Mitochondrial Haplogroups Affect Severity But Not Prevalence of Diabetic Retinopathy

Abstract

PurposeWe previously reported European mitochondrial haplogroup H to be a risk factor for and haplogroup UK to be protective against proliferative diabetic retinopathy (PDR) among Caucasian patients with diabetic retinopathy (DR). The purpose of this study was to determine whether these haplogroups are also associated with the risk of having DR among Caucasian patients with diabetes.MethodsDeidentified medical records for 637 Caucasian patients with diabetes (223 with DR) were obtained from BioVU, Vanderbilt University's electronic, deidentified DNA databank. An additional 197 Caucasian patients with diabetes (98 with DR) were enrolled from the Vanderbilt Eye Institute (VEI). We tested for an association between European mitochondrial haplogroups and DR status.ResultsThe percentage of diabetes patients with DR did not differ across the haplogroups (P = 0.32). The percentage of patients with nonproliferative DR (NPDR; P = 0.0084) and with PDR (P = 0.027) significantly differed across the haplogroups. In logistic regressions adjusting for sex, age, diabetes type, duration of diabetes, and hemoglobin A1c, neither haplogroup H nor haplogroup UK had a significant effect on DR compared with diabetic controls. Haplogroup UK was a significant risk factor (OR = 1.72 [1.13–2.59], P = 0.010) for NPDR compared with diabetic controls in the unadjusted analysis, but not in the adjusted analysis (OR = 1.29 [0.79–2.10], P = 0.20).ConclusionsMitochondrial haplogroups H and UK were associated with severity, but not presence, of DR. These data argue that the effect of these haplogroups is related to ischemia and neovascularization, the defining features of PDR.

Mitochondrial Haplogroups Modify the Effect of Diabetes Duration and HbA1c on Proliferative Diabetic Retinopathy Risk in Patients With Type 2 Diabetes

“…From the retina clinic of the VEI, we previously recruited Caucasian patients (age ≥ 18 years) who had been diagnosed with type 2 diabetes by their primary care physician or endocrinologist and were taking at least one diabetes medication. 7 , 8 All patients were evaluated for presence of DR via a comprehensive dilated ophthalmologic examination by a fellowship-trained retina specialist. Patients with type 2 diabetes and no evidence of DR were classified as diabetic controls ( n = 81), and those with evidence of DR ( n = 64) were graded on severity, either NPDR or PDR, as previously described.…”

“…Patients with type 2 diabetes and no evidence of DR were classified as diabetic controls ( n = 81), and those with evidence of DR ( n = 64) were graded on severity, either NPDR or PDR, as previously described. 7 , 8 Briefly, NPDR was determined by presence of blot hemorrhages, microaneurysms, cotton wool spots, or intraretinal microvascular abnormalities, as well as the absence of signs or history of retinal neovascularization. Diagnosis of PDR was based on presence of iris or retinal neovascularization, or evidence of laser photocoagulation treatment for PDR.…”

“…These DNA samples are linked to a de-identified version of the EMR called the Synthetic Derivative (SD). 9 In BioVU, we previously identified a cohort of diabetic patients with DR and a diabetic control group consisting of patients with diabetes and no evidence of DR. 8 Briefly, we identified all Caucasian individuals with existing genome-wide variant data whose records contained International Classification of Diseases-9 (ICD-9) codes for type 2 diabetes (250.00, 250.02, 250.50, or 250.52) with and without DR ICD-9 codes (362.0–362.07), as well as Current Procedural Terminology (CPT) codes for ophthalmology exams (92004 or 92014).…”

“… 7 Among patients with either type 1 or type 2 diabetes, we have demonstrated that those from haplogroup H are at increased risk for PDR, while patients from haplogroup UK are at decreased risk for PDR. 7 Furthermore, we have determined that, although mitochondrial haplogroups H and UK are associated with DR severity, they are not associated with the presence of DR, 8 suggesting mitochondrial haplogroups may impact ischemia and neovascularization, the hallmarks of PDR.…”

“…Building upon our previous work, we identified and genotyped additional patients, expanding our cohort of DR cases and controls for the current study. While our previous studies have included patients with either type 1 or type 2 diabetes, 7 , 8 the current study focused on patients with type 2 diabetes because the effect of mitochondrial haplogroups on DR severity was stronger in these patients. 7 Here, we investigated the relationship between mitochondrial haplogroups and both diabetes duration and HbA 1c to determine how this relationship influences PDR prevalence.…”