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A genome-wide association study for diabetic retinopathy in a Japanese population: potential association with a long intergenic non-coding RNA.

ABSTRACT: Elucidation of the genetic susceptibility factors for diabetic retinopathy (DR) is important to gain insight into the pathogenesis of DR, and may help to define genetic risk factors for this condition. In the present study, we conducted a three-stage genome-wide association study (GWAS) to identify DR susceptibility loci in Japanese patients, which comprised a total of 837 type 2 diabetes patients with DR (cases) and 1,149 without DR (controls). From the stage 1 genome-wide scan of 446 subjects (205 cases and 241 controls) on 614,216 SNPs, 249 SNPs were selected for the stage 2 replication in 623 subjects (335 cases and 288 controls). Eight SNPs were further followed up in a stage 3 study of 297 cases and 620 controls. The top signal from the present association analysis was rs9362054 in an intron of RP1-90L14.1 showing borderline genome-wide significance (Pmet?=?1.4×10(-7), meta-analysis of stage 1 and stage 2, allele model). RP1-90L14.1 is a long intergenic non-coding RNA (lincRNA) adjacent to KIAA1009/QN1/CEP162 gene; CEP162 plays a critical role in ciliary transition zone formation before ciliogenesis. The present study raises the possibility that the dysregulation of ciliary-associated genes plays a role in susceptibility to DR.

SUBMITTER: Awata T

PROVIDER: S-EPMC4218806 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A genome-wide association study for diabetic retinopathy in a Japanese population: potential association with a long intergenic non-coding RNA.

Awata Takuya T Yamashita Hisakuni H Kurihara Susumu S Morita-Ohkubo Tomoko T Miyashita Yumi Y Katayama Shigehiro S Mori Keisuke K Yoneya Shin S Kohda Masakazu M Okazaki Yasushi Y Maruyama Taro T Shimada Akira A Yasuda Kazuki K Nishida Nao N Tokunaga Katsushi K Koike Asako A

PloS one 20141103 11

Elucidation of the genetic susceptibility factors for diabetic retinopathy (DR) is important to gain insight into the pathogenesis of DR, and may help to define genetic risk factors for this condition. In the present study, we conducted a three-stage genome-wide association study (GWAS) to identify DR susceptibility loci in Japanese patients, which comprised a total of 837 type 2 diabetes patients with DR (cases) and 1,149 without DR (controls). From the stage 1 genome-wide scan of 446 subjects ...[more]

PMID: 25364816

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Project description:PurposeDiabetic retinopathy (DR) remains a pressing issue worldwide. Abnormal angiogenesis is a distinct vascular lesion in DR, and research has established that vascular endothelial growth factor A (VEGF-A) is a primary mediator of such changes. However, limitations in current anti-VEGF therapies suggest that our understanding of molecular networks underlying ocular angiogenesis remains far from complete. Based on our long non-coding RNA (lncRNA) array analyses, HOX antisense intergenic RNA (HOTAIR) was identified as one of the top upregulated lncRNAs in high glucose-cultured human retinal endothelial cells (HRECs). Given the well-documented roles of HOTAIR in cancer, no studies have examined the epigenetic implications of HOTAIR in DR, and we investigated such relationships herein.MethodsWe used HRECs exposed to various glucose concentrations and epigenetic modulators to examine HOTAIR, angiogenic, and DR-related molecular markers. Oxidative stress, angiogenesis, and mitochondrial dysfunction were assessed. Retinal tissues of diabetic rodents and the vitreous humor and serum of patients with proliferative DR were also investigated.ResultsHyperglycemia significantly augmented HOTAIR expression in HRECs and promoted angiogenesis, oxidative damage, and mitochondrial aberrations. Similarly, vitreous humor and serum from proliferative DR patients and retinas from diabetic animals demonstrated increased HOTAIR expression compared to non-diabetic controls. HOTAIR knockdown protected against glucose-induced increases of angiogenic and diabetes-associated molecules in the retina. Mechanistically, we showed that HOTAIR exerts its capabilities by preventing oxidative stress and modulating epigenetic pathways involving histone methylation, histone acetylation, DNA methylation, and transcription factors.ConclusionsOur findings suggest that HOTAIR is a critical lncRNA in the pathogenesis of DR and may potentially be important for diagnostic and therapeutic targeting.

Dataset Information

A genome-wide association study for diabetic retinopathy in a Japanese population: potential association with a long intergenic non-coding RNA.

Publications

A genome-wide association study for diabetic retinopathy in a Japanese population: potential association with a long intergenic non-coding RNA.

Similar Datasets

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