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

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.

SUBMITTER: Aung T

PROVIDER: S-EPMC6685441 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Aung Tin T Ozaki Mineo M Lee Mei Chin MC Schlötzer-Schrehardt Ursula U Thorleifsson Gudmar G Mizoguchi Takanori T Igo Robert P RP Haripriya Aravind A Williams Susan E SE Astakhov Yury S YS Orr Andrew C AC Burdon Kathryn P KP Nakano Satoko S Mori Kazuhiko K Abu-Amero Khaled K Hauser Michael M Li Zheng Z Prakadeeswari Gopalakrishnan G Bailey Jessica N Cooke JNC Cherecheanu Alina Popa AP Kang Jae H JH Nelson Sarah S Hayashi Ken K Manabe Shin-Ichi SI Kazama Shigeyasu S Zarnowski Tomasz T Inoue Kenji K Irkec Murat M Coca-Prados Miguel M Sugiyama Kazuhisa K Järvelä Irma I Schlottmann Patricio P Lerner S Fabian SF Lamari Hasnaa H Nilgün Yildirim Y Bikbov Mukharram M Park Ki Ho KH Cha Soon Cheol SC Yamashiro Kenji K Zenteno Juan C JC Jonas Jost B JB Kumar Rajesh S RS Perera Shamira A SA Chan Anita S Y ASY Kobakhidze Nino N George Ronnie R Vijaya Lingam L Do Tan T Edward Deepak P DP de Juan Marcos Lourdes L Pakravan Mohammad M Moghimi Sasan S Ideta Ryuichi R Bach-Holm Daniella D Kappelgaard Per P Wirostko Barbara B Thomas Samuel S Gaston Daniel D Bedard Karen K Greer Wenda L WL Yang Zhenglin Z Chen Xueyi X Huang Lulin L Sang Jinghong J Jia Hongyan H Jia Liyun L Qiao Chunyan C Zhang Hui H Liu Xuyang X Zhao Bowen B Wang Ya-Xing YX Xu Liang L Leruez Stéphanie S Reynier Pascal P Chichua George G Tabagari Sergo S Uebe Steffen S Zenkel Matthias M Berner Daniel D Mossböck Georg G Weisschuh Nicole N Hoja Ursula U Welge-Luessen Ulrich-Christoph UC Mardin Christian C Founti Panayiota P Chatzikyriakidou Anthi A Pappas Theofanis T Anastasopoulos Eleftherios E Lambropoulos Alexandros A Ghosh Arkasubhra A Shetty Rohit R Porporato Natalia N Saravanan Vijayan V Venkatesh Rengaraj R Shivkumar Chandrashekaran C Kalpana Narendran N Sarangapani Sripriya S Kanavi Mozhgan R MR Beni Afsaneh Naderi AN Yazdani Shahin S Lashay Alireza A Naderifar Homa H Khatibi Nassim N Fea Antonio A Lavia Carlo C Dallorto Laura L Rolle Teresa T Frezzotti Paolo P Paoli Daniela D Salvi Erika E Manunta Paolo P Mori Yosai Y Miyata Kazunori K Higashide Tomomi T Chihara Etsuo E Ishiko Satoshi S Yoshida Akitoshi A Yanagi Masahide M Kiuchi Yoshiaki Y Ohashi Tsutomu T Sakurai Toshiya T Sugimoto Takako T Chuman Hideki H Aihara Makoto M Inatani Masaru M Miyake Masahiro M Gotoh Norimoto N Matsuda Fumihiko F Yoshimura Nagahisa N Ikeda Yoko Y Ueno Morio M Sotozono Chie C Jeoung Jin Wook JW Sagong Min M Park Kyu Hyung KH Ahn Jeeyun J Cruz-Aguilar Marisa M Ezzouhairi Sidi M SM Rafei Abderrahman A Chong Yaan Fun YF Ng Xiao Yu XY Goh Shuang Ru SR Chen Yueming Y Yong Victor H K VHK Khan Muhammad Imran MI Olawoye Olusola O OO Ashaye Adeyinka O AO Ugbede Idakwo I Onakoya Adeola A Kizor-Akaraiwe Nkiru N Teekhasaenee Chaiwat C Suwan Yanin Y Supakontanasan Wasu W Okeke Suhanya S Uche Nkechi J NJ Asimadu Ifeoma I Ayub Humaira H Akhtar Farah F Kosior-Jarecka Ewa E Lukasik Urszula U Lischinsky Ignacio I Castro Vania V Grossmann Rodolfo Perez RP Sunaric Megevand Gordana G Roy Sylvain S Dervan Edward E Silke Eoin E Rao Aparna A Sahay Priti P Fornero Pablo P Cuello Osvaldo O Sivori Delia D Zompa Tamara T Mills Richard A RA Souzeau Emmanuelle E Mitchell Paul P Wang Jie Jin JJ Hewitt Alex W AW Coote Michael M Crowston Jonathan G JG Astakhov Sergei Y SY Akopov Eugeny L EL Emelyanov Anton A Vysochinskaya Vera V Kazakbaeva Gyulli G Fayzrakhmanov Rinat R Al-Obeidan Saleh A SA Owaidhah Ohoud O Aljasim Leyla Ali LA Chowbay Balram B Foo Jia Nee JN Soh Raphael Q RQ Sim Kar Seng KS Xie Zhicheng Z Cheong Augustine W O AWO Mok Shi Qi SQ Soo Hui Meng HM Chen Xiao Yin XY Peh Su Qin SQ Heng Khai Koon KK Husain Rahat R Ho Su-Ling SL Hillmer Axel M AM Cheng Ching-Yu CY Escudero-Domínguez Francisco A FA González-Sarmiento Rogelio R Martinon-Torres Frederico F Salas Antonio A Pathanapitoon Kessara K Hansapinyo Linda L Wanichwecharugruang Boonsong B Kitnarong Naris N Sakuntabhai Anavaj A Nguyn Hip X HX Nguyn Giang T T GTT Nguyn Trình V TV Zenz Werner W Binder Alexander A Klobassa Daniela S DS Hibberd Martin L ML Davila Sonia S Herms Stefan S Nöthen Markus M MM Moebus Susanne S Rautenbach Robyn M RM Ziskind Ari A Carmichael Trevor R TR Ramsay Michele M Álvarez Lydia L García Montserrat M González-Iglesias Héctor H Rodríguez-Calvo Pedro P PP Fernández-Vega Cueto Luis L Oguz Çilingir Ç Tamcelik Nevbahar N Atalay Eray E Batu Bilge B Aktas Dilek D Kasım Burcu B Wilson M Roy MR Coleman Anne L AL Liu Yutao Y Challa Pratap P Herndon Leon L Kuchtey Rachel W RW Kuchtey John J Curtin Karen K Chaya Craig J CJ Crandall Alan A Zangwill Linda M LM Wong Tien Yin TY Nakano Masakazu M Kinoshita Shigeru S den Hollander Anneke I AI Vesti Eija E Fingert John H JH Lee Richard K RK Sit Arthur J AJ Shingleton Bradford J BJ Wang Ningli N Cusi Daniele D Qamar Raheel R Kraft Peter P Pericak-Vance Margaret A MA Raychaudhuri Soumya S Heegaard Steffen S Kivelä Tero T Reis André A Reis André A Kruse Friedrich E FE Weinreb Robert N RN Pasquale Louis R LR Haines Jonathan L JL Thorsteinsdottir Unnur U Jonasson Fridbert F Allingham R Rand RR Milea Dan D Ritch Robert R Kubota Toshiaki T Tashiro Kei K Vithana Eranga N EN Micheal Shazia S Topouzis Fotis F Craig Jamie E JE Dubina Michael M Sundaresan Periasamy P Stefansson Kari K Wiggs Janey L JL Pasutto Francesca F Khor Chiea Chuen CC

Nature genetics 20170529 7

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 ...[more]

PMID: 28553957

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Project description:PURPOSE: Single nucleotide polymorphisms (SNPs) in the LOXL1 gene have been implicated in exfoliation syndrome (XFS) and exfoliation glaucoma (XFG). We have shown that these SNPs are not associated with the primary glaucomas such as primary open-angle (POAG) glaucoma and primary angle-closure glaucoma (PACG). To further establish the specificity of LOXL1 SNPs for XFS and XFG, we determined whether these SNPs were involved in pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG). METHODS: Three SNPs of LOXL1 (rs1048661, rs3825942, and rs2165241) were screened in a cohort of 78 unrelated and clinically well characterized glaucoma cases comprising of PG (n=44) and PDS (n=34) patients as well as 108 ethnically matched normal controls of Caucasian origin. The criteria for diagnosis of PDS/PG were Krukenberg spindle, hyperpigmentation of the trabecular meshwork, and wide open angle. Transillumination defects were detected by infrared pupillography, and the presence of a Zentmayer ring was considered as a confirmatory sign. All three SNPs were genotyped in cases and controls by resequencing the genomic region of LOXL1 harboring these variants and were further confirmed by polymerase chain reaction (PCR)-based restriction digestions. Haplotypes were generated from the genotype data, and the linkage disequilibrium (LD) and haplotype analysis were done with Haploview software that uses the expectation maximization (EM) algorithm. RESULTS: The LOXL1 SNPs showed no significant association with PDS or PG. There was no significant difference in the frequencies of the risk alleles of rs1048661 ('G' allele; p=0.309), rs3825942 ('G' allele' p=0.461), and rs2165241 ('T' allele; p=0.432) between PG/PDS cases and controls. Similarly, there was no involvement of the XFS/XFG-associated haplotypes, 'G-G' (p=0.643; [OR=1.08, 95%CI, 0.59-1.97]) and 'T-G' (p=0.266; [OR=1.35, 95%CI, 0.70-2.60]), with the PDS/PG phenotypes. The risk haplotype 'G-G' was observed in ~55% of the normal controls. CONCLUSIONS: There was no involvement of the LOXL1 SNPs in patients with PDS and PG. The results further indicate that the associations of these SNPs are specific to XFS/XFG.

Project description:PurposeIn Uygur populations, exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) occurred at a high frequency. In this study, we evaluate the association profiles of the lysyl oxidase-like 1 (LOXL1) gene polymorphisms with XFS in the Uygur population.MethodsSixty-four unrelated Uygur patients with XFS and 127 Uygur control subjects were included in this study. Genotypes of the three single nucleotide polymorphisms (SNPs) of LOXL1 (rs1048661, rs2165241, and rs3825942) were analyzed by direct sequencing, and a case-control association study was performed.ResultsThe three SNPs were significantly associated with XFS and XFG individually. The G allele of rs1048661 (OR [95%CI]: 1.92 [1.14-3.22]), G of rs3825942 (OR [95%CI]: 4.86 [2.02-11.68]), and T of rs2165241 (OR [95%CI]: 3.98 [2.54-6.25]) were risk alleles for the disorder. The genotypes GG for rs1048661 (OR [95%CI]: 2.13 [1.14-3.97]), GG for rs3825942 (OR [95%CI]: 5.68 [2.28-14.17]), and TT for rs2165241 (OR [95%CI]: 6.13 [2.68-14.01]) were risk genotypes for the disease. The haplotypes G-G for the SNPs rs1048661and rs3825942, G-T for the SNPs rs1048661 and rs2165241, and SNPs rs3825942 and rs2165241 were found to be significantly associated with XFS/G. The haplotypes G-G-T for the three SNPs were determined to be significantly associated with XFS/G. There were significant differences of the allelic and genotypic proportion in different gender/age patients and controls for all three SNPs. T allele of rs2165241 and G of rs3825942 were risk alleles for the disorder in both the male and female groups. G allele of rs1048661 was a risk allele for the disorder in the below 65-year-old group. T of rs2165241 was a risk allele for the disorder in both age groups. G of rs3825942 was a risk allele for the disorder in the over 65-year-old group. The genotypes also showed significant differences in the below 65-year-old group of rs1048661, both groups of rs2165241, and over 65-year-old group of rs3825942.ConclusionsLOXL1 is a susceptibility gene of XFS/XFG in Uygur populations. The risk alleles of rs1048661, rs3825942 and rs2165241 in Uygur subjects were found to be similar to those of populations in Iceland and the United States and different from Han populations in China. The genotypic and allelic distributions of these SNPs are similar between XFS and XFG.

Dataset Information

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

Publications

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

Similar Datasets

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