Genetic markers for risk management of atrial fibrillation, atrial flutter, and stroke
Inventors
Helgadottir, Anna • Gudbjartsson, Daniel
Assignees
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Publication Number
US-8637244-B2
Publication Date
2014-01-28
Expiration Date
Abstract
The invention relates to procedure and methods of determining a susceptibility to cardiac arrhythmia, including Atrial Fibrillation, Atrial Flutter and Stroke, by assessing the presence or absence of alleles at polymorphic markers found to be associated with Atrial Fibrillation, Atrial Flutter and Stroke. The invention further relates to kits encompassing reagents for assessing such markers, and diagnostic methods, uses and procedures for utilizing such susceptibility markers.
Core Innovation
The invention relates to determining genetic susceptibility to atrial fibrillation, atrial flutter, or stroke in a human individual by analyzing a nucleic acid sample for specified polymorphic marker allele T variants, including rs2220427, rs2200733, and rs10033464. The presence of at least one of these allele T variants is used to generate genotype-based susceptibility results, and the disclosure reports association context at chromosome 4q25, including ischemic stroke risk and stronger association for cardioembolic stroke.
The method further determines susceptibility by calculating a risk score that includes a relative risk (RR) or an odds ratio (OR) of at least 1.3 attributed to the presence of the at least one polymorphic marker allele. The disclosure addresses analyzing genotype data with respect to the polymorphic marker allele(s), generating an output based on the genotype data, and producing an output that comprises the risk score for susceptibility to atrial fibrillation, atrial flutter, or stroke.
The disclosure also ties the genetic findings to diagnostics and genetics-directed management, including determining susceptibility for downstream clinical assessment, earlier anticoagulation, treatment selection, and trial stratification. It describes genetic markers and risk scoring implemented using an apparatus comprising computer readable memory, a processor, and a routine stored on the computer readable memory that is executed on the processor to analyze genotype data and generate an output comprising the risk score.
Claims Coverage
The independent claims cover three related inventive features: genotype-based susceptibility determination using specified allele T polymorphic markers, calculation or output of a risk score incorporating RR or OR thresholds of at least 1.3, and a claim that follows genetic susceptibility determination with a physical examination. Across the claims, the inventive coverage centers on detecting rs2220427, rs2200733, and/or rs10033464 allele T and using the result to determine susceptibility to atrial fibrillation, atrial flutter, or stroke.
Allele T polymorphic marker susceptibility determination
Analyzing a nucleic acid sample to determine the presence or absence of at least one polymorphic marker allele selected from allele T of rs2220427, allele T of rs2200733, and allele T of rs10033464, and determining susceptibility to atrial fibrillation, atrial flutter, or stroke from the presence of the at least one allele.
Risk score calculation using RR or OR threshold
Determining susceptibility by calculating a risk score that includes a relative risk (RR) or an odds ratio (OR) of at least 1.3 attributed to the presence of the at least one polymorphic marker allele in the nucleic acid sample.
Computer-implemented genotype data analysis for susceptibility output
Performing the determining using an apparatus comprising a computer readable memory, a processor, and a routine stored on the computer readable memory, wherein the routine is adapted to be executed on the processor to analyze genotype data with respect to the at least one polymorphic marker and generate an output based on the genotype data, wherein the output comprises a risk score for susceptibility to atrial fibrillation, atrial flutter, or stroke.
Increased susceptibility determination followed by physical examination
Analyzing a nucleic acid sample to determine the presence or absence of at least one polymorphic marker allele selected from allele T of marker rs2220427, allele T of marker rs2200733, or allele T of marker rs10033464, determining that at least one of the allele T variants is present, determining an increased susceptibility to atrial fibrillation, atrial flutter or stroke from the presence of the at least one allele, and performing a physical examination for symptoms or evidence of atrial fibrillation, atrial flutter, or stroke on the individual determined to have the increased susceptibility.
Across the independent claims, the patent covers detecting specified allele T variants at rs2220427, rs2200733, and/or rs10033464 in nucleic acid samples and determining or calculating susceptibility to atrial fibrillation, atrial flutter, or stroke using a risk score that incorporates an RR or OR of at least 1.3. Claim coverage further includes generating the risk score output via a computer-implemented apparatus and, in one independent claim, using the genetic susceptibility result to prompt a physical examination for symptoms or evidence of atrial fibrillation or atrial flutter.
Stated Advantages
Provides a genotype-based susceptibility determination for atrial fibrillation, atrial flutter, or stroke using a risk score that includes RR or OR.
Enables risk score computation and output based on genotype data using a computer-implemented apparatus.
Supports earlier anticoagulation for at-risk genetic variant carrier status.
Influences treatment selection.
Supports trial stratification.
Enables directing a physical examination for symptoms or evidence of atrial fibrillation or atrial flutter in individuals determined to have increased susceptibility.
Documented Applications
Using the genetic susceptibility determination to perform a physical examination for symptoms or evidence of atrial fibrillation, atrial flutter, or stroke in an individual determined to have increased susceptibility.
Assessing susceptibility to atrial fibrillation, atrial flutter, or stroke by calculating and outputting a genotype-derived risk score using an apparatus with computer readable memory, a processor, and a routine.
Association study context for identifying risk variants at chromosome 4q25, including rs2200733 and rs10033464, linked to ischemic stroke risk and stronger association for cardioembolic stroke.
Clinical-risk interpretation context relating risk alleles to age at AF diagnosis and discussing that some cryptogenic or large-artery strokes may involve undiagnosed intermittent atrial fibrillation.
Genetics-directed management for atrial fibrillation, atrial flutter, and stroke using genotype-based susceptibility and risk determination.
Use of carrier status for at-risk genetic variants to support earlier anticoagulation and to influence treatment selection and trial stratification.
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