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Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma.

ABSTRACT: Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

SUBMITTER: Bailey JN

PROVIDER: S-EPMC4731307 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma.

Bailey Jessica N Cooke JN Loomis Stephanie J SJ Kang Jae H JH Allingham R Rand RR Gharahkhani Puya P Khor Chiea Chuen CC Burdon Kathryn P KP Aschard Hugues H Chasman Daniel I DI Igo Robert P RP Hysi Pirro G PG Glastonbury Craig A CA Ashley-Koch Allison A Brilliant Murray M Brown Andrew A AA Budenz Donald L DL Buil Alfonso A Cheng Ching-Yu CY Choi Hyon H Christen William G WG Curhan Gary G De Vivo Immaculata I Fingert John H JH Foster Paul J PJ Fuchs Charles C Gaasterland Douglas D Gaasterland Terry T Hewitt Alex W AW Hu Frank F Hunter David J DJ Khawaja Anthony P AP Lee Richard K RK Li Zheng Z Lichter Paul R PR Mackey David A DA McGuffin Peter P Mitchell Paul P Moroi Sayoko E SE Perera Shamira A SA Pepper Keating W KW Qi Qibin Q Realini Tony T Richards Julia E JE Ridker Paul M PM Rimm Eric E Ritch Robert R Ritchie Marylyn M Schuman Joel S JS Scott William K WK Singh Kuldev K Sit Arthur J AJ Song Yeunjoo E YE Tamimi Rulla M RM Topouzis Fotis F Viswanathan Ananth C AC Verma Shefali Setia SS Vollrath Douglas D Wang Jie Jin JJ Weisschuh Nicole N Wissinger Bernd B Wollstein Gadi G Wong Tien Y TY Yaspan Brian L BL Zack Donald J DJ Zhang Kang K Study Epic-Norfolk Eye EN Weinreb Robert N RN Pericak-Vance Margaret A MA Small Kerrin K Hammond Christopher J CJ Aung Tin T Liu Yutao Y Vithana Eranga N EN MacGregor Stuart S Craig Jamie E JE Kraft Peter P Howell Gareth G Hauser Michael A MA Pasquale Louis R LR Haines Jonathan L JL Wiggs Janey L JL

Nature genetics 20160111 2

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,5 ...[more]

PMID: 26752265

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Project description:BackgroundRecent studies suggest that glaucoma is a neurodegenerative disease in which secondary degenerative losses occur after primary insult by raised Intraocular pressure (IOP) or by other associated factors. It has been reported that polymorphisms in the IL1A and IL1B genes are associated with Primary Open Angle Glaucoma (POAG). The purpose of our study was to investigate the role of these polymorphisms in eastern Indian POAG patients.MethodsThe study involved 315 unrelated POAG patients, consisting of 116 High Tension Glaucoma (HTG) patients with intra ocular pressure (IOP) > 21 mmHg and 199 non-HTG patients (presenting IOP < 20 mmHg), and 301 healthy controls from eastern India. Genotypes were determined by polymerase chain reaction and restriction digestion for three single nucleotide polymorphisms (SNPs): IL1A (-889C/T; rs1800587), IL1B (-511C/T; rs16944) and IL1B (3953C/T; rs1143634). Haplotype frequency was determined by Haploview 4.1 software. The association of individual SNPs and major haplotypes was evaluated using chi-square statistics. The p-value was corrected for multiple tests by Bonferroni method.ResultsNo significant difference was observed in the allele and genotype frequencies for IL1A and IL1B SNPs between total pool of POAG patients and controls. However, on segregating the patient pool to HTG and non-HTG groups, weak association was observed for IL1A polymorphism (-889C/T) where -889C allele was found to portray risk (OR = 1.380; 95% CI = 1.041-1.830; p = 0.025) for non-HTG patients. Similarly, 3953T allele of IL1B polymorphism (+3953C/T) was observed to confer risk to HTG group (OR = 1.561; 95% CI = 1.022-2.385; p = 0.039). On haplotype analysis it was observed that TTC was significantly underrepresented in non-HTG patients (OR = 0.538; 95% CI = 0.356- 0.815; p = 0.003) while TCT haplotype was overrepresented in HTG patients (OR = 1.784; 95% CI = 1.084- 2.937; p = 0.022) compared to control pool. However, after correction for multiple tests by Bonferroni method, an association of only TTC haplotype with non-HTG cases sustained (pcorrected = 0.015) and expected to confer protection.ConclusionThe study suggests that the genomic region containing the IL1 gene cluster influences the POAG pathogenesis mostly in non-HTG patients in eastern India. A similar study in additional and larger cohorts of patients in other population groups is necessary to further substantiate the observation.

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Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma.

Publications

Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma.

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