Mitochondrial DNA haplogroups confer differences in risk for age-related macular degeneration: a case control study.

BACKGROUND: Age-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). METHODS: Total 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. RESULTS: The 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. CONCLUSIONS: There 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.

Storage age of transfused red blood cells during liver transplantation and its intraoperative and postoperative effects.

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.

Mitochondrial DNA haplogroups associated with age-related macular degeneration.

PURPOSE: To examine the mtDNA control regions in normal and age-related macular degeneration (AMD) retinas. To identify the mtDNA variations associated with AMD. METHODS: Retinas from 10 normal and 11 AMD globes were isolated and analyzed for mtDNA rearrangements by long extension-polymerase chain reaction (LX-PCR) and for the nature and frequency of single-nucleotide polymorphisms (SNPs) in the mtDNA control region by direct sequencing. Blood DNA was extracted from 99 AMD and 92 age-matched control subjects. The sequence variations that define haplogroups H, I, J, K, T, V, X, and U were characterized by PCR, restriction enzyme digestion, and/or sequencing. RESULTS: LX-PCR of retinal mtDNAs revealed high levels of rearrangements in the patients with AMD and the control subjects, consistent with the decline in mitochondrial function with age. However, the AMD retinas had higher oxidized DNA levels and a higher number of SNPs than controls (P = 0.02). The control region SNPs T16126C and A73G, commonly found in haplogroups J and T, were more frequent in the AMD retinas than in normal retinas. The associations between AMD and haplogroups J and T were confirmed and extended by analysis of blood DNA. SNPs at position a T16126C (J; odds ratio [OR] = 3.66), T16126C+G13368A (JT; OR = 10.27), A4917G+A73G (T4; OR = 5), and T3197C+A12308G (U5; OR = infinity), were all strongly associated with AMD. CONCLUSIONS: 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.