Genetic markers for risk management of atrial fibrillation, atrial flutter, and stroke

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.

1 . A method of determining a susceptibility to cardiac arrhythmia or stroke in a human individual, the method comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample from the individual, wherein the at least one polymorphic marker is selected from the polymorphic markers set forth in Table 5, and markers in linkage disequilibrium therewith,
 and wherein determination of the presence or absence of the at least one allele is indicative of a susceptibility to cardiac arrhythmia or stroke in the individual.   
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the at least one polymorphic marker is selected from the markers set forth in Table 9, and markers in linkage disequilibrium therewith. 
     
     
         4 . The method of  claim 1 , wherein the at least one polymorphic marker is selected from D4S406 (SEQ ID NO:45), rs2634073 (SEQ ID NO:33), rs2200733 (SEQ ID NO:28), rs2220427 (SEQ ID NO:1), rs10033464 (SEQ ID NO:41), and rs13143308 (SEQ ID NO:51), and markers in linkage disequilibrium therewith. 
     
     
         5 . The method of  claim 1 , wherein the presence of alleles-2, -4 and/or -8 in marker D4S406, allele A of marker rs2634073, allele T of marker rs2200733, allele T of marker rs2220427, allele T of marker rs10033464, and/or allele G of marker rs13143308 is indicative of increased susceptibility of cardiac arrhythmia or stroke in the individual. 
     
     
         6 . The method of  claim 1 , wherein the susceptibility is increased susceptibility characterized by an odds ratio (OR) of at least 1.3. 
     
     
         7 - 25 . (canceled) 
     
     
         26 . A method of determining a susceptibility to cardiac arrhythmia or stroke in a human individual, the method comprising determining the identity of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one marker is selected from the group of markers associated with the PITX2 gene, wherein the presence of the at least one allele is indicative of a susceptibility to cardiac arrhythmia or stroke in the individual. 
     
     
         27 . The method according to  claim 26 , wherein the at least one marker is selected from rs7668322 (SEQ ID NO:46), rs2197815 (SEQ ID NO:47), rs6831623 (SEQ ID NO:48) and rs259110 (SEQ ID NO:49), and markers in linkage disequilibrium therewith. 
     
     
         28 . The method of  claim 26 , wherein the susceptibility is increased susceptibility. 
     
     
         29 . (canceled) 
     
     
         30 . The method of  claim 1 , wherein the cardiac arrhythmia is atrial fibrillation or atrial flutter. 
     
     
         31 - 33 . (canceled) 
     
     
         34 . The method of  claim 1 , wherein the stroke is ischemic stroke. 
     
     
         35 . The method of  claim 1 , wherein linkage disequilibrium is characterized by numerical values for r 2  of greater than 0.2. 
     
     
         36 - 48 . (canceled) 
     
     
         49 . The method of  claim 1 , further comprising assessing at least one biomarker for atrial fibrillation, atrial flutter and/or stroke in a sample from the individual. 
     
     
         50 . The method of  claim 1 , further comprising analyzing non-genetic information to make risk assessment, diagnosis, or prognosis of the individual. 
     
     
         51 . The method of  claim 50 , wherein the non-genetic information is selected from age, age at onset of disease, gender, ethnicity, socioeconomic status, previous disease diagnosis, medical history of subject, family history of atrial fibrillation, atrial flutter and/or stroke, biochemical measurements, and clinical measurements. 
     
     
         52 . The method of  claim 49 , further comprising calculating overall risk by logistic regression. 
     
     
         53 - 74 . (canceled) 
     
     
         75 . An apparatus for determining a genetic indicator for cardiac arrhythmia and/or stroke in a human individual, comprising:
 a computer readable memory; and   a routine stored on the computer readable memory;   wherein the routine is adapted to be executed on a processor to analyze genotype and/or haplotype data for at least one human individual with respect to at least one polymorphic marker selected from the markers set forth in Table 5, and markers in linkage disequilibrium therewith, and generate an output based on the marker or haplotype data, wherein the output comprises a risk measure of the at least one marker or haplotype as a genetic indicator of cardiac arrhythmia and/or stroke for the human individual.   
     
     
         76 . The apparatus of  claim 75 , wherein the routine further comprises determining an indicator of the frequency of at least one allele of at least one polymorphic marker and/or at least one haplotype in a plurality of individuals diagnosed with cardiac arrhythmia and/or stroke, and an indicator of the frequency of at the least one allele of at least one polymorphic marker or at least one haplotype in a plurality of reference individuals, and calculating a risk measure for the at least one allele and/or haplotype based thereupon;
 and wherein a risk measure for the individual is calculated based on a comparison of the at least one marker and/or haplotype status for the individual to the calculated risk for the at least one marker and/or haplotype information for the plurality of individuals diagnosed with atrial fibrillation, atrial flutter and/or stroke.   
     
     
         77 . The apparatus of  claim 75 , wherein the at least one polymorphic marker is selected from D4S406 (SEQ ID NO:45), rs2634073 (SEQ ID NO:33), rs2200733 (SEQ ID NO:28), rs2220427 (SEQ ID NO:1), rs10033464 (SEQ ID NO:41), and rs13143308 (SEQ ID NO:51). 
     
     
         78 . The apparatus of  claim 75 , wherein the risk measure is characterized by an Odds Ratio (OR) or a Relative Risk (RR). 
     
     
         79 . The apparatus or medium of  claim 75 , wherein linkage disequilibrium is characterized by values of r 2  of greater than 0.2.