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WO 2013/043130 Al 28 March 2013 (28.03.2013) P O P C T

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WO 2013/043130 Al 28 March 2013 (28.03.2013) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/043130 Al 28 March 2013 (28.03.2013) P O P C T (51) International Patent Classification: Building Level 5, Singapore 16875 1 (SG). KHOR, Chiea- C12Q 1/68 (2006.01) Chuen; Genome Institute of Singapore, 60 Biopolis Street, Genome, Singapore 138672 (SG). (21) International Application Number: PCT/SG2012/00035 1 (74) Agent: CHUNG, Jing Yeng; Marks & Clerk Singapore LLP, Tanjong Pagar, P.O Box 636, Singapore 9108 16 (22) International Filing Date: (SG). 24 September 2012 (24.09.2012) (81) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of national protection available): AE, AG, AL, AM, (26) Publication Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (30) Priority Data: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 61/537,904 22 September 201 1 (22.09.201 1) US HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (71) Applicants: SINGAPORE HEALTH SERVICES PTE KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, LTD [SG/SG]; 31 Third Hospital Avenue, #03-03 Bowyer ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, Block C, Singapore 168753 (SG). AGENCY FOR SCI¬ NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, ENCE, TECHNOLOGY AND RESEARCH [SG/SG]; 1 RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, Fusionopolis Way, #20-10 Connexis, Singapore 138632 TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (SG). ZM, ZW. (72) Inventors: AUNG, Tin; Singapore Eye Research Institute, (84) Designated States (unless otherwise indicated, for every 11 Third Hospital Avenue, SNEC Building Level 5, Singa kind of regional protection available): ARIPO (BW, GH, pore 16875 1 (SG). VITHANA, Eranga; Singapore Eye GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, Research Institute, 11 Third Hospital Avenue, SNEC UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, [Continued on nextpage] (54) Title: METHOD AND/OR PROBE FOR DETERMINING GLAUCOMA SUSCEPTIBILITY AND/OR PREDICTING/DE TECTING SHALLOW ANTERIOR CHAMBER DEPTH (57) Abstract: The present invention provides a method and/or probe for predicting and/or detecting a shallow anterior chamber depth and/or determining susceptibility to glaucoma in a subject, comprising determining the geno type of the subject for at least one nucleic acid variation in ATP-binding cassette sub-family C member 5 (ABCC5) gene, wherein the nuc leic acid variation is correlated with anterior V chamber depth and/or susceptibility to angle closure glaucoma. - i Figure 1 WO 2013/043130 Al III III II II II III 11 TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Published: EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, — with international search report (Art. 21(3)) LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, — with sequence listing part of description (Rule 5.2(a)) GW, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: — of inventorship (Rule 4.17(iv)) Method and/or probe for determining glaucoma susceptibility and/or predicting/detecting shallow anterior chamber depth Field of the invention The present invention relates to the field of molecular biology, in particular in prediction and/or diagnosis of a condition and/or disease and/or determining susceptibility to the condition and/or disease. Background of the invention Glaucoma is known to be a leading cause of irreversible blindness worldwide, characterised by progressive loss of axons in the optic nerve and corresponding visual field damage. Categorized according to the anatomy of the anterior chamber angle, there are two main forms of glaucoma, primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG). While POAG is the predominant form of glaucoma among Caucasians and Africans, 80% of the estimated 5 million people afflicted with PACG live in Asia. PACG is responsible for substantial blindness in Mongolia, Singapore, China, and India, and it is estimated that PACG blinds proportionately more people than POAG globally. Both POAG and PACG have indications of being a complex disease with both genetic and environmental factors likely having a role in its etiology. The pathogenesis of PACG is thought to occur through the interplay of multiple anatomical and physiological factors. A major ocular anatomical risk for PACG is a shallow anterior chamber depth of the eye (Lowe 970). However, genes associated with shallow anterior chamber depth, PACG and POAG are largely unknown although a few genes have been reported to have an association with POAG [Burdon et a/., (201 1); Thorleifsson et al., (2010); Wiggs et a , (201 )]. Summary of the invention According to a first aspect, the present invention provides a method for predicting and/or detecting a shallow anterior chamber depth and/or determining susceptibility to angle closure glaucoma in a subject, comprising determining the genotype of the subject for at least one nucleic acid variation in ATP-binding cassette sub-family C member 5 (ABCC5) gene, wherein the nucleic acid variation is correlated with anterior chamber depth and/or susceptibility to angle closure glaucoma. The present invention also provides a probe for use in predicting and/or detecting a shallow anterior chamber depth and/or determining susceptibility to angle closure glaucoma in a subject, wherein the probe is for use in determining the genotype of the subject for at least one nucleic acid variation in ATP binding cassette sub-family C member 5 (ABCC5) gene, wherein the nucleic acid variation is correlated with shallow anterior chamber depth and/or susceptibility to angle closure glaucoma. According to another aspect, the method and/or probe may be for diagnosing a shallow anterior chamber depth and/or glaucoma in a subject. Accordingly, the method and/or probe may be used to determine susceptibility to and/or diagnose primary angle closure glaucoma (PACG). Brief description of the figures Figure 1 shows the regional association and linkage disequilibrium plot around ABCC5 rs 40 999. The horizontal axis denotes genomic position along Chromosome 3 in absolute base-pairs. The vertical axis shows -Log10 P- values derived from the unguided 2 degrees of freedom genotype. Figure 2 shows the Manhattan plot for genome-wide meta-analysis of anterior chamber depth in three populations (Singapore Malays, Singapore Indians, and Chinese from Beijing) totaling 4,473 individuals. Figure 3 shows plots of genetic ancestry using principal components for the Singapore GWAS sample (PACG cases and controls) against HapMap reference population panels. Figures 4A and 4B shows plots of genetic ancestry using principal components for the Singapore PACG cases and controls. Figure 5 shows the quantile-quantile plot of P-values from the meta-analysis of ACD across the 3 independent sample collections. Figure 6 shows expression analysis of ABCC5 in human ocular tissues. The 249bp RT-PCR product was observed in cornea (C), sclera (S), retina and retinal pigment epithelium (RPE), iris (I), lens (L), lens capsule (LC) and in the optic nerve (ON). The ubiquitously expressed gene, ACTB was used as the normalizing control. M denotes molecular-weight marker. Definitions "Determine" or "determining" means to find out or come to a decision about by investigation, reasoning, or calculation, or to settle or decide from alternatives or possibilities; "determine" or "determining" encompasses the meaning of "predicting" or "assessing". "Determining the genotype of a subject for a nucleic acid variation" refers to determining the genetic constitution or makeup of the subject for that nucleic acid variation and includes determining the absence or presence of the nucleic acid variation and; where the nucleic acid variation comprises several alternatives, determining the alternative in the subject. "Endophenotype" relates to a hereditary characteristic that is normally associated with some condition (for example, a disease) but is not a direct symptom of that condition. It may also be regarded as an intermediate phenotype of the condition. "Nucleic acid variation" includes, but is not limited to, a single nucleotide polymorphism (SNP), a double nucleotide polymorphism (DNP), a nucleotide deletion, a nucleotide addition, a nucleic acid amplification, a rearrangement of a nucleic acid sequence or a gene and/or and/or its corresponding transcriptional and/or translational product, and/or alternative splicing of the transcriptional and/or translational product. A "single polynucleotide polymorphism (SNP)" refers to a DNA and/or RNA sequence variation occurring when a single nucleotide in an organism's DNA sequence differs between members of the species (or between paired chromosomes in the organism). A "double polynucleotide polymorphism (DNP)" refers to two single polynucleotide polymorphisms, and includes the circumstances when the two SNPs are positioned next to each other, separated by other nucleotides, on different strands of the same nucleic acid molecules, or on different nucleic acid molecules. A "primer" refers to an oligonucleotide to which deoxyribonucleotides may be added by a DNA polymerase. A single primer may be used to amplify a DNA or RNA region, for example, for sequencing. A "primer pair" usually comprises a first primer complementary to one strand of a DNA or RNA molecule and a second primer complementary to a second strand of a DNA or RNA molecule, with both primers flanking a target DNA or RNA region, to be amplified by a DNA polymerase. Detailed description of the invention The present invention relates to a method for predicting and/or detecting a shallow anterior chamber depth and/or determining susceptibility to angle closure glaucoma in a subject, comprising determining the genotype of the subject for at least one nucleic acid variation in ATP-binding cassette sub-family C member 5 (ABCC5) gene, wherein the nucleic acid variation is correlated with susceptibility to angle closure glaucoma and/or shallow anterior chamber depth.
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