Claims for Patent: 7,933,722

Summary for Patent: 7,933,722

Title:	Methods of analysis of polymorphisms and uses thereof
Abstract:	The present invention provides methods for the assessment of diseases that result from the combined or interactive effects of two or more genetic variants, and in particular for diagnosing risk of developing such diseases in subjects using an analysis of genetic polymorphisms. Methods for the derivation of a net score indicative of a subject\'s risk of developing a disease are provided.
Inventor(s):	Young; Robert Peter (Auckland, NZ)
Assignee:	Synergenz Bioscience Limited (Hong Kong, CN)
Application Number:	11/432,770
Patent Claims:	1. A method of assessing a human subject's risk of developing a disease having a genetic basis, comprising: obtaining a biological sample from a human subject; analyzing said sample for a presence or absence of at least one protective polymorphism and for a presence or absence of at least one susceptibility polymorphism, wherein said at least one protective polymorphism and said at least one susceptibility polymorphism are associated with a disease having a genetic basis, and wherein the total number of susceptibility and protective polymorphisms analyzed is four or greater; assigning a positive score for each protective polymorphism and a negative score for each susceptibility polymorphism or vice versa; and calculating a net score for said subject, said net score representing a balance between a combined value of the at least one protective polymorphism and the combined value of the at least one susceptibility polymorphism present in the subject sample; wherein the disease is selected from the group consisting of lung cancer, chronic obstructive pulmonary disease (COPD), occupational chronic obstructive pulmonary disease (OCOPD), and emphysema, and wherein a net protective score is predictive of a reduced risk of developing said disease and a net susceptibility score is predictive of an increased risk of developing said disease. 2. The method according to claim 1, wherein the value assigned to each protective polymorphism is the same. 3. The method according to claim 1, wherein the value assigned to each susceptibility polymorphism is the same. 4. The method according to claim 1, wherein each protective polymorphism has a negative value and each susceptibility polymorphism having a positive value. 5. The method according to claim 1, wherein each protective polymorphism has a positive value and each susceptibility polymorphism has a negative value. 6. The method according to claim 1, wherein when the disease is a lung disease, the protective polymorphisms analysed is selected from one or more of the group consisting of: +760GG or +760CG within the gene encoding superoxide dismutase 3 (SOD3); -1296TT within the promoter of the gene encoding tissue inhibitor of metalloproteinase 3 (TIMP3); CC (homozygous P allele) within codon 10 of the gene encoding transforming growth factor beta (TGF.beta.); and 2G2G within the promoter of the gene encoding metalloproteinase 1 (MMP1). 7. The method according to claim 6, wherein all polymorphisms of the group are analysed. 8. The method according to claim 1, wherein when the disease is a lung disease, the susceptibility polymorphism analysed is selected from one or more of the group consisting of: -82AA within the promoter of the gene encoding human macrophage elastase (MMP12); -1562CT or -1562TT within the promoter of the gene encoding metalloproteinase 9 (MMP9); and 1237AG or 1237AA (Tt or tt allele genotypes) within the 3' region of the gene encoding .alpha.1-antitrypsin (.alpha.1AT). 9. The method according to claim 8, wherein all polymorphisms of the group are analysed. 10. The method according claim 1, wherein when the disease is COPD, the protective polymorphism analysed is selected from one or more of the group consisting of: -765 CC or CG in the promoter of the gene encoding cyclooxygenase 2 (COX2); Arg 130 Gln AA in the gene encoding Interleukin-13 (IL-13); Asp 298 Glu TT in the gene encoding nitric oxide synthase 3 (NOS3); Lys 420 Thr AA or AC in the gene encoding vitamin binding protein (VDBP); Glu 416 Asp TT or TG in the gene encoding VDBP; Ile 105 Val AA in the gene encoding glutathione S-transferase (GSTP1); MS in the gene encoding .alpha.1-antitrypsin (.alpha.1AT); +489 GG genotype in the gene encoding Tumor Necrosis factor .alpha.(TNF.alpha.); -308 GG genotype in the gene encoding TNF.alpha.; C89Y AA or AG genotype in the gene encoding SMAD3; 161 GG genotype in the gene genotype Mannose binding lectin 2 (MBL2); -1903 AA genotype in the gene encoding Chymase 1 (CMA1); Arg 197 Gln AA genotype in the gene encoding N-Acetyl transferase 2 (NAT2); His 139 Arg GG genotype in the gene encoding Microsomal epoxide hydrolase (MEH); -366 AA or AG genotype in the gene encoding 5 Lipo-oxygenase (ALOX5); HOM T2437C TT genotype in the gene encoding Heat Shock Protein 70 (HSP 70); exon 1 +49 CT or TT genotype in the gene encoding Elafin; Gln 27 Glu GG genotype in the gene encoding .beta.2 Adrenergic receptor (ADBR); and -1607 1G1G or 1G2G genotype in the promoter of the gene encoding Matrix Metalloproteinase 1 (MMP1). 11. The method according to claim 10, wherein all polymorphisms of the group are analysed. 12. The method according to claim 1, wherein when the disease is COPD, the susceptibility polymorphism analysed is selected from one or more of the group consisting of: Arg 16 Gly GG in the gene encoding .beta.2-adrenoreceptor (ADRB2); 105 AA in the gene encoding Interleukin-18 (IL-18); -133 CC in the promoter of the gene encoding IL-18; -675 5G5G in the promoter of the gene encoding plasminogen activator inhibitor 1 (PAI-1); -1055 TT in the promoter of the gene encoding IL-13; 874 TT in the gene encoding interferon gamma (IFN.gamma.); +489 AA or AG genotype in the gene encoding TNF.alpha.; -308 AA or AG genotype in the gene encoding TNF.alpha.; C89Y GG genotype in the gene encoding SMAD3; E469K GG genotype in the gene encoding Intracellular Adhesion molecule 1 (ICAM1); Gly 881 Arg GC or CC genotype in the gene encoding Caspase (NOD2); -511 GG genotype in the gene encoding IL1B; Tyr 113 His TT genotype in the gene encoding MEH; -366 GG genotype in the gene encoding ALOX5; HOM T2437C CC or CT genotype in the gene encoding HSP 70; +13924 AA genotype in the gene encoding Chloride Channel Calcium-activated 1 (CLCA1); and -159 CC genotype in the gene encoding Monocyte differentiation antigen CD-14 (CD-14). 13. The method according to claim 12, wherein all polymorphisms of the group are analysed. 14. The method according to claim 1, wherein when the disease is OCOPD, the protective polymorphism analysed is selected from one or more of the group consisting of: -765 CC or CG in the promoter of the gene encoding COX2; -251 AA in the promoter of the gene encoding interleukin-8 (IL-8); Lys 420 Thr AA in the gene encoding VDBP; Glu 416 Asp TT or TG in the gene encoding VDBP; exon 3 T/C RR in the gene encoding microsomal epoxide hydrolase (MEH); Arg 312 Gln AG or GG in the gene encoding SOD3; MS or SS in the gene encoding .alpha.1AT; Asp 299 Gly AG or GG in the gene encoding toll-like receptor 4 (TLR4); Gln 27 Glu CC in the gene encoding ADRB2; -518 AA in the gene encoding IL-11; and Asp 298 Glu TT in the gene encoding NOS3. 15. The method according to claim 14, wherein all polymorphisms of the group are analysed. 16. The method according to claim 1, wherein when the disease is OCOPD, the susceptibility polymorphism analysed is selected from one or more of the group consisting of: -765 GG in the promoter of the gene encoding COX2; 105 AA in the gene encoding IL-18; -133 CC in the promoter of the gene encoding IL-18; -675 5G5G in the promoter of the gene encoding PAI-1; Lys 420 Thr CC in the gene encoding VDBP; Glu 416 Asp GG in the gene encoding VDBP; Ile 105 Val GG in the gene encoding GSTP1; Arg 312 Gln AA in the gene encoding SOD3; -1055TT in the promoter of the gene encoding IL-13; 3' 1237 Tt or tt in the gene encoding .alpha.1AT; and -1607 2G2G in the promoter of the gene encoding MMP1. 17. The method according to claim 16, wherein all polymorphisms of the group are analysed. 18. The method according to claim 1, wherein when the disease is lung cancer, the protective polymorphism analysed is selected from one or more of the group consisting of: Asp 298 Glu TT genotype in the gene encoding NOS3; Arg 312 Gln CG or GG genotype in the gene encoding SOD3; Asn 357 Ser AG or GG genotype in the gene encoding MMP12; 105 AC or CC genotype in the gene encoding IL-18; -133 CG or GG genotype in the gene encoding IL-18; -765 CC or CG genotype in the promoter of the gene encoding COX2; -221 TT genotype in the gene encoding Mucin 5AC (MUC5AC); intron 1 C/T TT genotype in the gene encoding Arginase 1 (Arg1); Leu252Val GG genotype in the gene encoding Insulin-like growth factor II receptor (IGF2R); -1082GG genotype in the gene encoding Interleukin 10 (IL-10); -251AA genotype in the gene encoding Interleukin 8 (IL-8); Arg 399 Gln AA genotype in the X-ray repair complementing defective in Chinese hamster 1 (XRCC1) gene; A870G GG genotype in the gene encoding cyclin D (CCND1); -751 GG genotype in the promoter of the xeroderma pigmentosum complementation group D (XPD) gene ; Ile 462 Val AG or GG genotype in the gene encoding cytochrome P450 1A1 (CYP1A1); Ser 326 Cys GG genotype in the gene encoding 8-Oxoguanine DNA glycolase (OGG1); and Phe 257 Ser CC genotype in the gene encoding REV1. 19. The method according to claim 18, wherein all polymorphisms of the group are analysed. 20. The method according claim 1, wherein when the disease is lung cancer, the susceptibility polymorphisms analysed are selected from one or more of the group consisting of: -786 TT genotype in the promoter of the gene encoding NOS3; Ala 15 Thr GG genotype in the gene encoding anti-chymotrypsin (ACT); 105 AA genotype in the gene encoding IL-18; -133 CC genotype in the promoter of the gene encoding IL-18; 874 AA genotype in the gene encoding IFN.gamma.; -765 GG genotype in the promoter of the gene encoding COX2; -447 CC or GC genotype in the gene encoding Connective tissue growth factor (CTGF); and +161 AA or AG genotype in the gene encoding MBL2; -511 GG genotype in the gene encoding IL-1B; A-670G AA genotype in the gene encoding FAS (Apo-1/CD95); Arg 197 Gln GG genotype in the gene encoding N-acetyltransferase 2 (NAT2); Ile462 Val AA genotype in the gene encoding CYP1A1; 1019 G/C Pst I CC or CG genotype in the gene encoding cytochrome P450 2E1 (CYP2E1); C/T Rsa I TT or TC genotype in the gene encoding CYP2E1; GSTM null genotype in the gene encoding GSTM; -1607 2G/2G genotype in the promoter of the gene encoding MMP1; Gln 185 Glu CC genotype in the gene encoding Nibrin (NBS1); and Asp 148 Glu GG genotype in the gene encoding Apex nuclease (APE1). 21. The method according to claim 18, wherein all polymorphisms of the group are analysed. 22. The method according to claim 1, wherein each protective polymorphism is assigned a value of -1 and each susceptibility polymorphism is assigned a value of +1. 23. The method according to claim 1, wherein each protective polymorphism is assigned a value of +1 and each susceptibility polymorphism is assigned a value of -1. 24. The method according to claim 1, wherein the subject is or has been a smoker. 25. The method according to claim 1, wherein the method comprises an analysis of one or more risk factors, including one or more epidemiological risk factors, associated with the risk of developing said disease. 26. A method of determining a human subject's risk of developing a disease having a genetic basis, said method comprising: obtaining a sample from a human subject; obtaining a result of one or more analyses of said sample to determine a presence or absence of at least one protective polymorphism and a presence or absence of at least one susceptibility polymorphism, and wherein said protective and susceptibility polymorphisms are associated with said disease having a genetic basis, and wherein the total number of susceptibility and protective polymorphisms analyzed is four or greater; assigning a positive score for each protective polymorphism and a negative score for each susceptibility polymorphism or vice versa; and calculating a net score for said subject, said net score representing a balance between a combined value of the at least one protective polymorphism and a combined value of the at least one susceptibility polymorphism present in the subject sample, wherein the disease is selected from the group consisting of lung cancer, chronic obstructive pulmonary disease (COPD), occupational chronic obstructive pulmonary disease (OCOPD), and emphysema, and wherein a net protective score is predictive of a reduced risk of developing said disease and a net susceptibility score is predictive of an increased risk of developing said disease. 27. A method of assessing a human subject's risk of developing a disease having a genetic basis, comprising: obtaining a biological sample from a human subject; analyzing said sample for a presence or absence of at least one protective polymorphism and for a presence or absence of at least one susceptibility polymorphism, wherein said at least one protective polymorphism and said at least one susceptibility polymorphism are associated with a disease having a genetic basis, and wherein the total number of susceptibility and protective polymorphisms analyzed is five or greater; assigning a positive score for each protective polymorphism and a negative score for each susceptibility polymorphism or vice versa; and calculating a net score for said subject, said net score representing a balance between a combined value of the at least one protective polymorphism and the combined value of the at least one susceptibility polymorphism present in the subject sample; wherein the disease is selected from the group consisting of lung cancer, chronic obstructive pulmonary disease (COPD), occupational chronic obstructive pulmonary disease (OCOPD), and emphysema, and wherein a net protective score is predictive of a reduced risk of developing said disease and a net susceptibility score is predictive of an increased risk of developing said disease. 28. A method of assessing a human subject's risk of developing a disease having a genetic basis, comprising: obtaining a biological sample from a human subject; analyzing said sample for a presence or absence of at least one protective polymorphism and for a presence or absence of at least one susceptibility polymorphism, wherein said at least one protective polymorphism and said at least one susceptibility polymorphism are associated with a disease having a genetic basis, and wherein the total number of susceptibility and protective polymorphisms analyzed is six or greater; assigning a positive score for each protective polymorphism and a negative score for each susceptibility polymorphism or vice versa; and calculating a net score for said subject, said net score representing a balance between a combined value of the at least one protective polymorphism and the combined value of the at least one susceptibility polymorphism present in the subject sample; wherein the disease is selected from the group consisting of lung cancer, chronic obstructive pulmonary disease (COPD), occupational chronic obstructive pulmonary disease (OCOPD), and emphysema, and wherein a net protective score is predictive of a reduced risk of developing said disease and a net susceptibility score is predictive of an increased risk of developing said disease. 29. A method of assessing a human subject's risk of developing a disease having a genetic basis, comprising: obtaining a biological sample from a human subject; analyzing said sample for a presence or absence of at least one protective polymorphism and for a presence or absence of at least one susceptibility polymorphism, wherein said at least one protective polymorphism and said at least one susceptibility polymorphism are associated with a disease having a genetic basis, and wherein the total number of susceptibility and protective polymorphisms analyzed is seven or greater; assigning a positive score for each protective polymorphism and a negative score for each susceptibility polymorphism or vice versa; and calculating a net score for said subject, said net score representing a balance between a combined value of the at least one protective polymorphism and the combined value of the at least one susceptibility polymorphism present in the subject sample; wherein the disease is selected from the group consisting of lung cancer, chronic obstructive pulmonary disease (COPD), occupational chronic obstructive pulmonary disease (OCOPD), and emphysema, and wherein a net protective score is predictive of a reduced risk of developing said disease and a net susceptibility score is predictive of an increased risk of developing said disease. 30. The method of claim 1, wherein the value assigned to one of the susceptibility and protective polymorphisms analysed is weighted. 31. The method of claim 27, wherein the value assigned to one of the susceptibility and protective polymorphisms analysed is weighted. 32. The method of claim 28, wherein the value assigned to one of the susceptibility and protective polymorphisms analysed is weighted. 33. The method of claim 29, wherein the value assigned to one of the susceptibility and protective polymorphisms analysed is weighted.

Details for Patent 7,933,722

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2025-05-20
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2025-05-20
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2025-05-20