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Friday, November 19, 2004 11:49:53 PM
http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FP...
Notwithstanding the power of AIMs for disease gene and forensics analysis, no studies have been conducted to elucidate this power. As disclosed herein, 1) SNPs or deletion/insertion polymorphisms (collectively referred to as AIMs) in the human genome that are of potential use for drug response, disease gene or forensics research were identified; 2) biochemical and genetic test results are provided that demonstrate these AIMs can be useful for disease gene and forensics research; 3) the usefulness of AIMs derived from systematic screens of the human genome in actual drug response, disease gene or forensics research is demonstrated; 4) the usefulness of AIMs derived from systematic screens of the human genome to make an inference as to whether an individual is susceptible to acquire a disease, or to not respond to a drug, is demonstrated; 5) the usefulness of AIMs derived from systematic screens of the human genome to make an inference as to whether a crime scene DNA specimen was derived from an individual of, for example, an 80% European, 10% African and 10% Asian heritage or some other ratio/mix is demonstrated; 6) the usefulness of AIMs derived from systematic screens of the human genome to infer the ancestral proportions of an individual from their DNA (e.g., whether the individual is of 80% European, 10% African and 10% Asian heritage, or some other ratio/mix) is demonstrated; and 7) the usefulness of AIMs derived from systematic screens of the human genome to infer the ancestral proportions of a group of individuals from their DNA (for example, whether the group, which can be a population sample, a family, or a clinically defined group of persons, is of 80% European, 10% African and 10% Asian heritage, or some other ratio/mix) is demonstrated.
[0108] The present results demonstrate that AIMs are useful for the applications described above, and the sequences exemplified herein, as well as additional AIMs identified using the methods disclosed herein, enable these applications. The AIMs and methods of the invention are useful for the study of human diseases, drug response, and physical traits and, therefore, provide exceptional commercial potential. For example, in this dawning era of personalized drug prescription and disease risk assessment, the markers and methods of the invention provide the tools needed to proceed in this fledgling industry. As exemplified herein, an individual's response to a particular medication was dependent on the degree to which that individual exhibited a certain population structure (i.e., was of certain ancestral heritage) in addition to, but irrespective of, the person's genotype for drug target or xenobiotic metabolism gene sequences. As such, the compositions and methods of the invention provide a means to predict an individual's likelihood to respond to a particular drug.
[0109] For example, in screen of genetic markers associated with patient response to the cholesterol lowering drug, Lipitor.TM., in terms of low-density lipoprotein (LDL) response, which is an indicator of favorable response, some of the most powerful markers identified for LDL response to Lipitor.TM. were gene types that are not immediately recognized as relevant for drug response, including, for example, TYR, OCA2, TYRP, FDPS, and HMGCR (see, also, Intl. Publ. No. WO 03/002721 (PCT/US02/20847), and Intl. Publ. No. WO 03/045227 (PCT/US02/38345), each of which is incorporated herein by reference). When combined with markers from genes that are biologically relevant for response, they augment the ability to make accurate inferences of response from the DNA. Each of these markers also is an excellent AIM, indicating that the linkage of the AIMs to drug response is likely a function of ancestral differences in response proclivity (see Example 5). As such, ancestral heritage can be predictive of favorable response to Lipitor.TM.. This association has been observed for almost every type of response (n=54) to almost every type of drug (n=23) examined, thus confirming that the inference of drug response can be accomplished, at least in part, through the inference of ancestral proportions. As such, it appears that the genes truly relevant for drug response are a function, at least in part, of individual ancestry, and that the gene sequences relevant for drug response are statistically linked with markers that are informative as to ancestry (i.e., AIMs).
[0110] Screening genomes for the true identity of genes associated with a particular trait such as drug responsiveness is extraordinarily expensive and time consuming. As such, the use of AIMs for making inferences about individual proclivity to drugs provides a significant short-cut for the rapid development of tests that can be used to match patients with those drugs most appropriate for their genetic constitution. Thus, in addition to being useful for the admixture mapping of disease genes, the disclosed methods and exemplified markers provide tools that can direct treatment protocols by clinicians. The identification of AIMs from publicly available human genome data, and the ability to effectively use the AIMs for the development of patient-drug classification sets, admixture screening panels and forensics tools, was accomplished using the disclosed method, including screening the SNP database (see, for example, world wide web ("www") at URL "nih.ncbi.nlm.gov") for AIMs; screening the AIMs against a multi-ancestral panel of DNA samples to verify those that, indeed, are good AIMs; using the disclosed statistical and software methods for using the AIM sequences to make biologically relevant inferences; and recognizing that an individual's likelihood to respond to a drug or develop a disease can be predicted through a knowledge of their ancestry, which, in turn, is indicated through the individual's AIM sequences.
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