Mitochondrial Haplogroups Modify the Effect of Diabetes Duration and HbA_1c on Proliferative Diabetic Retinopathy Risk in Patients With Type 2 Diabetes

Abstract

PurposeWe previously demonstrated an association between European mitochondrial haplogroups and proliferative diabetic retinopathy (PDR). The purpose of this study was to determine how the relationship between these haplogroups and both diabetes duration and hyperglycemia, two major risk factors for diabetic retinopathy (DR), affect PDR prevalence.MethodsOur population consisted of patients with type 2 diabetes with (n = 377) and without (n = 480) DR. A Kruskal-Wallis test was used to compare diabetes duration and hemoglobin A1c (HbA1c) among mitochondrial haplogroups. Logistic regressions were performed to investigate diabetes duration and HbA1c as risk factors for PDR in the context of European mitochondrial haplogroups.ResultsNeither diabetes duration nor HbA1c differed among mitochondrial haplogroups. Among DR patients from haplogroup H, longer diabetes duration and increasing HbA1c were significant risk factors for PDR (P = 0.0001 and P = 0.011, respectively). Neither diabetes duration nor HbA1c was a significant risk factor for PDR in DR patients from haplogroup UK.ConclusionsEuropean mitochondrial haplogroups modify the effects of diabetes duration and HbA1c on PDR risk in patients with type 2 diabetes. In our patient population, longer diabetes duration and higher HbA1c increased PDR risk in patients from haplogroup H, but did not affect PDR risk in patients from haplogroup UK. This relationship has not been previously demonstrated and may explain, in part, why some patients with nonproliferative DR develop PDR and others do not, despite similar diabetes duration and glycemic control.

Diabetic Retinopathy Preferred Practice Pattern®

“…However, for patients with haplogroup UK, neither diabetes duration nor HbA1c level was a significant risk factor for PDR. 73 A larger more recent study looking at the same haplotypes failed to show that association. 74 Another genetic study evaluated patients with type 2 diabetes who were carriers of the HMGA1 rs139876191 variant.…”

Mitochondrial haplogroups are not associated with diabetic retinopathy in a large Australian and British Caucasian sample

“…Using the same cohort, Mitchell et al . found duration of diabetes and HbA1c was significantly associated with PDR in haplogroups H1 and H2, but not UK, suggesting that mitochondrial haplogroups modify these clinical risk factors for the development of PDR in type 2 diabetes 18 . In a different study, Kofler et al .…”

The Role of Mitonuclear Incompatibility in Bipolar Disorder Susceptibility and Resilience Against Environmental Stressors

“…While mtDNA variants can contribute to disease in humans ( Taylor and Turnbull, 2005 ; Tuppen et al, 2010 ) and mtDNA haplogroups have been reported to associate with various disorders including psychiatric ( Magri et al, 2007 ; Kazuno et al, 2009 ; Rollins et al, 2009 ), cardiovascular ( Benn et al, 2008 ; Veronese et al, 2019 ), and metabolic diseases ( Chinnery et al, 2007 ; Tavira et al, 2014 ; Mitchell et al, 2017 ; Zhao et al, 2019 ), these studies fail to encompass the complexity surrounding mitonuclear epistasis and environment interactions ( Mossman et al, 2016a ). Mitonuclear genetic variation embodies extraordinarily complex epistatic, pleiotropic and GxE interactions that function in non-additive ways to modify organismal fitness and survival.…”