Oxidative Stress and the Incidence of Proliferative Diabetic Retinopathy and Macular Edema: the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR)

Abstract

Purpose: To determine whether a biomarker of lipid peroxidation, oxidized low density lipoprotein (OxLDL) and genetic variants of 165 single nucleotide polymorphisms (SNPs) involved in the antioxidant pathways (superoxide dismutase 2 [SOD2], glutathione S-transferase mu 3 [GSTM3], retinoid X receptor alpha [RXRA], catalase [CAT] and OxLDL receptor gene 1 [OLR1]) are associated with the incidence of proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME) in the WESDR cohort with type 1 diabetes (T1D).

Methods: OxLDL was measured by ELISA assay from serum collected and frozen at -70°C at up to 5 examinations spaced approximately 5 years apart between 1990-1992 and 2012-2013. High OxLDL was defined as 4th quartile vs. 1st to 3rd quartile. Genotypes were ascertained using the Illumina Human Omni-Quad BeadChip. SNPs for candidate genes were analyzed with dominance models due to small numbers homozygous for the minor alleles in many genes. PDR and DME were assessed by grading of color stereo film fundus photographs. There were 167 persons with OxLDL and genotype information and at least 1 follow-up visit over the 22-year period which resulted in 1645 and 1857 total person-years at risk for the incidence of PDR and DME, respectively.

Results: The cohort at 1990-1992 examination (baseline) had a mean duration of T1D of 22.9 (±9.2) years, a mean glycosylated hemoglobin (A1c) of 9.1% (±1.5) and a mean OxLDL of 32.9 (±12.4) mg/dL. The incidences of PDR and DME were 1.7% and 1.3% per person-year, respectively. While adjusting for A1c, T1D duration and statin use, high OxLDL (≥41.2 mg/dL) was associated with the incidence of PDR (odds ratio [OR] 2.5, P=0.02) and DME (OR 2.4, P=0.04). After additional adjustment for high OxLDL, the SNPs most significantly associated with incidence of PDR were in RXRA including rs12339187 (OR 6.7, P<0.001) and rs3132294 (OR 2.9, P=0.015). The SNPs most significantly associated with incidence of DME were in GSTM and SOD2 including GSTM3 rs2234696 (OR 2.8, P=0.02) and SOD2 rs8031 (OR 4.5, P=0.04). No significant interactions between genotype and OxLDL were found.

Conclusions: OxLDL and genes in the antioxidant pathways were related to the incidence of PDR and DME, suggesting that oxidative stress may be involved in the pathogenesis of these retinal complications.

Keywords: 499 diabetic retinopathy • 462 clinical (human) or epidemiologic studies: outcomes/complications • 463 clinical (human) or epidemiologic studies: prevalence/incidence