Genetic variants as markers for use in diagnosis, prognosis and treatment of eosinophilia, asthma and myocardial infarction

Abstract

Polymorphic variants (e.g., certain alleles of polymorphic markers) that have been found to be associated with high blood eosinophil counts, conditions causative of eosinophilia (e.g., asthma, myocardial infarction), and/or hypertension are provided herein. Such polymorphic markers are useful for diagnostic purposes, such as in methods of determining a susceptility, and for prognostic purposes, including methods of predicting prognosis and methods of assessing an individual for probability of a response to a therapeutic agent, as further described herein. Further applications utilize the polymorphic markers of the invention include, screening methods and genotyping methods. The invention furthermore provides related kits, computer-readable medium, and apparatus.

1 - 22 . (canceled) 
     
     
         23 . A method of assessing an individual for probability of response to a therapeutic agent for preventing, treating, and/or ameliorating symptoms associated with myocardial infarction, 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 polymorphic marker is selected from the group consisting of rs3184504, rs653178, and markers in linkage disequilibrium therewith, and assessing probability of response from to the therapeutic agent from the identity of the at least one allele of the at least one marker. 
     
     
         24 . A kit for assessing susceptibility to myocardial infarction of a human individual, the kit comprising reagents for selectively detecting at least one allele of at least one polymorphic marker in the genome of the human individual, wherein the polymorphic marker is selected from the group consisting of rs3184504 and rs653178, and markers in linkage disequilibrium therewith, and a collection of data on a computer-readable medium comprising correlation data between the polymorphic markers and susceptibility to myocardial infarction. 
     
     
         25 . (canceled) 
     
     
         26 . The kit of  claim 24  or  25 , wherein the kit comprises reagents for selectively detecting no more than 55 alleles in the genome of the individual. 
     
     
         27 - 28 . (canceled) 
     
     
         29 . The kit according to  claim 24 , wherein the reagents include an oligonucleotide probe that hybridizes to a segment of a nucleic acid whose nucleotide sequence is given by any of SEQ ID NOs: 1-681, wherein the segment is 15-500 nucleotides in length. 
     
     
         30 . The kit of  claim 29 , wherein the segment of the nucleic acid to which the probe hybridizes comprises a polymorphic site. 
     
     
         31 - 35 . (canceled) 
     
     
         36 . A method of treatment comprising administering an anti-myocardial infarction agent to a human individual that has been tested for (a) the presence of at least one allele of at least one polymorphic marker selected from the group consisting of rs3184504 and rs653178, and markers in linkage disequilibrium therewith, and/or (b) the presence of an amino acid substitution in an amino acid sequence encoded by the at least one marker. 
     
     
         37 . The method of  claim 36 , wherein the at least one allele is the T allele of rs3184504 and/or the G allele of rs653178. 
     
     
         38 - 39 . (canceled) 
     
     
         40 . A method of diagnosing myocardial infarction or myocardial infarction risk in a human individual, comprising (A) one or a combination of: (i) considering the history of an illness and the symptoms experienced by the human individual, (ii) physically examining the human individual, (iii) conducting one or a combination of an electrocardiogram, a coronary angiogram, chest radiograph, echocardiogram on the human individual, (iv) testing blood of the human individual for cardiac markers, (v) detecting areas of reduced blood flow in conjunction with physiologic or pharmacologic stress, and (vi) determining the viability of tissue of the myocardium; and (B) obtaining sequence data identifying at least one allele of at least one polymorphic marker selected from the group consisting of rs3184504 and rs653178, and markers in linkage disequilibrium therewith. 
     
     
         41 - 77 . (canceled) 
     
     
         78 . A method of genotyping a nucleic acid sample, comprising determining the identity of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from a human individual at risk for, or diagnosed with, eosinophilia, wherein the marker is selected from the group consisting of rs1050152, rs11066320, rs11679137, rs11778166, rs11950562, rs12411706, rs9954643, rs12619285, rs1265566, rs12998521, rs1370631, rs1412426, rs1420101, rs1467412, rs1559930, rs1805419, rs184941, rs2079103, rs2164850, rs2165427, rs2188962, rs2244012, rs2269426, rs231228, rs2335050, rs233716, rs233722, rs2416257, rs2426358, rs2532072, rs2663041, rs272893, rs273148, rs2897443, rs3184504, rs3939286, rs4143832, rs4629469, rs4773225, rs4851400, rs4851411, rs4857855, rs6439132, rs6503609, rs653178, rs6730424, rs6871536, rs7150454, rs7223150, rs7315519, rs748065, rs7635061, rs927220, rs9494145, and rs992969, and markers in linkage disequilibrium therewith, whereupon the identity of no more than 110 alleles is determined. 
     
     
         79 - 80 . (canceled) 
     
     
         81 . A kit for assessing susceptibility to eosinophilia of a human individual, the kit comprising reagents for selectively detecting at least one allele of at least one polymorphic marker in the genome of the human individual, wherein the polymorphic marker is selected from the group consisting of rs1370631, rs4851400, rs4851411, rs12998521, rs1559930, rs6439132, rs2335050, rs11950562, rs272893, rs1050152, rs2188962, rs2244012, rs2897443, rs6871536, rs992969, rs1265566, rs7315519, rs927220, rs1467412, rs12411706, rs233722, rs233716, rs1805419, rs9954643, rs273148, rs3939286, rs1420101, rs11066320, rs4857855, rs9494145, rs2416257, rs2079103, rs2165427, rs3184504, rs2663041, rs1412426, rs11778166, rs4143832, rs653178, rs6730424, rs4629469, rs748065, rs11679137, rs2164850, rs12619285, rs2269426, rs7635061, rs184941, rs2532072, rs6503609, rs4773225, rs2426358, rs231228, rs7223150, and rs7150454, and markers in linkage disequilibrium therewith, and a computer-readable medium comprising a collection of data comprising correlation data between the polymorphic markers and susceptibility to eosinophilia. 
     
     
         82 . (canceled) 
     
     
         83 . The kit of  claim 81 , wherein the kit comprises reagents for selectively detecting no more than 55 alleles in the genome of the individual. 
     
     
         84 - 85 . (canceled) 
     
     
         86 . The kit according to  claim 81  that comprises an oligonucleotide probe that hybridizes to a segment of a nucleic acid whose nucleotide sequence is given by any of SEQ ID NOs: 1-681, wherein the segment is 15-500 nucleotides in length. 
     
     
         87 . The kit  claim 86 , wherein the segment of the nucleic acid to which the probe hybridizes comprises a polymorphic site. 
     
     
         88 - 93 . (canceled) 
     
     
         94 . A method of treatment comprising administering an anti-eosinophilia agent to a human individual that has been tested for (a) the presence of at least one allele of at least one polymorphic marker selected from the group consisting of rs1050152, rs11066320, rs11679137, rs11778166, rs11950562, rs12411706, rs9954643, rs12619285, rs1265566, rs12998521, rs1370631, rs1412426, rs1420101, rs1467412, rs1559930, rs1805419, rs184941, rs2079103, rs2164850, rs2165427, rs2188962, rs2244012, rs2269426, rs231228, rs2335050, rs233716, rs233722, rs2416257, rs2426358, rs2532072, rs2663041, rs272893, rs273148, rs2897443, rs3184504, rs3939286, rs4143832, rs4629469, rs4773225, rs4851400, rs4851411, rs4857855, rs6439132, rs6503609, rs653178, rs6730424, rs6871536, rs7150454, rs7223150, rs7315519, rs748065, rs7635061, rs927220, rs9494145, and rs992969, and markers in linkage disequilibrium therewith; and/or (b) the presence of an amino acid substitution in an amino acid sequence encoded by a marker of the group. 
     
     
         95 . The use of  claim 94 , wherein the at least one allele is selected from the group consisting of wherein the at least one allele is selected from the group consisting of the C allele of rs1050152, the A allele of rs11066320, the G allele of rs11679137, the C allele of rs11778166, the A allele of rs11950562, the G allele of rs12411706, the G allele of rs9954643, the A allele of rs12619285, the T allele of rs1265566, the T allele of rs12998521, the A allele of rs1370631, the T allele of rs1412426, the A allele of rs1420101, the A allele of rs1467412, the A allele of rs1559930, the G allele of rs1805419, the G allele of rs184941, the T allele of rs2079103, the C allele of rs2164850, the A allele of rs2165427, the C allele of rs2188962, the C allele of rs2244012, the T allele of rs2269426, the C allele of rs231228, the C allele of rs2335050, the G allele of rs233716, the C allele of rs233722, the G allele of rs2416257, the C allele of rs2426358, the C allele of rs2532072, the T allele of rs2663041, the A allele of rs272893, the G allele of rs273148, the A allele of rs2897443, the T allele of rs3184504, the A allele of rs3939286, the A allele of rs4143832, the G allele of rs4629469, the G allele of rs4773225, the A allele of rs4851400, the T allele of rs4851411, the C allele of rs4857855, the T allele of rs6439132, the A allele of rs6503609, the G allele of rs653178, the T allele of rs6730424, the C allele of rs6871536, the G allele of rs7150454, the G allele of rs7223150, the A allele of rs7315519, the A allele of rs748065, the A allele of rs7635061, the C allele of rs927220, the T allele of rs9494145, and the A allele of rs992969. 
     
     
         96 - 124 . (canceled) 
     
     
         125 . A kit for assessing susceptibility to asthma of a human individual, the kit comprising reagents for selectively detecting at least one allele of at least one polymorphic marker in the genome of the human individual, wherein the polymorphic marker is selected from the group consisting of rs1420101, rs3939286, rs2416257, and rs9494145, and markers in linkage disequilibrium therewith, and a computer-readable medium comprising collection of data comprising correlation data between the polymorphic markers and susceptibility to asthma,
 wherein the kit comprises reagents for selectively detecting no more than 55 alleles in the genome of the individual.   
     
     
         126 - 129 . (canceled) 
     
     
         130 . The kit of  claim 125  that comprises an oligonucleotide probe that hybridizes to a segment of a nucleic acid whose nucleotide sequence is given by any of SEQ ID NOs: 1-681, wherein the segment is 15-500 nucleotides in length. 
     
     
         131 . The kit of  claim 130 , wherein the segment of the nucleic acid to which the probe hybridizes comprises a polymorphic site. 
     
     
         132 - 137 . (canceled) 
     
     
         138 . A method of treatment that comprises administering an anti-asthma agent to a human individual that has been tested for (a) the presence of at least one allele of at least one polymorphic marker selected from the group consisting of rs1420101, rs3939286, rs2416257, and rs9494145, and markers in linkage disequilibrium therewith; and/or (b) the presence of an amino acid substitution in an amino acid sequence encoded by the at least one marker. 
     
     
         139 . The method of  claim 138 , wherein the at least one allele is selected from the group consisting of the at least one allele is the A allele of rs1420101, the A allele of rs3939286, the G allele of rs2416257, and/or the T allele of rs9494145. 
     
     
         140 - 143 . (canceled)