32 research outputs found
Meta-Analysis of 28,141 Individuals Identifies Common Variants within Five New Loci That Influence Uric Acid Concentrations
Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (pâ=â5.2Ă10â201), ABCG2 (pâ=â3.1Ă10â26), SLC17A1 (pâ=â3.0Ă10â14), SLC22A11 (pâ=â6.7Ă10â14), SLC22A12 (pâ=â2.0Ă10â9), SLC16A9 (pâ=â1.1Ă10â8), GCKR (pâ=â1.4Ă10â9), LRRC16A (pâ=â8.5Ă10â9), and near PDZK1 (pâ=â2.7Ă10â9). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (pâ=â4.0Ă10â26) and propionyl-L-carnitine (pâ=â5.0Ă10â8) concentrations, which in turn were associated with serum UA levels (pâ=â1.4Ă10â57 and pâ=â8.1Ă10â54, respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels
COENZYME-Q SATURATION KINETICS OF MITOCHONDRIAL-ENZYMES - THEORY, EXPERIMENTAL ASPECTS AND BIOMEDICAL IMPLICATIONS
Inhibition of glycerophosphate-dependent H2O2 generation in brown fat mitochondria by idebenone
The established protective effect of coenzyme Q (CoQ) analogs is dependent on the location of reactive oxygen species (ROS) generation. One of these analogs\u2014idebenone (hydroxydecyl-ubiquinone) is used as an antioxidative therapeutic drug. We tested its scavenging effect on the glycerophosphate (GP)-dependent ROS production as this enzyme was shown as a new site in the mitochondrial respiratory chain where ROS can be generated. We observed that idebenone inhibits both GP- and succinate-dependent ROS production. Idebenone and CoQ1 were found to be more efficient in the scavenging activity (IC50: 0.052 and 0.075 \u3bcM, respectively) than CoQ3 (IC50: 45.8 \u3bcM). Idebenone also inhibited ferricyanide (FeCN)-activated, GP-dependent ROS production. Our data thus extend previous findings on the scavenging effect of idebenone and show that it can also eliminate GP-dependent ROS generation