Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly population in the developed world and it is anticipated that its prevalence will rise. Risk factors for AMD include Caucasian race, smoking and family history. Clinical characteristics of early AMD are subretinal drusen and loss of retinal pigment epithelium (RPE). Late AMD exists in two forms: dry AMD (atrophic, stage 4) which has progressive loss of RPE cells and overlying photoreceptors and wet AMD (neovascular, stage 5) which makes up approximately 15% of the cases and is characterized by choroidal neovascularization and disciform scar formation. Both forms can result in severe central vision loss.
Mitochondria are critical organelles that provide energy to the cell via oxidative phosphorylation (OXPHOS). Mitochondria are unique in that they have their own DNA (mtDNA) which is highly polymorphic with 16,569 nucleotide pairs that code for 37 genes including 13 OXPHOS protein subunits, 2 ribosomal RNAs and 22 transfer RNAs [1, 2]. The mtDNA lacks histones and has poor DNA repair systems so it is at greater risk of damage compared to nuclear DNA. Human retinal cells are very metabolically active and have evidence of oxidative damage in the retinal mtDNA, including high degrees of pathologic heteroplasmy, large deletions and nucleotide substitutions. Recently, studies have shown that aging and AMD retinas have increased mitochondrial structural abnormalities and elevated levels of mtDNA damage [3–7].
Another mechanism by which diseases can occur is through the association of mtDNA haplogroups which represent different ethnic populations of the world. A specific haplogroup is defined by variations in mtDNA sequences within the maternal lineages that have accumulated over thousands of years and represent the geographic origin of that population. The oldest haplogroups (L1-L3) originated from Africa (130 K-170 K years) while the most recent haplogroups (A, B, C, D, X) originated within the North and South American continents (18 K-34 K years) (http://www.mitomap.org). The European haplogroups (H, I, J, K, T, U, V, W and X) are approximately 30 K-50 K years old. It is likely that the haplogroup single nucleotide polymorphism (SNP) variants may have functional consequences. Since mitochondria are critical for energy production, the haplogroup-related SNPs may be related to partial uncoupling of OXPHOS and decreased efficiency of ATP production [8–10]. This means that each haplogroup, with its different set of SNPs, can have unique bioenergetic properties and responses to oxidative stressors. The haplogroup defining SNPs may modify the required mitochondrial energetics of that population to meet the needs of their environment  and therefore may have varying biological effects on the cells.
Studies have shown that the age-related diseases, such as Alzheimer’s and Parkinson’s, are associated with specific haplogroups [12–15]. Large soft drusen, retinal pigment abnormalities and the wet forms of AMD, an age-related eye disease, have also been shown to be associated with some European haplogroups [16–20]. Correlations between other ocular diseases and haplogroups are also being reported. Susceptibility to pseudoexfoliation glaucoma is decreased in patients with a U haplogroup but increased with T or L2 haplogroups [21, 22]. In a Saudi Arabian population, there is an increased risk of primary open-angle glaucoma in patients with the African L haplogroups, excluding L2 haplogroup . In addition, there is a higher prevalence of diabetic retinopathy in type 2 diabetic patients with the mtDNA T haplogroup background .
There are two major susceptibility genes associated with AMD in certain populations. The CFH gene polymorphism (rs1061170), T1277C (Tyr402His) has been associated with the development and progression of AMD [25–29] in Caucasian populations but not Asians [30–32]. The CFH protein blocks C3 to C3b activation, causes C3b degradation, and thereby regulates the alternative complement pathway. Both aging and smoking can decrease the CFH plasma levels  and which can lead to increased inflammation [34, 35]. The ARMS2/LOC387715 gene polymorphism (rs10490924) is a missense SNP transversion from G > T (Ala69Ser). In a North American population, TT homozygosity is associated with the wet and dry forms of advanced AMD, showing an allele-dose effect . Studies based on Japanese AMD populations have found that the SNP (rs10490924) in the LOC387715 gene is associated with the wet form of AMD, [37–39] which has been confirmed in both American [40–42] and Indian populations . Fritsche and coworkers expressed the LOC387715 mRNA  and reported a mitochondrial association  although this has not been found by others . Some investigators suggest that the ARMS2 gene codes for a secreted protein that binds to extracellular matrix . Baas and coworkers have shown significant association for three SNPs of the glucose transporter gene (SLC2A1) in a single cohort, but when applied to additional study populations, the results showed an inconsistent, non-significant association . Based upon these findings, they suggest that across populations there is heterogeneity of AMD risk factors which exists as the rule rather than the exception.
It has already been shown that the clinical phenotypes of diseases can be influenced through synergistic effects of nuclear genes with the mitochondrial genome [49, 50]. For example, Leber’s hereditary optic neuropathy (LHON) individuals harboring the milder mutations at positions 11778, 14484, and 10663 have increased severity and probability of blindness if they have a J haplogroup background [49, 51]. The LHON patients with the 3460 mutation on a Uk mtDNA haplogroup background were higher risk for vision loss  while the H haplogroup protected from the disease . In contrast, the J haplogroup background in HIV infected patients protects them against progression of neuroretinal disorder (NRD) . The present study was designed to assess the frequency of the JTU haplogroup cluster in our AMD population and examine the potential additive associations of the ARMS2-rs10490924 and CFH-rs1061170 risk alleles.