological sample, wherein the primer or primer pair is complementary or partially complementary to a region proximal to or including the polymorphism, and is capable of initiating nucleic acid polymerization by a polymerase on the nucleic acid template; and, b) extending the primer or primer pair in a DNA polymerization reaction comprising a polymerase and the template nucleic acid to generate the amplicon.
“The amplicon may, for example, be detected by a process that includes one or more of: hybridizing the amplicon to an array, digesting the amplicon with a restriction enzyme, or real-time PCR analysis.
“In another embodiment, the amplification comprises performing a polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), or ligase chain reaction (LCR) using nucleic acid isolated from the organism or biological sample as a template in the PCR, RT-PCR, or LCR.
“In yet another embodiment, the method may further comprises cleaving amplified nucleic acid.
“A further embodiment, the biological sample is derived from a bodily fluid, such as saliva or blood.
“In other embodiments, the method further comprises the step of making a decision on the timing and/or frequency of beta-blocker responsiveness diagnostic testing for the subject and/or on the timing and/or frequency of beta-blocker treatment for the subject of European ancestry/descent who is diagnosed with heart failure.
“In a still further embodiment, the method comprises determination of the presence or absence of risk alleles for all single nucleotide polymorphisms set forth in Table 1, and the beta-blocker polygenic response predictor (PRP) score is calculated based on such determination, and provided in FIGS. 4A, 4B and 4C.
“In another embodiment, the method further comprises the step of recording the results of said determination on a computer readable medium.
“In yet another embodiment, the results are communicated to the subject or the subject’s physician and/or are recorded in the form of a report.
“In another aspect, the invention concerns a report comprising the results of the methods herein.
“The device integrates multimodal data, is quantitative rather than qualitative, is objective rather than subjective, and also provides an option for outputting actionability (e.g., steps that can be taken to counter the increased risk). The systems and methods can be implemented in a minimally invasive manner, wherein the only invasive component is a routine blood draw. Actionability permits identification of factors that an individual may modify to improve their prognosis. Moreover, early screening may reduce or even eliminate psychological tension and even with a positive diagnosis, an at-risk patient can take steps to mitigate the risk.
“In some embodiments, the disclosure relates to a computer readable medium comprising computer-executable instructions, which, when executed by a processor, cause the processor to carry out a method or a set of steps for diagnosing beta-blocker responsiveness which results in a statistically significant outcome in the treatment of heart failure in a heart failure subject of European ancestry or descent, the method or steps comprising, a) extracting, into a diagnostic model, a plurality of features comprising (1) at least 20 SNPs from the group of 44 SNPs in Table 3; b) mathematically calculating a polygenic response predictor score which is calculated using Formula (I):
“<maths id=’MATH-US-00001’ num=’00001’> <math overflow=’scroll’> <mtable> <mtr> <mtd> <mrow> <mrow> <mi> score <mo> = <mrow> <munderover> <mo> ∑ <mrow> <mi> j <mo> = <mn> 1 <mi> X <mtext> <mrow> <msub> <mi> w <mi> j <mo> * <msub> <mi> SNP <mi> j <mo> , <mtd> <mrow> <mi> Formula <mo> <mtext> <mrow> <mo> ( <mi> I <mo> )
“wherein the score is the sum of the SNP weight (wj) multiplied by the SNP genotype (SNP) (0, 1, 2) summed over all the SNPS in the score (any number of SNPs ranging from 20 to 44 of the SNPs listed in Table 3); and outputting a beta-blocker polygenic response predictor (PRP) score based on the summed scores; and d) diagnosing whether the heart failure patient is a responder or non-responder to beta-blocker treatment based on the beta-blocker polygenic response predictor score, wherein the beta-blocker responder has a PRP score of 12 or less when 20 SNPs are used or a PRP score of 68 or less when 41 to 44 SNPs from Table 3 are used.”
There is additional summary information. Please visit full patent to read further.”
The claims supplied by the inventors are:
“1. A method for treating heart failure in a Caucasian human subject of European descent in need thereof, the method comprising (a) identifying a subject diagnosed with heart failure as being at risk for developing heart failure, comprising: (1) detecting in a biological sample from said subject the presence or absence of alleles of common allelic variants associated with responsiveness to beta-blocker treatment at least 20 of 44 independent loci selected from single nucleotide polymorphisms set forth in Table 3, (2) calculating a polygenic response predictor score for said subject in accordance with Formula (I) <maths id=”MATH-US-00006” num=”00006”> <math overflow=”scroll”> <mtable> <mtr> <mtd> <mrow> <mi> score <mo> = <mrow> <munderover> <mo> ∑ <mrow> <mi> j <mo> = <mn> 1 <mi> X <mtext> <mrow> <msub> <mi> w <mi> j <mo> * <msub> <mi> SNP <mi> j <mtd> <mrow> <mi> Formula <mo> <mtext> <mrow> <mo> ( <mi> I <mo> ) wherein the PRP score is calculated on the basis of at least 20 of the 44 SNPs each of said single nucleotide polymorphisms in Table 3 and then, adding the products to provide a sum (the PRP score), and (3) identifying the human subject as being a responder to beta-blocker treatment when the PRP score is less than 68, when the top 41-44 SNPs from Table 3 are used in Formula (I), or a PRP score is less than 12, when the top 20 SNPs from Table 3 are used in Formula (I), or any proportion thereof, or any proportion thereof, and (b) treating the subject identified as being a responder to beta-blocker treatment with a beta-blocker, wherein the heart failure treatment comprises administration of a therapeutically effective amount of said beta-blocker.
“2. The method of claim 1, wherein the subject has been diagnosed with NYHA Class I heart failure.
“3. The method of claim 1, wherein the subject has been diagnosed with NYHA Class II heart failure.
“4. The method of claim 1, wherein detecting the presence or absence of alleles is achieved by amplification of a nucleic acid from said sample.
“5. The method of claim 4, wherein amplification comprises polymerase chain reaction (PCR).
“6. The method of claim 5, wherein primers for amplification are located on a chip.
“7. The method of claim 6, wherein said primers for amplification are specific for alleles of said common genetic variants.
“8. The method of claim 4, wherein the amplification comprises: a) admixing an amplification primer or amplification primer pair with a nucleic acid isolated from the biological sample, wherein the primer or primer pair is complementary or partially complementary to a region proximal to or including the single nucleotide polymorphism, and is capable of initiating nucleic acid polymerization by a polymerase on the nucleic acid; and, b) extending the primer or primer pair in a DNA polymerization reaction comprising a polymerase and the nucleic acid to generate an amplicon.
“9. The method of claim 8, wherein the amplicon is detected by a process that includes one or more of: hybridizing the amplicon to an array, digesting the amplicon with a restriction enzyme, or real-time PCR analysis.
“10. The method of claim 4, wherein the amplification comprises performing PCR, reverse transcriptase PCR (RT-PCR), or a ligase chain reaction (LCR) using a nucleic acid isolated from the biological sample as a template in the PCR, RT-PCR, or LCR.
“11. The method of claim 4, further comprising cleaving amplified nucleic acid.
“12. The method of claim 4, wherein said sample is derived from saliva or blood.
“13. The method according to claim 1, wherein detecting the presence or absence of alleles is achieved by whole genome sequencing of a nucleic acid from said sample.
“14. The method according to claim 1, wherein the 20 SNPs assayed comprises the Ref SNP ID Nos.
“15. The method of claim 1, wherein the treatment comprises administration of a beta-blocker medicament is selected from the group consisting of acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), betaxolol (Betoptic S), bisoprolol fumarate (Zebeta), carteolol (Cartrol), carvedilol (Coreg), esmolol (Brevibloc), labetalol (Trandate [Normodyne]), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), nebivolol (Bystolic), penbutolol (Levatol), pindolol (Visken), propranolol (Hemangeol, Inderal LA, InderalXL, InnoPran XL), sotalol (Betapace, Sorine), timolol (Blocadren), and/or timolol ophthalmic solution (Timoptic, Betimol, Istalol).
“16. The method of claim 1, further comprising the step of recording the results of said detecting on a computer readable medium.
“17. The method of claim 16, wherein said results are communicated to the subject or the subject’s physician.
“18. The method of claim 16, wherein said results are recorded in the form of a report.
“19. A report comprising the results of the method of claim 1.
“20. A method of treating a subject suffering from heart failure, comprising: a) obtaining a nucleic acid sample from the subject; b) detecting in the nucleic acid sample of the subject the presence or absence of a plurality of single nucleotide polymorphisms (SNPs) required for the determination of a beta-blocker polygenic response predictor (BB-PRP) indicative of the likelihood of survival benefit of beta-blocker treatment; c) identifying the subject as a: i) BB responder; or ii) BB non-responder; and d) administering treatment to the subject identified in step c(i), wherein the treatment comprises a beta-blocker drug.
“21. A method of treating a subject suffering from heart failure, comprising: a) sequencing or genotyping a nucleic acid sample from the subject; b) detecting in the nucleic acid sample of the subject the presence or absence of a plurality of single nucleotide polymorphisms (SNPs) required for the determination of a beta-blocker polygenic response predictor (BB-PRP) indicative of the likelihood of survival benefit of beta-blocker treatment; c) identifying the subject as a: i) BB responder; or ii) BB non-responder; and d) administering treatment to the subject identified in step c(i), wherein the treatment comprises a beta-blocker drug.
“22. A method of treating a subject suffering from heart failure, comprising: a) detecting in cells of the subject the presence or absence of a variance in each single nucleotide polymorphism (SNP) of Table 2, wherein the combination of the presence or absence of the variance for each SNP is indicative that said treatment will be effective, more effective, less effective or ineffective in the subject; and b) administering to the subject a treatment comprising a beta-blocker drug based on detection in step (a) indicative of an effective or more effective treatment for the subject.
“23. A composition comprising a plurality of primers operable to hybridize to at least 20 SNPs of 44 SNPs in Table 3 for calculating a beta-blocker polygenic response predictor score, and at least one excipient.
“24. A kit comprising: a) a chip or container containing at least 20 nucleic acid molecules that are capable of hybridizing to at least 20 SNPs provided in Table 3; and b) instructions for detecting the at least 20 SNPs from the total of 44 SNPs in Table 3.
“25. The kit of claim 24, wherein the kit is an array with at least 1,000 or at least 10,000, or at least 100,000 genetic variants to permit whole genome analysis, which comprises the 44 SNPs of Table 3.”
For additional information on this patent application, see: LANFEAR,
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