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3. Next-generation sequencing--based genetic testing and phenotype correlation in retinitis pigmentosa patients from India

Author

Parveen Sen, Natarajan Srikrupa, Puja Maitra, Sundaramurthy Srilekha, Periyasamy Porkodi, Harshavardhini Gnanasekaran, Muna Bhende, Vikas Khetan, Sinnakaruppan Mathavan, Pramod Bhende, Dhanashree Ratra, Rajiv Raman, Chetan Rao, and Sarangapani Sripriya

Subjects
genotype–phenotype correlation, next-generation sequencing, retinitis pigmentosa, Ophthalmology, RE1-994
Abstract

Purpose: Inherited retinal dystrophies (IRD) are a heterogeneous group of retinal diseases leading to progressive loss of photoreceptors through apoptosis. Retinitis pigmentosa (RP) is considered the most common form of IRD. Panel-based testing in RP has proven effective in identifying the causative genetic mutations in 70% and 80% of the patients. This is a retrospective, observational, single-center study of 107 RP patients who had undergone next-generation sequencing-based targeted gene panel testing for IRD genes. These patients were inspected for common phenotypic features to arrive at meaningful genotype–phenotype correlation. Methods: Patients underwent complete ophthalmic examination, and blood was collected from the proband for DNA extraction after documenting the pedigree. Targeted Next Generation Sequencing (NGS) was done by panel-based testing for IRD genes followed by co-segregation analysis wherever applicable. Results: Of the 107 patients, 72 patients had pathogenic mutations. The mean age of onset of symptoms was 14 ± 12 years (range: 5–55). Mean (Best Corrected Visual Acuity) BCVA was 6/48 (0.9 logMAR) (range 0.0–3.0). At presentation, over one-third of eyes had BCVA worse than 6/60 (

Published
2023
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4. IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis

Author

Chekuri, Anil, Guru, Aditya A, Biswas, Pooja, Branham, Kari, Borooah, Shyamanga, Soto-Hermida, Angel, Hicks, Michael, Khan, Naheed W, Matsui, Hiroko, Alapati, Akhila, Raghavendra, Pongali B, Roosing, Susanne, Sarangapani, Sripriya, Mathavan, Sinnakaruppan, Telenti, Amalio, Heckenlively, John R, Riazuddin, S Amer, Frazer, Kelly A, Sieving, Paul A, and Ayyagari, Radha

Subjects
Eye Disease and Disorders of Vision, Neurosciences, Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Alleles, CRISPR-Cas Systems, Ciliopathies, Female, Gene Editing, Genetic Predisposition to Disease, HeLa Cells, Homozygote, Humans, Male, Middle Aged, Mutation, Pedigree, Retina, Retinal Degeneration, Tumor Suppressor Proteins, Whole Genome Sequencing, Hela Cells, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity
Abstract

Whole genome sequencing (WGS) was performed to identify the variants responsible for inherited retinal degeneration (IRD) in a Caucasian family. Segregation analysis of selected rare variants with pathogenic potential identified a set of compound heterozygous changes p.Arg266*:c.796C>T and p.Ala568Thr:c.1702G>A in the intraflagellar transport protein-88 (IFT88) gene segregating with IRD. Expression of IFT88 with the p.Arg266* and p.Ala568Thr mutations in mIMDC3 cells by transient transfection and in HeLa cells by introducing the mutations using CRISPR-cas9 system suggested that both mutations result in the formation of abnormal ciliary structures. The introduction of the IFT88 p.Arg266* variant in the homozygous state in HeLa cells by CRISPR-Cas9 genome-editing revealed that the mutant transcript undergoes nonsense-mediated decay leading to a significant depletion of IFT88 transcript. Additionally, abnormal ciliogenesis was observed in these cells. These observations suggest that the rare and unique combination of IFT88 alleles observed in this study provide insight into the physiological role of IFT88 in humans and the likely mechanism underlying retinal pathology in the pedigree with IRD.

Published
2018

5. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.

Author

Aung, Tin, Ozaki, Mineo, Lee, Mei, Schlötzer-Schrehardt, Ursula, Thorleifsson, Gudmar, Mizoguchi, Takanori, Igo, Robert, Haripriya, Aravind, Williams, Susan, Astakhov, Yury, Orr, Andrew, Burdon, Kathryn, Nakano, Satoko, Mori, Kazuhiko, Abu-Amero, Khaled, Hauser, Michael, Li, Zheng, Prakadeeswari, Gopalakrishnan, Bailey, Jessica, Cherecheanu, Alina, Kang, Jae, Nelson, Sarah, Hayashi, Ken, Manabe, Shin-Ichi, Kazama, Shigeyasu, Zarnowski, Tomasz, Inoue, Kenji, Irkec, Murat, Coca-Prados, Miguel, Sugiyama, Kazuhisa, Järvelä, Irma, Schlottmann, Patricio, Lerner, S, Lamari, Hasnaa, Nilgün, Yildirim, Bikbov, Mukharram, Park, Ki, Cha, Soon, Yamashiro, Kenji, Zenteno, Juan, Jonas, Jost, Kumar, Rajesh, Perera, Shamira, Chan, Anita, Kobakhidze, Nino, George, Ronnie, Vijaya, Lingam, Do, Tan, Edward, Deepak, de Juan Marcos, Lourdes, Pakravan, Mohammad, Moghimi, Sasan, Ideta, Ryuichi, Bach-Holm, Daniella, Kappelgaard, Per, Wirostko, Barbara, Thomas, Samuel, Gaston, Daniel, Bedard, Karen, Greer, Wenda, Yang, Zhenglin, Chen, Xueyi, Huang, Lulin, Sang, Jinghong, Jia, Hongyan, Jia, Liyun, Qiao, Chunyan, Zhang, Hui, Liu, Xuyang, Zhao, Bowen, Wang, Ya-Xing, Xu, Liang, Leruez, Stéphanie, Reynier, Pascal, Chichua, George, Tabagari, Sergo, Uebe, Steffen, Zenkel, Matthias, Berner, Daniel, Mossböck, Georg, Weisschuh, Nicole, Hoja, Ursula, Welge-Luessen, Ulrich-Christoph, Mardin, Christian, Founti, Panayiota, Chatzikyriakidou, Anthi, Pappas, Theofanis, Anastasopoulos, Eleftherios, Lambropoulos, Alexandros, Ghosh, Arkasubhra, Shetty, Rohit, Porporato, Natalia, Saravanan, Vijayan, Venkatesh, Rengaraj, Shivkumar, Chandrashekaran, Kalpana, Narendran, Sarangapani, Sripriya, Kanavi, Mozhgan, Beni, Afsaneh, and Yazdani, Shahin

Subjects
Aged, 80 and over, Alleles, Amino Acid Oxidoreductases, Amino Acid Substitution, Asian People, Calcium Channels, Cell Adhesion, Exfoliation Syndrome, Extracellular Matrix, Eye, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Humans, Male, Molecular Chaperones, Mutation, Missense, Point Mutation, RNA, Messenger, Spheroids, Cellular
Abstract

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10-14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10-8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Published
2017

7. Whole-exome sequencing identifies two novel ALMS1 mutations in Indian patients with Leber congenital amaurosis

Author

Natarajan N. Srikrupa, Sarangapani Sripriya, Suriyanarayanan Pavithra, Parveen Sen, Ravi Gupta, and Sinnakaruppan Mathavan

Subjects
Genetics, QH426-470, Life, QH501-531
Abstract

Abstract Leber congenital amaurosis (LCA) is a severe autosomal recessive retinal degenerative disease. The current study describes exome sequencing results for two unrelated Indian LCA patients carrying novel nonsense p.(Glu636*) and frameshift p.(Pro2281Leufs*63) mutations in the ALMS1 gene. Although ALMS1 gene mutations are associated with Alstrom syndrome (AS), the current patients did not exhibit typical syndromic features of AS. These data suggest that ALMS1 should be included in the candidate gene panel for LCA to improve diagnostic efficiency.

Published
2021
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8. Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma

Author

Khor, Chiea Chuen, Do, Tan, Jia, Hongyan, Nakano, Masakazu, George, Ronnie, Abu-Amero, Khaled, Duvesh, Roopam, Chen, Li Jia, Li, Zheng, Nongpiur, Monisha E, Perera, Shamira A, Qiao, Chunyan, Wong, Hon-Tym, Sakai, Hiroshi, Barbosa de Melo, Mônica, Lee, Mei-Chin, Chan, Anita S, Azhany, Yaakub, Dao, Thi Lam Huong, Ikeda, Yoko, Perez-Grossmann, Rodolfo A, Zarnowski, Tomasz, Day, Alexander C, Jonas, Jost B, Tam, Pancy OS, Tran, Tuan Anh, Ayub, Humaira, Akhtar, Farah, Micheal, Shazia, Chew, Paul TK, Aljasim, Leyla A, Dada, Tanuj, Luu, Tam Thi, Awadalla, Mona S, Kitnarong, Naris, Wanichwecharungruang, Boonsong, Aung, Yee Yee, Mohamed-Noor, Jelinar, Vijayan, Saravanan, Sarangapani, Sripriya, Husain, Rahat, Jap, Aliza, Baskaran, Mani, Goh, David, Su, Daniel H, Wang, Huaizhou, Yong, Vernon K, Yip, Leonard W, Trinh, Tuyet Bach, Makornwattana, Manchima, Nguyen, Thanh Thu, Leuenberger, Edgar U, Park, Ki-Ho, Wiyogo, Widya Artini, Kumar, Rajesh S, Tello, Celso, Kurimoto, Yasuo, Thapa, Suman S, Pathanapitoon, Kessara, Salmon, John F, Sohn, Yong Ho, Fea, Antonio, Ozaki, Mineo, Lai, Jimmy SM, Tantisevi, Visanee, Khaing, Chaw Chaw, Mizoguchi, Takanori, Nakano, Satoko, Kim, Chan-Yun, Tang, Guangxian, Fan, Sujie, Wu, Renyi, Meng, Hailin, Nguyen, Thi Thuy Giang, Tran, Tien Dat, Ueno, Morio, Martinez, Jose Maria, Ramli, Norlina, Aung, Yin Mon, Reyes, Rigo Daniel, Vernon, Stephen A, Fang, Seng Kheong, Xie, Zhicheng, Chen, Xiao Yin, Foo, Jia Nee, Sim, Kar Seng, Wong, Tina T, Quek, Desmond T, Venkatesh, Rengaraj, Kavitha, Srinivasan, Krishnadas, Subbiah R, Soumittra, Nagaswamy, Shantha, Balekudaru, Lim, Boon-Ang, Ogle, Jeanne, de Vasconcellos, José PC, Costa, Vital P, Abe, Ricardo Y, de Souza, Bruno B, and Sng, Chelvin C

Subjects
Neurodegenerative, Human Genome, Eye Disease and Disorders of Vision, Aging, Genetics, Cell Line, Chromosome Mapping, Female, Gene Expression, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glaucoma, Angle-Closure, Humans, Male, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.

Published
2016

9. Assessment of single nucleotide polymorphisms associated with steroid-induced ocular hypertension

Author

Lakshmi Badrinarayanan, Srujana Chitipothu, Sharada Ramasubramanyan, Sarangapani Sripriya, Pukhraj Rishi, Ekta Rishi, Ronnie George, Baddireddi Subhadra Lakshmi, and Sailaja V. Elchuri

Subjects
triamcinolone-acetonide, dexamethasone, ocular hypertension, single nucleotide polymorphisms, diabetes, neurodegeneration, myopia, Ophthalmology, RE1-994
Abstract

AIM: To access the association of forty-eight single nucleotide polymorphisms (SNPs) identified from Caucasian population with steroid-induced ocular hypertension (OHT) in India population. METHODS: Fifty-four triamcinolone-acetonide (TA) and forty-seven dexamethasone (Dex) administered subjects were enrolled in the study after a written consent. Intraocular pressure (IOP) values were recorded for a period of 6-month post steroid injections and patients were grouped as steroid-responders (SR: IOP≥21 mm Hg) and non-responders (NR: IOP≤20 mm Hg). Genomic DNA was isolated from peripheral venous blood. Forty-eight SNPs identified in TA treated Caucasian patients by genome wide association study (GWAS) were genotyped using iPLEXTM MassARRAY among TA as well as Dex administered Indian patients. Genotyping data of 48 general subjects from a previous study were considered as reference controls for statistical analysis. Genotypic frequencies were calculated and P-value, Chi-square and odds ratio at 95% confidence-interval of group A (steroid treated vs controls), group B (SR vs NR), group C (phenotype correlation: influence of time, severity and gender on IOP rise), were calculated. P30 mm Hg) and immediate (

Published
2020
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11. Whole-exome sequencing identifies two novel ALMS1 mutations in Indian patients with Leber congenital amaurosis

Author

Suriyanarayanan Pavithra, Natarajan N Srikrupa, Sarangapani Sripriya, Parveen Sen, Sinnakaruppan Mathavan, and Ravi Gupta

Subjects
Candidate gene, Genetic testing, genetic structures, lcsh:QH426-470, media_common.quotation_subject, Nonsense, lcsh:Life, Biochemistry, Frameshift mutation, 03 medical and health sciences, Degenerative disease, Genetics research, Data Report, Genetics, medicine, Molecular Biology, Exome sequencing, 030304 developmental biology, media_common, 0303 health sciences, ALMS1 GENE, business.industry, 030305 genetics & heredity, medicine.disease, Leber congenital amaurosis, eye diseases, lcsh:Genetics, lcsh:QH501-531, sense organs, business, Alström syndrome
Abstract

Leber congenital amaurosis (LCA) is a severe autosomal recessive retinal degenerative disease. The current study describes exome sequencing results for two unrelated Indian LCA patients carrying novel nonsense p.(Glu636*) and frameshift p.(Pro2281Leufs*63) mutations in the ALMS1 gene. Although ALMS1 gene mutations are associated with Alstrom syndrome (AS), the current patients did not exhibit typical syndromic features of AS. These data suggest that ALMS1 should be included in the candidate gene panel for LCA to improve diagnostic efficiency.

Published
2021

13. Genetic testing in four Indian families with suspected Stickler syndrome.

Author

Kandeeban, Suganya, Kandale, Kaustubh, Periyasamy, Porkodi, Bhende, Muna, Bhende, Pramod, Sinnakaruppan, Mathavan, and Sarangapani, Sripriya

Abstract

Purpose: Stickler syndrome is associated with the development of rhegmatogenous retinal detachment (RRD), and often presents with ocular, auditory, skeletal, and orofacial abnormalities. Molecular analysis has proven effective in diagnosis, confirmation and classification of the disease. We aimed to describe the utility of next-generation sequencing (NGS) in genetic analysis of four Indian families with suspected Stickler syndrome.Methods: The index cases presented with retinal detachment with family history. Genetic analysis in the index case was performed by next-generation sequencing of inherited retinal degeneration genes, and validated by Sanger sequencing followed by co-segregation analysis in the other family members.Results: Twenty patients were included for the genetic analysis (15 males and 5 females from four families). Clinical details were available for 15 patients (30 eyes). Fourteen eyes (11 patients) developed RRD. In the 16 eyes without RRD, 8 underwent barrage laser to lattice degeneration and 8 were under observation. Disease segregating heterozygous mutations with pathogenic/likely pathogenic effect was identified in COL2A1 (c.4318-1G>A, c.141G>A, c.1221+1G>A for 3 families) and COL11A1 (c.1737+1 G>A for 1 family) gene. In addition to the mutation in the COL2A1 gene, a pathogenic heterozygous variant associated with risk for arrhythmogenic right ventricular cardiomyopathy (ARVC) was identified in one member.Conclusion: NGS testing confirmed the presence of the causative gene for Stickler syndrome in the index case followed by evaluation of family members and confirmation of genetic and ocular findings. We believe that this may be the first such report of families with RRD from India. [ABSTRACT FROM AUTHOR]

Published
2022
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15. Homozygosity Mapping for Autosomal Recessive Ocular Diseases

Author

Nagasamy Soumittra, Karthikeyan Sudha, Sundaramoorthy Srilekha, Chandrasekar SatyaPriya, and Sarangapani Sripriya

Subjects
Disease gene, Genetics, genetic structures, Locus (genetics), Disease, Biology, Disease gene identification, eye diseases, symbols.namesake, Genetic linkage, Mendelian inheritance, symbols, Allele, Gene
Abstract

Genetic eye diseases play a major role in causing visual impairment and blindness affecting all the structures of the eye from the anterior to posterior segment. They are inherited as either Mendelian or complex and in Mendelian inheritance, auotosomal dominant, autosomal recessive or X-linked recessive patterns are commonly observed. Linkage and homozygosity mapping is based on the information provided by the non-recombinants on the chromosomal segments to map disease genes. In Homozygosity mapping the large stretches of homozygous alleles inherited due to identity-by-descent (IBD) and shared between the affected individual(s) and absent in the unaffected in the family are compared to map the disease gene locus. A small family with one each of affected and unaffected provides sufficient data to map disease locus/gene using homozygosity mapping unlike linkage studies where larger multi-generation families with many affected and unaffected are required. An increased prevalence of autosomal recessive disorders observed in genetically isolated or highly inbred families have aided in mapping many ocular diseases genes using homozygosity mapping. This chapter details the history, methodology and the different ocular diseases where homozygosity mapping has been applied to identify the causative genes.

Published
2017
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17. Correlation of Aqueous Humor Lysyl Oxidase Activity with TGF-ß Levels and LOXL1 Genotype in Pseudoexfoliation

Author

Lingam Vijaya, Karunakaran Coral, Panday Manish, Krishnamoorthy Sripriya, Balekudaru Shantha, Ferdinamarie Sharmila, Sarangapani Sripriya, Angayarkanni Narayanasamy, George Ronnie, and Ramakrishnan Gayathri

Subjects
0301 basic medicine, Male, genetic structures, Genotype, Glaucoma, Single-nucleotide polymorphism, Lysyl oxidase, Enzyme-Linked Immunosorbent Assay, Biology, Exfoliation Syndrome, Extracellular matrix, Aqueous Humor, Protein-Lysine 6-Oxidase, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Transforming Growth Factor beta, medicine, Humans, Prospective Studies, Aged, Genetics, Polymorphism, Genetic, Pseudoexfoliation, DNA, Middle Aged, medicine.disease, Molecular biology, eye diseases, Sensory Systems, Ophthalmology, 030104 developmental biology, Haplotypes, Case-Control Studies, 030221 ophthalmology & optometry, biology.protein, Female, sense organs, Amino Acid Oxidoreductases, Elastin, Transforming growth factor
Abstract

Pseudoexfoliation (PXF) is a microfibrillopathy involving disordered elastogenesis. Abnormal extracellular matrix (ECM) production underlies the pathophysiology of PXF. The enzyme Lysyl oxidase (LOX) and its isoforms are known to cross-link the elastin and collagen. Though the etiopathogensis of PXF is not well understood, studies report on the genetic risk involving LOXL1 gene. This study aims to screen LOXL1 coding variants rs1048661 and rs3825942 in the South Indian population and the implication of the single nucleotide polymorphism (SNP) with LOX activity. The levels of transforming growth factor β (TGF-β) in aqueous humor and its correlation with the LOX activity were also examined.Blood, plasma, and aqueous aspirates were prospectively collected from PXF cases with and without glaucoma and cataract cases as controls. DNA was extracted from 48 PXF cases without glaucoma, 12 PXF cases with glaucoma, and 40 age-matched cataract-alone controls without PXF/glaucoma for analyzing LOX SNPs. LOX activity was measured in aqueous humor and plasma of 30 PXF cases without glaucoma, 24 age-matched cataract-alone controls without PXF/glaucoma, and 14 PXF cases with glaucoma. Protein levels of LOX, LOXL1, LOXL2, and total TGF-β were estimated in plasma and aqueous humor by ELISA.The specific activity of LOX in aqueous humor was found to be significantly lowered in PXF cases compared with cataract-alone controls (p = 0.014). This decrease in LOX activity in PXF cases was associated with high-risk GG haplotype. However, this was not statistically significant and a larger sample size is warranted. TGF-β1 and TGF-β2 negatively correlated with LOX activity in aqueous humor (p = 0.028; p = 0.046, respectively).The LOXL1 SNPs, rs1048661 and rs3825942, are associated with PXF in the South Indian population correlating with lowered LOX activity in the aqueous humor. The increased level of total TGF-β in the aqueous humor of PXF cases is possibly associated with LOX regulation which needs further investigation.

Published
2016

18. Family-Based Genome-Wide Association Study of South Indian Pedigrees SupportsWNT7Bas a Central Corneal Thickness Locus

Author

Jim Gauderman, Veronique Vitart, Jonathan L. Haines, S.E. Moroi, Srinivasan Sacikala, René Höhn, Angela J. Cree, Xueli Chen, Terri L. Young, Francesca Pasutto, Robert N. Weinreb, Joel S. Schuman, William K. Scott, Jae H. Kang, Pirro G. Hysi, Richard K. Lee, Tin Aung, Kuldev Singh, Anthony P Khawaja, Michael A. Hauser, Henriette Springelkamp, David S. Friedman, Anthony Realini, Rashima Asokan, Donald J. Zack, D. L. Budenz, Gadi Wollstein, Unnur Thorsteinsdottir, Robert P. Igo, Lingam Vijaya, Caroline C W Klaver, Jessica N. Cooke Bailey, Kathryn P. Burdon, Tien Wong, Paul Mitchell, Jerome I. Rotter, Robert Wojciechowski, Julia R. Richards, Terry Gaasterland, Douglas Vollrath, Adriana I. Iglesias Gonzalez, David A. Mackey, Puya Gharahkhani, X. Raymond Gao, Yutao Liu, R. Rand Allingham, Rohit Varma, Stuart MacGregor, Arthur J. Sit, John H. Fingert, Nisha Sondhi, Baojian Fan, Cornelia M. van Duijn, Nagasamy Soumittra, Calvin C P Pang, Doug Rhee, Paul R. Lichter, P. Ferdinamarie Sharmila, Douglas E. Gaasterland, Sarangapani Sripriya, Murray H. Brilliant, Jamie E Craig, Ching-Yu Cheng, Aniket Mishra, Alex W. Hewitt, Ananth C. Viswanathan, Janey L. Wiggs, Peter Kraft, Jost B. Jonas, Tanja Zeller, Louis R. Pasquale, Gudmar Thorleifsson, Ronnie George, Robert Ritch, Chiea Chuen Khor, Christopher J Hammond, Clinical Genetics, Ophthalmology, Epidemiology, Obstetrics & Gynecology, and Psychiatry

Subjects
Adult, Male, 0301 basic medicine, Adolescent, Corneal Pachymetry, Genotyping Techniques, genetic association, WNT7B, genetic structures, Quantitative Trait Loci, Population, India, Locus (genetics), Genome-wide association study, Single-nucleotide polymorphism, Pedigree chart, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Cohort Studies, Cornea, quantitative trait, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Asian People, Genetics, Humans, SNP, education, ocular PheWAS, Aged, Genetic association, Aged, 80 and over, Family Health, education.field_of_study, cornea central thickness, Organ Size, Middle Aged, Introns, eye diseases, Pedigree, Wnt Proteins, 030104 developmental biology, 030221 ophthalmology & optometry, Female, sense organs, Genome-Wide Association Study
Abstract

PURPOSE: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. METHODS: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. RESULTS: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95% confidence interval CI: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95% CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. CONCLUSIONS: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.

Published
2018
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20. Transforming Growth Factor β-1 −509C>T Polymorphism in Indian Patients with Primary Open Angle Glaucoma

Author

Tirumalai Karthiyayini, Mani Baskaran, Prema Raju, Lingam Vijaya, Ronnie George, Hemamalini Arvind, Govindasamy Kumaramanickavel, Sarangapani Sripriya, and S. V. Ramesh

Subjects
Adult, medicine.medical_specialty, Intraocular pressure, genetic structures, Open angle glaucoma, India, Glaucoma, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Transforming Growth Factor beta1, Ophthalmology, Genetics, medicine, Humans, SNP, Aged, Aged, 80 and over, Pharmacology, business.industry, General Medicine, Middle Aged, medicine.disease, eye diseases, Genotype frequency, medicine.anatomical_structure, Molecular Medicine, sense organs, Trabecular meshwork, business, Glaucoma, Open-Angle, Transforming growth factor
Abstract

Background: Extracellular matrix (ECM) accumulation in the trabecular meshwork tissues of glaucoma patients has been demonstrated as one of the factors that contribute to glaucoma pathology. Transforming growth factor-β (TGFβ) has its fundamental function in regulating the ECM molecules and has been implicated in glaucoma pathology. In this study, the association of the TGFB1 −-509C>T single nucleotide polymorphism (SNP) with primary open angle glaucoma (POAG) in patients from India is analyzed. Methods: One-hundred and six POAG patients and 104 controls were selected after comprehensive ophthalmic examinations. TGFB1 alleles were typed by restriction enzyme digestion with the isoschizomer Eco81I of Bsu36I, whose site is altered by the −509C>T SNP, and statistically analyzed for any significant association. Two clinical variables, vertical cup disc ratio (CDR) and intraocular pressure (IOP), were compared at diagnosis by the Mann-Whitney test for any significant association with the polymorphism. Results: Statistical analysis between the two groups did not suggest any significant difference in the distribution of allele and genotype frequencies. The Mann-Whitney test did not show any significant p value for the clinical parameters IOP (p = 0.29 and 0.59) and CDR (p = 0.26 and 0.17). Conclusions: The current study shows that the TGFB1 ∼-509C>T polymorphism might not be associated with POAG. Analysis of the other polymorphisms in the regulatory region of the TGFB1 gene could give a better understanding of the role of TGFβ in POAG pathogenesis.

Published
2007
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22. Molecular Genetic Analysis of a Consanguineous South Indian Family with Congenital Glaucoma: Relevance of Genetic Testing and Counseling

Author

Ronnie George, Vedam L. Ramprasad, Govindasamy Kumaramanickavel, Nirmaladevi J, Sarangapani Sripriya, and Lingam Vijaya

Subjects
Adult, Male, Congenital glaucoma, Genotype, Genetic Linkage, Genetic counseling, DNA Mutational Analysis, India, Genetic Counseling, Penetrance, Consanguinity, Myopia, medicine, Humans, Genetic Testing, Allele, Child, Genetics (clinical), Aged, Genetic testing, Genetics, medicine.diagnostic_test, business.industry, Infant, Glaucoma, Middle Aged, Pedigree, Molecular analysis, Ophthalmology, Haplotypes, Cytochrome P-450 CYP1B1, Mutation, Pediatrics, Perinatology and Child Health, Female, Aryl Hydrocarbon Hydroxylases, business
Abstract

The genetic background of congenital glaucoma in a consanguineous south Indian family was examined by homozygosity analyses. Significant evidence for the homozygosity of alleles was detected for markers D2S177 and D2S1346 that are tightly linked to the CYP1B1 gene, and further involvement of this gene was confirmed by the co-segregation of a novel truncating mutation (Q110X) in exon 2 with the disease in all affected members. Newborn genetic screening and carrier identification were also performed in the family. The role of consanguinity and the risk of autosomal recessive disease were discussed and genetic counseling was given.

Published
2007
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23. Correlation of Aqueous Humor Lysyl Oxidase Activity with TGF-ß Levels and LOXL1 Genotype in Pseudoexfoliation

Author

Ramakrishnan Gayathri, Karunakaran Coral, Ferdinamarie Sharmila, Sarangapani Sripriya, Krishnamoorthy Sripriya, Panday Manish, B. Shantha, George Ronnie, Lingam Vijaya, Angayarkanni Narayanasamy, Ramakrishnan Gayathri, Karunakaran Coral, Ferdinamarie Sharmila, Sarangapani Sripriya, Krishnamoorthy Sripriya, Panday Manish, B. Shantha, George Ronnie, Lingam Vijaya, and Angayarkanni Narayanasamy

Abstract

Purpose: Pseudoexfoliation (PXF) is a microfibrillopathy involving disordered elastogenesis. Abnormal extracellular matrix (ECM) production underlies the pathophysiology of PXF. The enzyme Lysyl oxidase (LOX) and its isoforms are known to cross-link the elastin and collagen. Though the etiopathogensis of PXF is not well understood, studies report on the genetic risk involving LOXL1 gene. This study aims to screen LOXL1 coding variants rs1048661 and rs3825942 in the South Indian population and the implication of the single nucleotide polymorphism (SNP) with LOX activity. The levels of transforming growth factor β (TGF-β) in aqueous humor and its correlation with the LOX activity were also examined.Methods: Blood, plasma, and aqueous aspirates were prospectively collected from PXF cases with and without glaucoma and cataract cases as controls. DNA was extracted from 48 PXF cases without glaucoma, 12 PXF cases with glaucoma, and 40 age-matched cataract-alone controls without PXF/glaucoma for analyzing LOX SNPs. LOX activity was measured in aqueous humor and plasma of 30 PXF cases without glaucoma, 24 age-matched cataract-alone controls without PXF/glaucoma, and 14 PXF cases with glaucoma. Protein levels of LOX, LOXL1, LOXL2, and total TGF-β were estimated in plasma and aqueous humor by ELISA.Results: The specific activity of LOX in aqueous humor was found to be significantly lowered in PXF cases compared with cataract-alone controls (p = 0.014). This decrease in LOX activity in PXF cases was associated with high-risk GG haplotype. However, this was not statistically significant and a larger sample size is warranted. TGF-β1 and TGF-β2 negatively correlated with LOX activity in aqueous humor (p = 0.028; p = 0.046, respectively).Conclusions: The LOXL1 SNPs, rs1048661 and rs3825942, are associated with PXF in the South Indian population correlating with lowered LOX activity in the aqueous humor. The increased level

Published
2016
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24. Low frequency of myocilin mutations in Indian primary open-angle glaucoma patients

Author

Arvind Hemamalini, G. Kumaramanickavel, Ronnie George, J. Amali, Pradeep G. Paul, Sarangapani Sripriya, Satagopan Uthra, Lingam Vijaya, and R. Sangeetha

Subjects
Genetics, Mutation, education.field_of_study, genetic structures, Open angle glaucoma, Population, Glaucoma, Biology, medicine.disease_cause, medicine.disease, eye diseases, Exon, medicine, Missense mutation, education, Allele frequency, Genetics (clinical), Myocilin
Abstract

Glaucoma is one of the major causes of blindness in the Indian population. Mutations in the myocilin (MYOC) gene have been reported in different populations. However, reports on MYOC mutations in Indian primary open-angle glaucoma (POAG) patients and juvenile open-angle glaucoma (JOAG) patients are sparse. We therefore screened 100 unrelated POAG/JOAG patients for MYOC mutations. Patients with POAG/JOAG were clinically diagnosed. Genomic DNA from such patients was collected and studied for MYOC mutations by direct sequencing. Nucleotide variations were compared with unrelated healthy controls by restriction enzyme digestion. Secondary structure prediction for the sequence variants was performed by Chou-Fasman method. A novel mutation in exon 1 (144 G-->Alpha) resulting in Gln48His substitution was observed in 2% of the patients. Four other polymorphisms were also observed. The novel mutation was seen in four other affected family members of a JOAG patient. The novel mutation was found to alter the secondary structure in the glycosaminoglycan initiation site of the protein. MYOC mutations were found in 2% of the population studied. MYOC gene may not be playing a significant role in causing POAG in the Indian population.

Published
2004
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25. A common variant near TGFBR3 is associated with primary open angle glaucoma

Author

Zhenglin Yang, Tien Yin Wong, Zheng Li, Kei Tashiro, R. Rand Allingham, Julia E. Richards, Nobuo Fuse, Wee Yang Meah, Robert Ritch, Yik Ying Teo, Dan Milea, Takanori Mizoguchi, Puya Gharahkhani, David F. Garway-Heath, David Goh, Yoko Ikeda, Allison E. Ashley Koch, Wang Xu, Baskaran Mani, Ronnie George, Masakazu Nakano, Jessica N. Cooke Bailey, Janey L. Wiggs, Ying Lin, Yutao Liu, Xiao Yu Ng, Hong Zhang, Stuart MacGregor, Leon W. Herndon, Mei Chin Lee, Elaine Chua, Jost B. Jonas, Tran Nguyen Bich Chau, Balekudaru Shantha, Cameron P. Simmons, SR Krishnadas, Kazuhiko Mori, Ching-Lin Ho, Rupert R A Bourne, Augusto Azuara Blanco, Ching-Yu Cheng, Kathryn P. Burdon, Liza-Sharmini Ahmad Tajudin, Shamira A. Perera, Do Nhu Hon, Louis R. Pasquale, Monisha E. Nongpiur, Khaled K. Abu-Amero, Tin Aung, Rahat Husain, Anil Negi, Ningli Wang, Chukai Huang, Jinghong Sang, Mineo Ozaki, Sarangapani Sripriya, E-Shyong Tai, Saleh A. Al-Obeidan, Jong Chul Han, Chiea Chuen Khor, Jia Nee Foo, Mingzhi Zhang, David C Broadway, David A. Mackey, Ryuichi Sato, Songhomita Panda-Jonas, Prasanthi Namburi, Jamie E Craig, Merwyn Chew, Nihong Zhang, Christopher A. Girkin, Jae H. Kang, Blanche Lim, Anita S Y Chan, Yuhong Chen, Michael A. Hauser, Douglas E. Gaasterland, Chi Pui Pang, Daniel H. Su, Pascal Reynier, Azhany Yakub, Pratap Challa, Alex W. Hewitt, Bowen Zhao, Victor H. K. Yong, Saravanan Vijayan, Yi Xin Zeng, Jonathan L. Haines, Essam A. Osman, Pansy O.S. Tam, Lingam Vijaya, Xinghuai Sun, Aurelien Goncalves, Jianjun Liu, Morio Ueno, Sayoko E. Moroi, Shigeru Kinoshita, Liyun Jia, Kengo Yoshii, Seang-Mei Saw, Tina T. Wong, Yaan Fun Chong, Philomenadin Ferdinamarie Sharmila, Changwon Kee, Tan Do, Periasamy Sundaresan, Jin-Xin Bei, Eranga N. Vithana, Christopher Kai-shun Leung, Sohn Seongsoo, and Li Jia Chen

Subjects
Male, Open angle glaucoma, genetic structures, Genotype, Population, Glaucoma, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, SNP, Humans, education, Molecular Biology, Exome, Genetics (clinical), Alleles, 030304 developmental biology, Aged, Aged, 80 and over, 0303 health sciences, education.field_of_study, Association Studies Articles, Genetic Variation, General Medicine, Odds ratio, Middle Aged, medicine.disease, eye diseases, 3. Good health, 030221 ophthalmology & optometry, Female, Proteoglycans, sense organs, Receptors, Transforming Growth Factor beta, Glaucoma, Open-Angle
Abstract

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.

Published
2014

28. Genetic homogeneity for inherited congenital microcoria loci in an Asian Indian pedigree

Author

Vedam Lakshmi, Ramprasad, Sarangapani, Sripriya, George, Ronnie, Derek, Nancarrow, Sandeep, Saxena, Arvind, Hemamalini, Dipak, Kumar, Lingam, Vijaya, and Govindasamy, Kumaramanickavel

Subjects
Adult, Male, Adolescent, Genotype, Genetic Linkage, India, Cell Cycle Proteins, Polymerase Chain Reaction, Cytochrome P-450 Enzyme System, Risk Factors, Transcription Factor TFIIIA, Myopia, Humans, Point Mutation, Child, Eye Proteins, Aged, Glycoproteins, Chromosomes, Human, Pair 13, Membrane Transport Proteins, Middle Aged, Miosis, Pedigree, Cytoskeletal Proteins, Child, Preschool, Cytochrome P-450 CYP1B1, Female, Aryl Hydrocarbon Hydroxylases, Lod Score, Glaucoma, Open-Angle, Microsatellite Repeats
Abstract

Congenital microcoria is a rare autosomal dominant developmental disorder of the iris associated with myopia and juvenile open angle glaucoma. Linkage to the chromosomal locus 13q31-q32 has previously been reported in a large French family. In the current study, a three generation Asian Indian family with 15 congenital microcoria (pupils with a diameter2 mm) affected members was studied for linkage to candidate microsatellite markers at the 13q31-q32 locus.Twenty-four members of the family were clinically examined and genomic DNA was extracted. Microsatellite markers at 13q31-q32 were PCR amplified and run on an ABI Prism 310 genetic analyzer and genotyped with the GeneScan analysis. Two point and multipoint linkage analyses were performed using the MLINK and SUPERLINK programs.Peak two point LOD scores of 3.5, 4.7, and 5.3 were found co-incident with consecutive markers D13S154, DCT, and D13S1280. Multipoint analysis revealed a 4 cM region encompassing D13S1300 to D13S1280 where the LOD remains just over 6.0 Thus we confirm localization of the congenital microcoria locus to chromosomal locus 13q31-q32. In addition, eight individuals who had both microcoria and glaucoma were screened for glaucoma genes: myocilin (MYOC), optineurin (OPTN) and CYP1B1. Using direct sequencing a point mutation (144 GA) resulting in a Q48H substitution in exon 1 of the MYOC gene was observed in five of the eight glaucoma patients, but not in unaffected family members and 100 unrelated controls.We have confirmed the localization of the congenital microcoria locus (MCOR) to 13q31-q32 in a large Asian Indian family and conclude that current information suggests this is a single locus disorder and genetically homogeneous. When combined with the initial linkage paper our haplotype and linkage data map the MCOR locus to a 6-7 cM region between D13S265 and D13S1280. The DCT locus, a member of the tyrosinase family involved in pigmentation, maps within this region. Data presented here supports the hypothesis that congenital microcoria is a potential risk factor for glaucoma, although this observation is complicated by the partial segregation of MYOC Q48H (1q24.3-q25.2), a mutation known to be associated with glaucoma in India. Fine mapping and candidate gene analysis continues with the hope that characterizing the micocoria gene will lead to a better understanding of microcoria and glaucoma causation. The relationship between microcoria, glaucoma, and the MYOC Q48H mutation in this family is discussed.

Published
2005

29. Methods and design of the Chennai Glaucoma Study

Author

Pradeep G. Paul, Ronnie George, Prema Raju, Mani Baskaran, S. Ve Ramesh, Lingam Vijaya, Sarangapani Sripriya, Govindasamy Kumaramanickavel, Sukumar Balu, Bickol N. Mukesh, Hemamalini Arvind, and Catherine A. McCarty

Subjects
Research design, Adult, Male, Rural Population, Biomedical Research, genetic structures, Urban Population, Epidemiology, Cross-sectional study, Population, Glaucoma, India, Physical examination, Urban area, medicine, Prevalence, Humans, education, Estimation, education.field_of_study, geography, geography.geographical_feature_category, medicine.diagnostic_test, business.industry, medicine.disease, eye diseases, Ophthalmology, Cross-Sectional Studies, Sample size determination, Research Design, Optometry, Female, business, Demography
Abstract

PURPOSE To describe the methodology of a population-based study to estimate the prevalence of glaucoma in a rural and urban South Indian population and to study the genetics of glaucoma in this population. METHODS A sample size of 4758 each for rural and urban populations in the Indian state of Tamil Nadu was calculated. Eligible subjects aged 40 years and above from the rural study area covering 32 contiguous villages and the urban area comprising five random clusters in Chennai city are enumerated. Demographic data are collected in the field. A detailed clinical examination, including glaucoma diagnostic procedures, is conducted at the examination centre. Pedigree ascertainment and genetic studies are performed for subjects with occludable angles or glaucoma. Data are recorded in a computerised database. CONCLUSIONS This study is expected to result in an estimation of the prevalence and a better understanding of the genetics of glaucoma in this region.

Published
2003

30. Z-2 aldose reductase allele and diabetic retinopathy in India

Author

Vedam L. Ramprasad, Neelam Kumari Upadyay, Sarangapani Sripriya, Govindasamy Kumaramanickavel, Tarun Sharma, and Pradeep G. Paul

Subjects
Male, medicine.medical_specialty, Genotype, Population, India, Polymerase Chain Reaction, Macular Degeneration, Polymorphism (computer science), Aldehyde Reductase, Risk Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Allele, education, Dinucleotide Repeats, Genetics (clinical), Alleles, Proliferative retinopathy, DNA Primers, education.field_of_study, Aldose reductase, Diabetic Retinopathy, Polymorphism, Genetic, business.industry, Diabetic retinopathy, DNA, Middle Aged, medicine.disease, Ophthalmology, Endocrinology, Diabetes Mellitus, Type 2, Case-Control Studies, Pediatrics, Perinatology and Child Health, Maculopathy, Female, business, Retinopathy, Microsatellite Repeats
Abstract

Genetic factors have been identified that regulate the severity and the rapidity of onset of retinopathy in diabetic patients. Polymorphisms in (CA)( n) present upstream of the promoter of the aldose reductase (ALR2 ) gene have been shown to be associated with retinopathy in different ethnic populations. We aimed to study the association between the (CA)( n) polymorphism and type 2 diabetic patients with and without retinopathy in the Asian Indian population. We screened 105 diabetic patients with retinopathy (DR) and 109 diabetic patients without retinopathy (DNR) for the (CA)( n) polymorphism and compared the results with those of an unrelated healthy control group (CT). We identified 13 alleles in our diabetic population. The Z-2 allele (136 bp) showed an association with the DR group (13.81%) with a significant p value (p = 0.029) when compared with the DNR group (7.34%). The Z-2 allele also showed a significant association with those DR patients who had proliferative retinopathy (PDR) and maculopathy (MAC) (p = 0.004). The Z-2 allele is, therefore, a high-risk allele for diabetic retinopathy in the Asian Indian patients.

Published
2003

31. Association of Gly82Ser polymorphism in the RAGE gene with diabetic retinopathy in type II diabetic Asian Indian patients

Author

Vedam L. Ramprasad, Sarangapani Sripriya, Neelam Kumari Upadyay, Govindasamy Kumaramanickavel, Pradeep G. Paul, and Tarun Sharma

Subjects
Glycation End Products, Advanced, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Receptor for Advanced Glycation End Products, Glycine, India, Blood Pressure, Polymerase Chain Reaction, White People, Exon, Endocrinology, Diabetes mellitus, Internal medicine, Genotype, Internal Medicine, medicine, Serine, Humans, Allele, Receptors, Immunologic, DNA Primers, Glycated Hemoglobin, Diabetic Retinopathy, Polymorphism, Genetic, Base Sequence, business.industry, Diabetic retinopathy, Exons, Middle Aged, medicine.disease, Genotype frequency, Amino Acid Substitution, Diabetes Mellitus, Type 2, Female, Restriction fragment length polymorphism, business, Retinopathy
Abstract

Aim/hypothesis: The binding of advanced glycation end products (AGE) to the receptor induces cellular oxidative stress and vascular dysfunction and this is implicated in the pathogenesis of diabetic retinopathy (DR). This study aims to investigate the frequency of Gly82Ser polymorphism in exon 3 of the receptor for AGE (RAGE) gene and its association with DR in Asian Indian patients who have type II diabetes. Methods: 200 Asian Indian patients with at least 15-year duration of type II diabetes were identified. This group included (1) 100 patients with retinopathy (DR) and (2) 100 patients without retinopathy (DNR). Fifty unrelated healthy controls (CT) were also included in the study. Genotype frequencies of Gly82Ser polymorphism were studied by polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism analysis using AluI enzyme. Later, the nucleotide change was confirmed by DNA sequencing. Results: The frequency of the Ser82 allele was significantly higher, 18% in the DNR group compared to 7% in the DR group ( P =.03). The same genotype was 2% in the CT group. Conclusion/interpretation: Our result suggests that Ser82 allele in the receptor for AGE gene is a low-risk allele for developing DR in Asian Indian patients who have type II diabetes.

Published
2002

32. Tumor necrosis factor allelic polymorphism with diabetic retinopathy in India

Author

Lingam Gopal, B Sukumar, Neelam Kumari Upadyay, Sengamedu S. Badrinath, Authiappan Vidhya, Sarangapani Sripriya, Govindasamy Kumaramanickavel, Ravi Nagaraj Vellanki, T. Arokiasamy, Biju Joseph, and Tarun Sharma

Subjects
medicine.medical_specialty, Asia, Endocrinology, Diabetes and Metabolism, India, Type 2 diabetes, Gastroenterology, Polymerase Chain Reaction, Endocrinology, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, Allele, Dinucleotide Repeats, Promoter Regions, Genetic, Base Pairing, Alleles, Genetics, Diabetic Retinopathy, Polymorphism, Genetic, business.industry, Tumor Necrosis Factor-alpha, Promoter, General Medicine, Diabetic retinopathy, medicine.disease, Population study, Microsatellite, business, Retinopathy
Abstract

The association of tumor necrosis factor (TNF) with diabetic retinopathy (DR) has been described previously. A total of 207 Asian Indian patients of 15-year duration of type 2 diabetes were identified. This group included (i) 100 patients with DR and (ii) 107 patients without retinopathy (DNR). In this study, we correlated the length of the (GT)n microsatellite di-nucleotide repeat upstream to the promoter region of TNF gene with susceptibility for the development of retinopathy. The microsatellite was polymerase chain reaction amplified and electrophoresed on polyacrylamide gel and silver stained. In our study population, there were 18 alleles ranging from 97 to 131 base pairs (bp). Allele 4 (103 bp) had a higher prevalence (9.81%) in the DNR group compared to that (2.5%) in the DR group (P=0.002). Patients with retinopathy and allele 8 (111 bp) had a tendency to develop proliferative diabetic retinopathy (PDR). In this study of Indian subjects, it is suggested that allele 4 is a low risk allele for developing retinopathy and allele 8 (111 bp) shows an association with PDR.

Published
2001

33. Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma

Author

Vithana, Eranga N, primary, Khor, Chiea-Chuen, additional, Qiao, Chunyan, additional, Nongpiur, Monisha E, additional, George, Ronnie, additional, Chen, Li-Jia, additional, Do, Tan, additional, Abu-Amero, Khaled, additional, Huang, Chor Kai, additional, Low, Sancy, additional, Tajudin, Liza-Sharmini A, additional, Perera, Shamira A, additional, Cheng, Ching-Yu, additional, Xu, Liang, additional, Jia, Hongyan, additional, Ho, Ching-Lin, additional, Sim, Kar Seng, additional, Wu, Ren-Yi, additional, Tham, Clement C Y, additional, Chew, Paul T K, additional, Su, Daniel H, additional, Oen, Francis T, additional, Sarangapani, Sripriya, additional, Soumittra, Nagaswamy, additional, Osman, Essam A, additional, Wong, Hon-Tym, additional, Tang, Guangxian, additional, Fan, Sujie, additional, Meng, Hailin, additional, Huong, Dao T L, additional, Wang, Hua, additional, Feng, Bo, additional, Baskaran, Mani, additional, Shantha, Balekudaru, additional, Ramprasad, Vedam L, additional, Kumaramanickavel, Govindasamy, additional, Iyengar, Sudha K, additional, How, Alicia C, additional, Lee, Kelvin Y, additional, Sivakumaran, Theru A, additional, Yong, Victor H K, additional, Ting, Serena M L, additional, Li, Yang, additional, Wang, Ya-Xing, additional, Tay, Wan-Ting, additional, Sim, Xueling, additional, Lavanya, Raghavan, additional, Cornes, Belinda K, additional, Zheng, Ying-Feng, additional, Wong, Tina T, additional, Loon, Seng-Chee, additional, Yong, Vernon K Y, additional, Waseem, Naushin, additional, Yaakub, Azhany, additional, Chia, Kee-Seng, additional, Allingham, R Rand, additional, Hauser, Michael A, additional, Lam, Dennis S C, additional, Hibberd, Martin L, additional, Bhattacharya, Shomi S, additional, Zhang, Mingzhi, additional, Teo, Yik Ying, additional, Tan, Donald T, additional, Jonas, Jost B, additional, Tai, E-Shyong, additional, Saw, Seang-Mei, additional, Hon, Do Nhu, additional, Al-Obeidan, Saleh A, additional, Liu, Jianjun, additional, Chau, Tran Nguyen Bich, additional, Simmons, Cameron P, additional, Bei, Jin-Xin, additional, Zeng, Yi-Xin, additional, Foster, Paul J, additional, Vijaya, Lingam, additional, Wong, Tien-Yin, additional, Pang, Chi-Pui, additional, Wang, Ningli, additional, and Aung, Tin, additional

Published
2012
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34. Screening for mutation hotspots in Bardet–Biedl syndrome patients from India.

Author

Chandrasekar, Sathya, Namboothiri, Sheela, Sen, Parveen, and Sarangapani, Sripriya

Subjects
*LAURENCE-Moon-Biedl syndrome, *GENETIC mutation, *GENETIC disorder diagnosis, *GENETIC disorders, *NUCLEIC acid isolation methods, *NUCLEOTIDE sequencing, *GENETICS, *PATIENTS
Abstract

Background & objectives: Bardet–Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder characterized by multiple organ defects involving retina, kidney, liver and brain. Disease-causing mutations in BBS genes narrowed down by homozygosity mapping in small consanguineous and non-consanguineous pedigrees were reported in 80 per cent of the study population. This study was aimed to screen these genes (BBS3, BBS10) and specific exons of BBS genes (BBS1, BBS5, MKKS, BBS9, BBS11 and BBS12) for recurrent mutations in a selected sample of BBS patients. Methods: The recurrent mutations in BBS genes were screened in the BBS affected individuals by PCR based direct sequencing. The pathogenicity of the observed mutations were confirmed by co-segregation analysis, screening of healthy unrelated controls and in silico analysis. Results: In the 64 BBS patients (44 males, 20 females) were studied, mutations were predominant in BBS10 and ARL6 genes; the c.272T>C; p.(I91T) mutation in ARL6 gene was a recurrent mutation. One novel non-sense mutation c.425T>G; p(L142FNx01) was obtained in BBS5 gene (family BSI-31). Interpretation & conclusions: BBS10 gene mutations clustered in exon 2 of the gene suggesting the exon as a probable hotspot for mutations in Indian population. A cost- and time-effective strategy for the molecular diagnosis of BBS was designed based on these results. [ABSTRACT FROM AUTHOR]

Published
2018
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35. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Author

Daniele Cusi, Etsuo Chihara, Leyla Al-Jasim, Ya Xing Wang, Tero Kivelä, Jinghong Sang, Adeyinka O. Ashaye, Bowen Zhao, Tan Do, Susanne Moebus, Ursula Schlötzer-Schrehardt, Shamira A. Perera, Augustine W O Cheong, Afsaneh Naderi Beni, Francisco A. Escudero-Domínguez, Yoshiaki Kiuchi, Tomomi Higashide, DS Klobassa, Friedrich E. Kruse, Nicole Weisschuh, Chunyan Qiao, Muhammad Imran Khan, Martin L. Hibberd, Arthur J. Sit, Jamie E Craig, Akitoshi Yoshida, Periasamy Sundaresan, Humaira Ayub, Kathryn P. Burdon, Jonathan G Crowston, Kazunori Miyata, Marisa Cruz-Aguilar, Markus M. Nöthen, Hasnaa Lamari, Michael A. Hauser, Louis R. Pasquale, Anneke I. den Hollander, Eija Vesti, Ursula Hoja, Raphael Q Soh, Burcu Kasım, Adeola O Onakoya, Rachel W. Kuchtey, Eugeny L. Akopov, Liang Xu, Juan Carlos Zenteno, Chaiwat Teekhasaenee, Saleh A. Al-Obeidan, Eleftherios Anastasopoulos, Anita S Y Chan, Nagahisa Yoshimura, John Kuchtey, Naris Kitnarong, Yaan Fun Chong, Boonsong Wanichwecharugruang, R.R. Fayzrakhmanov, Paul Mitchell, N Kalpana, Unnur Thorsteinsdottir, Kei Tashiro, Rajesh Kumar, Jin Wook Jeoung, Deepak P. Edward, Frederico Martinon-Torres, Bilge Batu, Anavaj Sakuntabhai, Robert N. Weinreb, Héctor González-Iglesias, Sasan Moghimi, Jia Nee Foo, Nkechi J Uche, Karen Curtin, Kenji Inoue, Lingam Vijaya, Makoto Aihara, Dilek Aktas, Norimoto Gotoh, Wasu Supakontanasan, Laura Dallorto, Takako Sugimoto, Jonathan L. Haines, Olusola Olawoye, Janey L. Wiggs, Sripriya Sarangapani, Craig J. Chaya, Theofanis Pappas, Fotis Topouzis, Eranga N. Vithana, Steffen Heegaard, Fridbert Jonasson, Kazuhiko Mori, Idakwo Ugbede, Hongyan Jia, Anthi Chatzikyriakidou, Robert P. Igo, Soon Cheol Cha, Yueming Chen, Su-Ling Ho, Zhenglin Yang, Jost B. Jonas, Francesca Pasutto, Ken Hayashi, Rahat Husain, Georg Mossböck, S Fabian Lerner, R. Rand Allingham, Priti Sahay, Fumihiko Matsuda, Yanin Suwan, Teresa Rolle, Robert Ritch, Peter Kraft, Trevor R. Carmichael, Kar Seng Sim, Raheel Qamar, Gordana Sunaric Megevand, Tomasz Zarnowski, Shazia Micheal, Scott Thomas, Paolo Frezzotti, Vera Vysochinskaya, Linda M. Zangwill, Alina Popa Cherecheanu, Tin Aung, Jessica N. Cooke Bailey, Kyu Hyung Park, Edward Dervan, Suhanya Okeke, Pablo Fornero, Sidi M Ezzouhairi, Pascal Reynier, Gudmar Thorleifsson, Michael V. Dubina, Kazuhisa Sugiyama, Sylvain Roy, Per Kappelgaard, Mineo Ozaki, Vijayan Saravanan, Carlo Lavia, Wenda L. Greer, Takanori Mizoguchi, Alireza Lashay, A. Binder, Daniel Berner, Su Qin Peh, Balram Chowbay, Nino Kobakhidze, Ifeoma N. Asimadu, Delia Sivori, Gopalakrishnan Prakadeeswari, Alexandros Lambropoulos, Michael Coote, Sergei Y. Astakhov, Shahin Yazdani, Dan Milea, Montserrat García, Lydia Álvarez, Kenji Yamashiro, Soumya Raychaudhuri, Pratap Challa, Aparna Rao, Jae H. Kang, Khai Koon Heng, Richard K. Lee, Tien Yin Wong, Alex W. Hewitt, Yoko Ikeda, Kessara Pathanapitoon, Panayiota Founti, Daniella Bach-Holm, Emmanuelle Souzeau, Margaret A. Pericak-Vance, Michèle Ramsay, Nkiru Kizor-Akaraiwe, Yosai Mori, Antonio Maria Fea, Chandrashekaran Shivkumar, Xiao Yu Ng, Jie Jin Wang, Erika Salvi, Giang T T Nguyn, Steffen Uebe, Tamara Zompa, Anne L. Coleman, Werner Zenz, Min Sagong, Luis Fernández-Vega Cueto, Farah Akhtar, Susan Williams, Sarah C. Nelson, Bradford J. Shingleton, Ryuichi Ideta, Leon W. Herndon, Zheng Li, Murat Irkec, M. Roy Wilson, Ewa Kosior-Jarecka, Christian Y. Mardin, Mozhgan Rezaei Kanavi, Tsutomu Ohashi, Abderrahman Rafei, Rengaraj Venkatesh, Stefan Herms, George Chichua, Mohammad Pakravan, Robyn M. Rautenbach, Shi Qi Mok, Trình V Nguyn, Patricio G. Schlottmann, Nassim Khatibi, Daniel Gaston, Masaru Inatani, Morio Ueno, Mukharram M. Bikbov, Eoin Silke, Homa Naderifar, Linda Hansapinyo, Paolo Manunta, Z. Xie, Urszula Lukasik, Eray Atalay, Lulin Huang, Xuyang Liu, Chie Sotozono, Shuang Ru Goh, John H. Fingert, Richard A. Mills, Khaled K. Abu-Amero, Xiao Yin Chen, Matthias Zenkel, Sergo Tabagari, Irma Järvelä, Xueyi Chen, Stéphanie Leruez, Yury S. Astakhov, Sonia Davila, Yildirim Nilgün, Ronnie George, Shin-ichi Manabe, Miguel Coca-Prados, Masahiro Miyake, Ignacio Lischinsky, Rogelio González-Sarmiento, Arkasubhra Ghosh, A. Emelyanov, Çilingir Oguz, Masakazu Nakano, Rohit Shetty, Karen Bedard, Toshiya Sakurai, Yutao Liu, Barbara M Wirostko, Hui Zhang, Ulrich-Christoph Welge-Luessen, Toshiaki Kubota, Vania Castro, Hip X Nguyn, Liyun Jia, Ari Ziskind, Hideki Chuman, Andrew C. Orr, Satoko Nakano, Daniela Paoli, Masahide Yanagi, Aravind Haripriya, Kari Stefansson, Pedro Pablo Rodríguez-Calvo, Hui Meng Soo, Chiea Chuen Khor, Gyulli M. Kazakbaeva, Osvaldo Cuello, Mei Chin Lee, Ki Ho Park, Natalia Porporato, Lourdes de Juan Marcos, Ching-Yu Cheng, Shigeyasu Kazama, Shigeru Kinoshita, Axel M. Hillmer, Alan S. Crandall, Victor H. K. Yong, Ohoud Owaidhah, Rodolfo Perez Grossmann, Jeeyun Ahn, André Reis, Nevbahar Tamçelik, Satoshi Ishiko, Antonio Salas, Ningli Wang, Singapore Eye Research Institute [Singapore] (SERI), Ozaki Eye Hospital [Miyazaki], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), deCODE genetics [Reykjavik], Mizoguchi Eye Hospital [Sasebo], Case Western Reserve University [Cleveland], Aravind Eye Hospital [Madurai, India], University of the Witwatersrand [Johannesburg] (WITS), Pavlov First Saint Petersburg State Medical University [St. Petersburg], Dalhousie University [Halifax], Flinders University [Adelaide, Australia], Kyoto Prefectural University of Medicine [Kyoto, Japon], King Saud University [Riyadh] (KSU), Genome Institute of Singapore (GIS), Aravind Medical Research Foundation (AMRF), Université de Médecine Carol Davila, Harvard Medical School [Boston] (HMS), University of Washington [Seattle], Hayashi Eye Hospital [Fukuoka], Shinjo Eye Clinic [Nagoya], Medical University of Lublin, Inoue Eye Hospital [Tokyo], Hacettepe University = Hacettepe Üniversitesi, Universidad de Oviedo [Oviedo], Kanazawa University (KU), Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Organizacion Medica de Investigacion (OMI BUENOS AIRES), Fundacion para el Estudio del Glaucoma [Buenos Aires], Chercheur indépendant, Eskisehir Osmangazi University, Ufa Eye Research Institute [Bashkortostan], Seoul National University Hospital, Yeungnam University [South Korea], Kyoto University, Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Universität Heidelberg [Heidelberg] = Heidelberg University, Birla Institute of Scientific Research (BISR), B. M. Birla Science and Technology Center, Faculty of Computer Science, Department of Pathology and Immunology, Geneva University Hospital (HUG), Key Laboratory for Information System Security, ministry of education, Numerical modeling and high performance computing for evolution problems in complex domains and heterogeneous media (NACHOS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (LJAD), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institute of Human Genetics [Erlangen, Allemagne], Department of Ophthalmology, School of Medicine [Thessaloniki, Grèce], Aristotle University of Thessaloniki, Università degli Studi di Siena = University of Siena (UNISI), Department of Medicine, Surgery, and Dentistry, University of Milano, Japan Advanced Institute of Science and Technology (JAIST), Etudes génomiques trans-ethniques des maladies multifactorielles, Kyoto University-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Archaeogenetics Laboratory, Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Rheinische Friedrich-Wilhelms-Universität Bonn, University of Kentucky (UK), Helsinki University Eye Hospital, Turku University Hospital, Turku, Finland, COMSATS Institute of Information Technology (CIIT), Department of Epidemiology, Harvard School of Public Health, University of Miami Leonard M. Miller School of Medicine (UMMSM), Brigham and Women's Hospital [Boston], Department of Neuroscience and Pharmacology, Section of Eye Pathology, University of Copenhagen, University of Copenhagen = Københavns Universitet (UCPH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of California [San Diego] (UC San Diego), University of California (UC), University of Iceland [Reykjavik], New York Eye and Ear Infirmary of Mount Sinai [New York] (NYEE), Oita University Faculty of Medicine [Oita, Japon], Radboud University Medical Center [Nijmegen], Oogheelkunde, RS: FHML non-thematic output, Kyoto University [Kyoto], Universidad Nacional Autónoma de México (UNAM), Universität Heidelberg [Heidelberg], Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (JAD), Dipartimento di Scienze oftalmologiche e Neurochirurgiche, Universita' degli Studi di Siena, Siena, Kyoto University [Kyoto]-Institut National de la Santé et de la Recherche Médicale (INSERM), Rothschild Hospital, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Kentucky, University of Copenhagen = Københavns Universitet (KU), University of California, Aung, Tin, Ozaki, Mineo, Lee, Mei Chin, Schlötzer Schrehardt, Ursula, Thorleifsson, Gudmar, Mizoguchi, Takanori, Igo, Robert P, Haripriya, Aravind, Williams, Susan E, Astakhov, Yury S, Orr, Andrew C, Burdon, Kathryn P, Nakano, Satoko, Mori, Kazuhiko, Abu Amero, Khaled, Hauser, Michael, Li, Zheng, Prakadeeswari, Gopalakrishnan, Bailey, Jessica N. Cooke, Cherecheanu, Alina Popa, Kang, Jae H, Nelson, Sarah, Hayashi, Ken, Manabe, Shin Ichi, Kazama, Shigeyasu, Zarnowski, Tomasz, Inoue, Kenji, Irkec, Murat, Coca Prados, Miguel, Sugiyama, Kazuhisa, Järvelä, Irma, Schlottmann, Patricio, Lerner, S. Fabian, Lamari, Hasnaa, Nilgün, Yildirim, Bikbov, Mukharram, Park, Ki Ho, Cha, Soon Cheol, Yamashiro, Kenji, Zenteno, Juan C, Jonas, Jost B, Kumar, Rajesh S, Perera, Shamira A, Chan, Anita S. Y, Kobakhidze, Nino, George, Ronnie, Vijaya, Lingam, Do, Tan, Edward, Deepak P, de Juan Marcos, Lourde, Pakravan, Mohammad, Moghimi, Sasan, Ideta, Ryuichi, Bach Holm, Daniella, Kappelgaard, Per, Wirostko, Barbara, Thomas, Samuel, Gaston, Daniel, Bedard, Karen, Greer, Wenda L, Yang, Zhenglin, Chen, Xueyi, Huang, Lulin, Sang, Jinghong, Jia, Hongyan, Jia, Liyun, Qiao, Chunyan, Zhang, Hui, Liu, Xuyang, Zhao, Bowen, Wang, Ya Xing, Xu, Liang, Leruez, Stéphanie, Reynier, Pascal, Chichua, George, Tabagari, Sergo, Uebe, Steffen, Zenkel, Matthia, Berner, Daniel, Mossböck, Georg, Weisschuh, Nicole, Hoja, Ursula, Welge Luessen, Ulrich Christoph, Mardin, Christian, Founti, Panayiota, Chatzikyriakidou, Anthi, Pappas, Theofani, Anastasopoulos, Eleftherio, Lambropoulos, Alexandro, Ghosh, Arkasubhra, Shetty, Rohit, Porporato, Natalia, Saravanan, Vijayan, Venkatesh, Rengaraj, Shivkumar, Chandrashekaran, Kalpana, Narendran, Sarangapani, Sripriya, Kanavi, Mozhgan R, Beni, Afsaneh Naderi, Yazdani, Shahin, Lashay, Alireza, Naderifar, Homa, Khatibi, Nassim, Fea, Antonio, Lavia, Carlo, Dallorto, Laura, Rolle, Teresa, Frezzotti, Paolo, Paoli, Daniela, Salvi, Erika, Manunta, Paolo, Mori, Yosai, Miyata, Kazunori, Higashide, Tomomi, Chihara, Etsuo, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Aihara, Makoto, Inatani, Masaru, Miyake, Masahiro, Gotoh, Norimoto, Matsuda, Fumihiko, Yoshimura, Nagahisa, Ikeda, Yoko, Ueno, Morio, Sotozono, Chie, Jeoung, Jin Wook, Sagong, Min, Park, Kyu Hyung, Ahn, Jeeyun, Cruz Aguilar, Marisa, Ezzouhairi, Sidi M, Rafei, Abderrahman, Chong, Yaan Fun, Ng, Xiao Yu, Goh, Shuang Ru, Chen, Yueming, Yong, Victor H. K, Khan, Muhammad Imran, Olawoye, Olusola O, Ashaye, Adeyinka O, Ugbede, Idakwo, Onakoya, Adeola, Kizor Akaraiwe, Nkiru, Teekhasaenee, Chaiwat, Suwan, Yanin, Supakontanasan, Wasu, Okeke, Suhanya, Uche, Nkechi J, Asimadu, Ifeoma, Ayub, Humaira, Akhtar, Farah, Kosior Jarecka, Ewa, Lukasik, Urszula, Lischinsky, Ignacio, Castro, Vania, Grossmann, Rodolfo Perez, Megevand, Gordana Sunaric, Roy, Sylvain, Dervan, Edward, Silke, Eoin, Rao, Aparna, Sahay, Priti, Fornero, Pablo, Cuello, Osvaldo, Sivori, Delia, Zompa, Tamara, Mills, Richard A, Souzeau, Emmanuelle, Mitchell, Paul, Wang, Jie Jin, Hewitt, Alex W, Coote, Michael, Crowston, Jonathan G, Astakhov, Sergei Y, Akopov, Eugeny L, Emelyanov, Anton, Vysochinskaya, Vera, Kazakbaeva, Gyulli, Fayzrakhmanov, Rinat, Al Obeidan, Saleh A, Owaidhah, Ohoud, Aljasim, Leyla Ali, Chowbay, Balram, Foo, Jia Nee, Soh, Raphael Q, Sim, Kar Seng, Xie, Zhicheng, Cheong, Augustine W. O, Mok, Shi Qi, Soo, Hui Meng, Chen, Xiao Yin, Peh, Su Qin, Heng, Khai Koon, Husain, Rahat, Ho, Su Ling, Hillmer, Axel M, Cheng, Ching Yu, Escudero Domínguez, Francisco A, González Sarmiento, Rogelio, Martinon Torres, Frederico, Salas, Antonio, Pathanapitoon, Kessara, Hansapinyo, Linda, Wanichwecharugruang, Boonsong, Kitnarong, Nari, Sakuntabhai, Anavaj, Nguyn, Hip X, Nguyn, Giang T. T, Nguyn, Trình V, Zenz, Werner, Binder, Alexander, Klobassa, Daniela S, Hibberd, Martin L, Davila, Sonia, Herms, Stefan, Nöthen, Markus M, Moebus, Susanne, Rautenbach, Robyn M, Ziskind, Ari, Carmichael, Trevor R, Ramsay, Michele, Álvarez, Lydia, García, Montserrat, González Iglesias, Héctor, Rodríguez Calvo, Pedro P, Cueto, Luis Fernández Vega, Oguz, Çilingir, Tamcelik, Nevbahar, Atalay, Eray, Batu, Bilge, Aktas, Dilek, Kasım, Burcu, Wilson, M. Roy, Coleman, Anne L, Liu, Yutao, Challa, Pratap, Herndon, Leon, Kuchtey, Rachel W, Kuchtey, John, Curtin, Karen, Chaya, Craig J, Crandall, Alan, Zangwill, Linda M, Wong, Tien Yin, Nakano, Masakazu, Kinoshita, Shigeru, den Hollander, Anneke I, Vesti, Eija, Fingert, John H, Lee, Richard K, Sit, Arthur J, Shingleton, Bradford J, Wang, Ningli, Cusi, Daniele, Qamar, Raheel, Kraft, Peter, Pericak Vance, Margaret A, Raychaudhuri, Soumya, Heegaard, Steffen, Kivelä, Tero, Reis, André, Kruse, Friedrich E, Weinreb, Robert N, Pasquale, Louis R, Haines, Jonathan L, Thorsteinsdottir, Unnur, Jonasson, Fridbert, Allingham, R. Rand, Milea, Dan, Ritch, Robert, Kubota, Toshiaki, Tashiro, Kei, Vithana, Eranga N, Micheal, Shazia, Topouzis, Foti, Craig, Jamie E, Dubina, Michael, Sundaresan, Periasamy, Stefansson, Kari, Wiggs, Janey L, Pasutto, Francesca, Khor, Chiea Chuen, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and University of Helsinki

Subjects
0301 basic medicine, Male, Calcium Channels/genetics, Messenger, Medizin, PSEUDOEXFOLIATION SYNDROME, Genome-wide association study, BLOOD-PRESSURE, Disease, Exfoliation Syndrome, Eye, Exfoliation Syndrome/ethnology/genetics, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, PARKINSONS-DISEASE, 80 and over, ta319, Missense mutation, Genetics, Aged, 80 and over, Amino Acid Oxidoreductases/genetics/physiology, Alleles, Amino Acid Oxidoreductases, Amino Acid Substitution, Asian Continental Ancestry Group, Calcium Channels, Cell Adhesion, Extracellular Matrix, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Haplotypes, Humans, Molecular Chaperones, RNA, Messenger, Spheroids, Cellular, Genome-Wide Association Study, Mutation, Missense, Point Mutation, Metaanalysis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, ALZHEIMERS-DISEASE, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Molecular Chaperones/biosynthesis/genetics, Biology, SYNONYMOUS MUTATIONS, ta3111, Article, 03 medical and health sciences, Asian People, Asian Continental Ancestry Group/genetics, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Allele, Risk factor, GENOME-WIDE ASSOCIATION, Eye/metabolism, Aged, Genetic association, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Haplotype, Individuals, Glaucoma, Odds ratio, Extracellular Matrix/metabolism, RNA, Messenger/biosynthesis, MACULAR DEGENERATION, RISK LOCI, eye diseases, COMMON SEQUENCE VARIANTS, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, 030221 ophthalmology & optometry, RNA, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cellular, Spheroids, Missense, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Polymorphisms, purl.org/pe-repo/ocde/ford#1.06.07 [https], INFLAMMATORY-BOWEL-DISEASE
Abstract

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Published
2017
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