April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
A Candidate-Wide Association Study of Diabetic Retinopathy in Latinos Implicates TNF Receptor Pathophysiology: Genetics of Latino Diabetic Retinopathy (GOLDR) and Los Angeles Latino Eye (LALES) studies
Author Affiliations & Notes
  • Jane Z. Kuo
    Shiley Eye Center and the Department of Ophthalmology, University of California at San Diego, La Jolla, CA
  • Xiaoyi Gao
    Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL
    Doheny Eye Institute and the Departments of Ophthalmology and Preventive Medicine, University of Southern California, Los Angeles, CA
  • Xiuqing Guo
    Institute for Translational Genomics and Biomedical Sciences, Harbor-UCLA Medical Center, Torrance, CA
  • Kent D Taylor
    Institute for Translational Genomics and Biomedical Sciences, Harbor-UCLA Medical Center, Torrance, CA
  • Ronald Klein
    Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI
  • Barbara E K Klein
    Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI
  • Eli Ipp
    Division of Endocrinology and Metabolism, Harbor-UCLA Medical Center, Torrance, CA
  • Yii-Der Ida Chen
    Institute for Translational Genomics and Biomedical Sciences, Harbor-UCLA Medical Center, Torrance, CA
  • Rohit Varma
    Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL
    Doheny Eye Institute and the Departments of Ophthalmology and Preventive Medicine, University of Southern California, Los Angeles, CA
  • Jerome I Rotter
    Institute for Translational Genomics and Biomedical Sciences, Harbor-UCLA Medical Center, Torrance, CA
  • Footnotes
    Commercial Relationships Jane Kuo, None; Xiaoyi Gao, None; Xiuqing Guo, None; Kent Taylor, None; Ronald Klein, None; Barbara Klein, None; Eli Ipp, None; Yii-Der Ida Chen, None; Rohit Varma, Allergan (C), AqueSys (C), Bausch + Lomb (C), Genentech (C), Merck & Co (C), Replenish (C); Jerome Rotter, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 4509. doi:https://doi.org/
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      Jane Z. Kuo, Xiaoyi Gao, Xiuqing Guo, Kent D Taylor, Ronald Klein, Barbara E K Klein, Eli Ipp, Yii-Der Ida Chen, Rohit Varma, Jerome I Rotter; A Candidate-Wide Association Study of Diabetic Retinopathy in Latinos Implicates TNF Receptor Pathophysiology: Genetics of Latino Diabetic Retinopathy (GOLDR) and Los Angeles Latino Eye (LALES) studies. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4509. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: To evaluate the associations of candidate genes from cardiovascular and metabolic trait loci to diabetic retinopathy (DR) in Latinos with type 2 diabetes using a fine-mapping approach.

Methods: A prospective, multicenter cohort of 1599 Latinos with type 2 diabetes with and without retinopathy were included in this study. Retinopathy status was assessed using the Early Treatment Diabetic Retinopathy Study scale, defined as any DR (cases; level ≥ 14) and no DR (controls; level < 14). We conducted a candidate-wide association study including 565 Latinos from the GOLDR study (discovery), who were genotyped with the Illumina Cardio-Metabochip, a custom array to enhance fine-mapping of cardiovascular and metabolic trait loci. In silico replications of the top signals (selected by multiple hits per locus) were performed in 1034 Latinos from the LALES cohort (replication), who were genotyped with the Illumina OmniExpress and imputed with 1000 Genome. Analysis was conducted in R using the GWAF package and in METAL for meta-analysis, Bonferroni correction for 20 loci.

Results: Association analysis of in silico replication of the top findings and meta-analysis confirmed 4 potential DR susceptibility loci. They are RBKS-BRE (rs72854438, P.meta=1.03x10-3), DNAH1 (rs28481563, P.meta=3.81x10-4), RGS21-RGS1 (rs1323295; P.meta=3.32x10-5) and SMAD3 (rs12324036; P.meta=1.24x10-5), the latter two loci were associated independent of the level of HbA1c and diabetes duration. In addition, quantitative trait analysis of levels of tumor necrosis factor (TNF) receptors 1 (P<10-3) and 2 (P<10-4) to BRE, a TNF-receptor super family 1A modulator, supports the involvement of TNF-receptors in DR.

Conclusions: We identified 4 novel potential loci to DR in Latinos with type 2 diabetes. Furthermore, our findings support our prior reported quantitative role of TNF receptors in DR, which may provide critical insights into the pathophysiology of DR in Latinos.

Keywords: 539 genetics • 499 diabetic retinopathy  
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