AMD retinas exhibited increased mtDNA control region SNPs compared to normal retinas. This correlated with an increased frequency of mtDNA SNPs associated with haplogroups J, T and U in patients with AMD. These results implicate mitochondrial alterations in the etiology of AMD.

BackgroundAge-related macular degeneration (AMD) is the leading cause of vision loss in elderly, Caucasian populations. There is strong evidence that mitochondrial dysfunction and oxidative stress play a role in the cell death found in AMD retinas. The purpose of this study was to examine the association of the Caucasian mitochondrial JTU haplogroup cluster with AMD. We also assessed for gender bias and additive risk with known high risk nuclear gene SNPs, ARMS2/LOC387715 (G > T; Ala69Ser, rs10490924) and CFH (T > C; Try402His, rs1061170).MethodsTotal DNA was isolated from 162 AMD subjects and 164 age-matched control subjects located in Los Angeles, California, USA. Polymerase chain reaction (PCR) and restriction enzyme digestion were used to identify the J, U, T, and H mitochondrial haplogroups and the ARMS2-rs10490924 and CFH-rs1061170 SNPs. PCR amplified products were sequenced to verify the nucleotide substitutions for the haplogroups and ARMS2 gene.ResultsThe JTU haplogroup cluster occurred in 34% (55/162) of AMD subjects versus 15% (24/164) of normal (OR = 2.99; p = 0.0001). This association was slightly greater in males (OR = 3.98, p = 0.005) than the female population (OR = 3.02, p = 0.001). Assuming a dominant effect, the risk alleles for the ARMS2 (rs10490924; p = 0.00001) and CFH (rs1061170; p = 0.027) SNPs were significantly associated with total AMD populations. We found there was no additive risk for the ARMS2 (rs10490924) or CFH (rs1061170) SNPs on the JTU haplogroup background.ConclusionsThere is a strong association of the JTU haplogroup cluster with AMD. In our Southern California population, the ARMS2 (rs10490924) and CFH (rs1061170) genes were significantly but independently associated with AMD. SNPs defining the JTU mitochondrial haplogroup cluster may change the retinal bioenergetics and play a significant role in the pathogenesis of AMD.

Background Recent studies suggest that the storage age of red blood cells (RBCs) may be associated with morbidity and mortality in surgical patients. We studied perioperative effects of RBC storage age in patients undergoing orthotopic liver transplant (OLT). Methods Adult patients who received ≥5 U of RBCs during OLT between January 2004 and June 2009 were studied. The subjects were divided into two groups according to the mean storage age of RBCs they received: new or old RBCs (stored ≤14 or >14 days, respectively). Effects of storage age of transfused RBCs during OLT on intraoperative potassium (K+) concentrations, incidence of hyperkalemia (K+ ≥5.5 mmol/L), postoperative morbidity, and patient and graft survival were studied. Results The mean serum K+ concentrations and the incidence of hyperkalemia during OLT were significantly associated with storage age of the RBCs. Logistic analysis showed that storage age of RBCs was an independent risk factor for intraoperative hyperkalemia (odds ratios 1.067–1.085, p < 0.001) in addition to baseline K+ concentration and units of RBCs transfused. Patient and graft survival and postoperative morbidity including postoperative ventilation, reoperation, acute renal dysfunction defined by the RIFLE criteria was not associated with old RBCs. Conclusions Transfusion of RBCs stored for a longer time was associated with intraoperative hyperkalemia but not with postoperative adverse outcomes in adult OLT. Prevention and treatment of potentially harmful hyperkalemia should be considered when old RBCs are administered.

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Purpose: The purpose of this study was to screen for mutations within mitochondrial creatine kinase (CKMT) genes, which encode for isoenzymes critical for high energy metabolism, such as that found in retina.Methods: DNA was extracted from lymphocytes of clinically characterized age-related macular degeneration (AMD) patients (n=71). Flanking primers were used to polymerase chain reaction (PCR) amplify and sequence the exons, the open reading frame, and promoter regions of the CKMT1A, CKMT1B and CKMT2 genes. An additional 72 individuals with AMD were screened for the novel CKMT2 mutation in exon 4 (NM_001825.2 c.274C>T) by PCR and enzyme digestion. The RNA was extracted from cultured human retinal pigment epithelial cells (ARPE-19) and reverse transcript-PCR (RT-PCR) was performed with primers for the CKMT2 gene. Results:With our screening procedure, we identified 5 DNA variants in the CKMT2 gene, 2 of which were novel (NM_001825.2 c.274C>T; 92Q>X, Exon 4 and NM_001825.2.-498G>GA; 5'UTR, Exon 1). The putative termination mutation in the CKMT2 gene (NM_001825.2 c.274C>T; 92Q>X) was in a proband individual but lacking in his unaffected son and 142 unrelated AMD patients. Cultured human RPE cells can express the sarcomeric mitochondrial CKMT2 gene product. Conclusions:This is the first report of a termination mutation within the human CKMT2 gene, which is critical for transfer of high-energy phosphate from mitochondria to creatine, a cytosolic carrier. Clinically, the subject had AMD, exercise fatigue, atrial fibrillation and deafness, all of which are known to be related to mitochondrial dysfunctions. Based upon our finding, we propose this CKMT2 mutation may be a candidate gene for the phenotypes that include this quartet of symptoms.