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Patrice Persad, Monique Dorcel Courtenay, Gaofeng Wang, William Cade, Anita Agarwal, Stephen G Schwartz, Jaclyn L Kovach, Jonathan L Haines, Margaret A Pericak-Vance, William K Scott; Genome-Wide Analysis of Mitochondrial DNA (mtDNA)-Nuclear DNA Interaction in Age-Related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2014;55(13):2220.
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© ARVO (1962-2015); The Authors (2016-present)
Reactive oxygen species (ROS) contribute to retinal pigment epithelium (RPE) degeneration and mitochondrial dysfunction, both of which characterize AMD. Prior studies suggested that mtDNA haplogroup H was protective for AMD and was associated with increased CFH and C3 expression (Kenney et al., 2013). We examined joint effects of mtDNA variants and nuclear DNA in a genome-wide analysis.
An existing genome-wide association study (GWAS) dataset (Naj et al., 2013) of 668,238 single nucleotide polymorphisms (SNPs) from the Affymetrix 6.0 chipset was analyzed. A total of 1,419 people with smoking history were included: 894 cases (CARMS grades 3, 4, and 5) and 525 controls (grades 1 and 2). A two-degree of freedom joint test of gene-gene interaction was conducted using PLINK. In this test, a model including the nuclear SNP (coded additively), the mtDNA SNP (coded 0,1), and the nuclear SNP-mtDNA SNP interaction term was compared to a second model excluding the nuclear SNP and interaction terms. Both models were adjusted for age, sex, and smoking. Interaction was assessed for 26 mtDNA SNPs and all 668,212 nuclear SNPs available.
Joint effects of mtDNA SNP rs3928306 and nuclear DNA variants rs13375236, rs6428369, and rs2336503 in the CFH region achieved genome-wide statistical significance (p<5.00x10-8) with interaction effects being nominally statistically significant (p<0.01). No novel nuclear DNA variants demonstrated genome-wide statistical significance.
The mtDNA variant rs3928306 (which is found on mitochondrial subhaplogroup H1) may be a modifier of the association of variation in the CFH region with AMD. However, further investigation is required to determine the exact biological significance in mechanisms concerning AMD and to confirm consistency in other datasets.
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