Mitochondrial haplogroups are associated with severity of diabetic retinopathy

Abstract

Purpose: To determine if specific mitochondrial haplogroups associate with nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR).

Methods: Deidentified medical records for Caucasian patients with diabetic retinopathy (DR; 153 NPDR and 138 PDR) were obtained from BioVU, Vanderbilt University's electronic, deidentified DNA databank. An independent cohort of Caucasian patients with DR (44 NPDR and 57 PDR) from the Vanderbilt Eye Institute (VEI) was used for validation. We tested for an association between mitochondrial haplogroups and PDR among patients with DR.

Results: In the BioVU cohort, PDR frequency among Caucasian DR patients differed significantly by mitochondrial haplogroup (P = 0.027). Replication in the VEI cohort confirmed this association (P = 0.0064). In the combined cohort, patients from the common haplogroup H were more likely to have PDR (odds ratio [OR] = 2.0 [95% confidence interval (CI) = 1.3-3.0], P = 0.0012), while patients from haplogroup Uk were less likely to have PDR (OR = 0.5 [95% CI = 0.3-0.8], P = 0.0049). In logistic regression analyses, the addition of diabetes duration, hemoglobin A1c (HgbA1c) levels, and hypertension had no effect on the associations of haplogroups H and Uk with PDR.

Conclusions: In this study, DR patients from mitochondrial haplogroup H were more likely to have PDR, while DR patients from haplogroup Uk were less likely to have PDR. The association was independent of the major clinical variables affecting PDR. The mitochondrial haplogroups were as strong a risk factor for PDR as were elevated HgbA1c levels.

Keywords: diabetes; diabetic retinopathy; genetics; mitochondrial DNA; mitochondrial genetics; mitochondrial haplogroup; proliferative diabetic retinopathy.

Figure 1

Frequency of PDR within Caucasian patients with DR, split by major European mitochondrial haplogroups. Both the BioVU and the VEI cohorts have statistically significant differences in PDR frequency by mitochondrial haplogroup.

Figure 2

Odds ratios and 95% confidence intervals for PDR in patients with DR, measured in the combined BioVU and VEI cohorts. The two most common European mitochondrial haplogroups have significant odds ratios for PDR, but haplogroups T, J, and others (all rarer haplogroups) are not significant.

Figure 3

Odds ratios for PDR in DR patients broken down by diabetes type. For mitochondrial haplogroup H, the susceptibility to PDR is strongest and only significant in the T2DM patients, not the T1DM patients. Both the odds ratio and the P value improve in the T2DM subgroup compared to the combined group, indicating that this association is likely driven by the T2DM patients. In contrast, the protective effect in the Uk haplogroup is similar in both T1DM and T2DM patients, indicating that the same protective effect is occurring in both patient groups.

Figure 4

Frequency of macular edema separated by major European mitochondrial haplogroups in the combined cohort. No significant difference by haplogroup occurs for macular edema (P = 0.95).

Figure 5

Major clinical variables for PDR separated by mitochondrial haplogroups. (A) Duration of diabetes had no significant variation by haplogroup for NPDR patients (P = 0.10 for H versus not-H, P = 0.33 for Uk versus not-Uk) or for PDR patients (P = 0.34 for H versus not-H, P = 0.90 for Uk versus not-Uk). (B) The proportion of patients with HgbA1c levels > 8% was significantly elevated in PDR compared to NPDR patients in both haplogroup H and the other minor haplogroups, but was nearly identical in the Uk haplogroup (P = 0.5).