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 - 99 . (canceled) 
     
     
         100 . A method of determining a susceptibility to asthma in a human individual, comprising:
 (a) obtaining sequence data about a human individual identifying 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, wherein different alleles of the at least one polymorphic marker is associated with different susceptibilities to asthma in humans, and   (b) determining a susceptibility to asthma from the sequence data.   
     
     
         101 . The method of  claim 100 , wherein the sequence data is nucleic acid sequence data. 
     
     
         102 . The method of  claim 100 , comprising obtaining sequence data about each polymorphic marker of the group. 
     
     
         103 . The method of  claim 101 , wherein obtaining nucleic acid sequence data comprises identifying at least one allele of a marker in linkage disequilibrium with at least one of the polymorphic markers of the group. 
     
     
         104 . The method of  claim 100 , wherein the marker in linkage disequilibrium is selected from a group consisting of: rs12475055, rs4399750, rs11685424, rs1921622, rs10204137, rs10192157, rs10206753, rs12998521, rs1035130, rs4851004, rs2287033, rs1420094, rs3755266, rs2310300, rs10490204, rs3771150, rs11465730, rs10051830, rs1037684, rs390047, rs9326826, rs1072056, rs184941, rs1469441, rs919334, rs1547247, rs9399137, rs9376092, rs10484494, rs2026937, rs12663543, rs10124250, rs10119713, rs2079, rs2890704, rs1412426, rs1342326, rs992969, rs928413, and rs2066362. 
     
     
         105 . The method of any one of  claim 100 , wherein obtaining nucleic acid sequence data comprises obtaining a biological sample or a genotype dataset from the human individual and analyzing sequence of the at least one polymorphic marker in the sample or dataset. 
     
     
         106 . The method of  claim 100 , wherein analyzing sequence of the at least one polymorphic marker comprises determining the presence or absence of at least one allele of the polymorphic marker. 
     
     
         107 . (canceled) 
     
     
         108 . The method of  claim 100 , comprising determining the presence or absence of an amino acid substitution in an amino acid sequence, wherein the presence or absence of the amino acid substitution identifies at least one allele of the at least one polymorphic marker. 
     
     
         109 - 110 . (canceled) 
     
     
         111 . The method of  claim 100 , wherein determining a susceptibility comprises comparing the sequence data to a database containing correlation data between polymorphic markers and susceptibility to asthma. 
     
     
         112 . The method of  claim 111 , wherein the database comprises at least one measure of susceptibility to asthma for the polymorphic markers. 
     
     
         113 . The method of  claim 111 , wherein the database comprises a look-up table containing at least one measure of susceptibility to asthma for the polymorphic markers. 
     
     
         114 . The method of  claim 100 , wherein the at least one allele is associated with an increased susceptibility to asthma in humans, characterized by a relative risk or an odds ratio of at least about 1.10. 
     
     
         115 . (canceled) 
     
     
         116 . The method of  claim 100 , wherein the asthma is atopic asthma. 
     
     
         117 . The method of  claim 114 , wherein 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. 
     
     
         118 . The method of  claim 114 , wherein the asthma is non-atopic asthma. 
     
     
         119 . The method of  claim 118 , wherein the at least one allele is the A allele of rs1420101. 
     
     
         120 . The method of  claim 100 , further comprising reporting the susceptibility to at least one entity selected from the group consisting of the human individual, a guardian of the human individual, a genetic service provider, a physician, a medical organization, and a medical insurer. 
     
     
         121 . The method of  claim 100 , wherein the human individual is Icelandic, German, British, Danish, Dutch, Australian, or Korean. 
     
     
         122 - 133 . (canceled) 
     
     
         134 . An apparatus for determining a genetic indicator for asthma in a human individual, comprising:
 a processor   a computer readable memory having computer executable instructions adapted to be executed on the processor to analyze marker and/or haplotype information for at least one human individual with respect to at least one polymorphic marker selected from the group consisting of rs1420101, rs3939286, rs2416257, rs9494145, rs1420101, and markers in linkage disequilibrium therewith, and generate an output based on the marker or haplotype information, wherein the output comprises a measure of susceptibility of the at least one marker or haplotype as a genetic indicator of asthma for the human individual.   
     
     
         135 . The apparatus according to  claim 134 , wherein the computer readable memory further comprises data indicative of the frequency of at least one allele of at least one polymorphic marker or at least one haplotype in a plurality of individuals diagnosed with, or presenting symptoms associated with, asthma, and data indicative 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 wherein a measure of susceptibility is based on a comparison of the at least one marker and/or haplotype status for the human individual to the data indicative of the frequency of the at least one marker and/or haplotype information for the plurality of individuals diagnosed with asthma. 
     
     
         136 . The apparatus according to  claim 134 , wherein the computer readable memory further comprises data indicative of the risk of developing asthma associated with at least one allele of at least one polymorphic marker or at least one haplotype, and wherein a measure of susceptibility for the human individual is based on a comparison of the at least one marker and/or haplotype status for the human individual to the risk associated with the at least one allele of the at least one polymorphic marker or the at least one haplotype. 
     
     
         137 . The apparatus according to  claim 136 , wherein the computer readable memory further comprises data indicative of the frequency of at least one allele of at least one polymorphic marker or at least one haplotype in a plurality of individuals diagnosed with, or presenting symptoms associated with, asthma, and data indicative 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 wherein risk of developing asthma is based on a comparison of the frequency of the at least one allele or haplotype in individuals diagnosed with, or presenting symptoms associated with, asthma, and reference individuals. 
     
     
         138 - 139 . (canceled) 
     
     
         140 . A method of diagnosing asthma in a human individual, comprising (A) one or a combination of (i) considering symptoms experienced by the human individual and/or the family history of the human individual, (ii) physically examining the upper respiratory tract, chest, and skin of the human individual, and (iii) conducting a breathing test on the human individual, and (B) obtaining sequence data identifying 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. 
     
     
         141 . The method of  claim 140 , 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. 
     
     
         142 - 143 . (canceled)