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Nicole Restrepo, Robert Goodloe, Sabrina Mitchell, Dana Crawford; The Role of Mitochondrial Variants in the Risk of Diabetic Retinopathy in Diverse Populations within the National Health and Nutrition Examination Surveys. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2239.
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Limited progress has been made in identifying susceptibility variants for diabetic retinopathy (DR). Most genetic studies have focused on the nuclear genome and excluded analysis of the mitochondrial genome, regardless that mitochondria are known to play a pathological role in DR. Hyperglycemia-induced oxidative stress has been shown to impair mitochondrial function, damage mtDNA, and increase apoptosis of retinal capillary cells resulting in damage to the retinal microvasculature and development of DR. A major goal of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE)) study is to describe the underlying genetic architecture of common, complex diseases such as DR across diverse populations.
EAGLE accessed the National Health and Nutrition Examination Surveys (NHANES) III and 2007-2008 for targeted genotyping of 60 mitochondrial SNPs. DR cases were type-2 diabetics (T2D) >40 years with mild, moderate, or proliferative DR determined by fundus photography. Controls had T2D and determined free of DR by fundus exam. A total of 77, 76, and 60 cases and 190, 101, and 96 controls from European American (EA), African Americans (AA), and Mexican Americans (MA) respectively, were available for study. A meta-analysis was performed on genotyped variants and haplogroups following logistic regression assuming an additive genetic model and adjusted for age, sex, body mass index, and glycated hemoglobin levels (HbA1c).
In AA rs2853520 (A) was associated with DR at p=0.052. Although not significant (p< 0.05), this variant is interesting for various reasons. In the individual NHANES III analysis, rs2853520 was significant at p=0.047. Notably, the ancestral allele frequency (A) is 14.5 % in the general HapMap Yoruba population but was ~22% in our NHANES AA populations (23.5% and 21.7%, NHANES III & 07-08). We did not find a significant association between mitochondrial variants/haplogroups and DR in EA or MA.
The variant rs2853520 found in the mitochondrially encoded 12s RNA gene, was found to trend towards significance in our AA DR cases. The allele frequency of this variant was enriched in our AA population (~22% vs 14.5%). Further studies are needed to determine if lack of association is due to statistical power or differences in linkage disequilibrium and allelic distribution across diverse populations.
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