SUMMARY Chronic reactive oxygen species (ROS) production by mitochondria may contribute to the development of insulin resistance, a primary feature of type 2 diabetes. In recent years it has become apparent that ROS generation in response to physiological stimuli such as insulin may also facilitate signaling by reversibly oxidizing and inhibiting protein tyrosine phosphatases (PTPs). Here we report that mice lacking one of the key enzymes involved in the elimination of physiological ROS, glutathione peroxidase 1 (Gpx1), were protected from high fat diet-induced insulin resistance. The increased insulin sensitivity in Gpx1−/− mice was attributed to insulin-induced phosphatidylinositol-3-kinase/Akt signaling and glucose uptake in muscle and could be reversed by the anti-oxidant N-acetylcysteine. Increased insulin signaling correlated with enhanced oxidation of the PTP family member PTEN, which terminates signals generated by phosphatidylinositol-3-kinase. These studies provide causal evidence for the enhancement of insulin signaling by ROS in vivo.
Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10−8) level: 14q24.2 (rs227425, P-value 3.98 × 10−13, SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10−9, CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n = 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.
We investigate the relevance of the genetic determination of bone mineral density (BMD) variation to that of differential risk to osteoporotic fractures (OF). The high heritability (h(2)) of BMD and the significant phenotypic correlations between high BMD and low risk to OF are well known. Little is reported on h(2) for OF. Extensive molecular genetic studies aimed at uncovering genes for differential risks to OF have focussed on BMD as a surrogate phenotype. However, the relevance of the genetic determination of BMD to that of OF is unknown. This relevance can be characterized by genetic correlation between BMD and OF. For 50 Caucasian pedigrees, we estimated that h(2) at the hip is 0.65 (P < 0.0001) for BMD and 0.53 (P < 0.05) for OF; however, the genetic correlation between BMD and OF is nonsignificant (P > 0.45) and less than 1% of additive genetic variance is shared between them. Hence, most genes found important for BMD may not be relevant to OF at the hip. The phenotypic correlation between high BMD and low risk to OF at the hip (approximately -0.30) is largely due to an environmental correlation (rho(E) = -0.73, P < 0.0001). The search for genes for OF should start with a significant h(2) for OF and should include risk factors (besides BMD) that are genetically correlated with OF. All genes found important for various risk factors must be tested for their relevance to OF. Ideally, employing OF per se as a direct phenotype for gene hunting and testing can ensure the importance and direct relevance of the genes found for the risk of OF. This study may have significant implications for the common practice of gene search for complex diseases through underlying risk factors (usually quantitative traits).
Arbidol, ethyl-6-bromo-4-[(dimethylamino)-methyl]-5-hydroxy-1-methyl-2-[(phenylthio)methyl]-in dole-3-carboxylate hydrochloride monohydrate, is an antiviral chemical agent. In this report, we studied the antiviral activity of arbidol against a panel of human respiratory viruses, namely influenza A virus (FLU-A, A/PR/8/34 H1N1), respiratory syncytial virus (RSV), human rhinovirus type 14 (HRV 14), coxsackie virus B3 (CVB3) and adenovirus type 7 (AdV-7) in vitro in cell culture. Arbidol was found to present potent inhibitory activity against enveloped and non-enveloped RNA viruses, including FLU-A, RSV, HRV 14 and CVB3 when added before, during, or after viral infection, with 50% inhibitory concentration (IC50) ranging from 2.7 to 13.8 microg/ml. However, arbidol showed selective antiviral activity against AdV-7, a DNA virus, only when added after infection (therapeutic index (TI) = 5.5). Orally administered arbidol at 50 or 100 mg/kg/day beginning 24 h pre-virus exposure for 6 days significantly reduced mean pulmonary virus yields and the rate of mortality in mice infected with FLU-A (A/PR/8/34 H1N1). Our results suggest that arbidol has the ability to elicit protective broad-spectrum antiviral activity against a number of human pathogenic respiratory viruses.
Osteoporotic fractures (OFs) are a major public health problem. Direct evidence of the importance and, particularly, the magnitude of genetic determination of OF per se is essentially nonexistent. Colles' fractures (CFs) are a common type of OF. In a metropolitan white female population in the midwestern United States, we found significant genetic determination of CF. The prevalence (K) of CF is, respectively, 11.8% (؎SE 0.7%) in 2471 proband women aged 65.55 years (0.21), 4.4% (0.3%) in 3803 sisters of the probands, and 14.6% (0.7%) in their mothers. The recurrence risk (K 0 ), the probability that a woman will suffer CF if her mother has suffered CF is 0.155 (0.017). The recurrence risk (K s ), the probability that a sister of a proband woman will suffer CF given that her proband sister has suffered CF is 0.084 (0.012). The relative risk (the ratio of the recurrence risk to K), which measures the degree of genetic determination of complex diseases such as CF,
Osteoporosis is an important health problem, particularly in the elderly women. Bone mineral density (BMD) is a major determinant of osteoporosis. For a sample of 53 pedigrees that contain 1249 sibling pairs, 1098 grandparent-grandchildren pairs, and 2589 first cousin pairs, we performed a whole- genome linkage scan using 380 microsatellite markers to identify genomic regions that may contain quantitative trait loci (QTL) of BMD. Each pedigree was ascertained through a proband with BMD values belonging to the bottom 10% of the population. We conducted two-point and multipoint linkage analyses. Several potentially important genomic regions were suggested. For example, the genomic region near the marker D10S1651 may contain a QTL for hip BMD variation (with two-point analysis LOD score of 1.97 and multipoint analysis LOD score of 2.29). The genomic regions near the markers D4S413 and D12S1723 may contain QTLs for spine BMD variation (with two-point analysis LOD score of 2.12 and 2.17 and multipoint analysis LOD score of 3.08 and 2.96, respectively). The genomic regions identified in this and some earlier reports are compared for exploration in extension studies with larger samples and/or denser markers for confirmation and fine mapping to eventually identify major functional genes involved in osteoporosis.
Human height is a complex trait under the control of both genetic and environment factors. In order to identify genomic regions underlying the variation of stature, we performed a whole-genome linkage analysis on a sample of 53 human pedigrees containing 1,249 sib pairs, 1,098 grandparent-grandchildren pairs, 1,993 avuncular pairs, and 1,172 first-cousin pairs. Several genomic regions were suggested by our study to be linked with human height variation. These regions include 5q31 at 144 cM from pter on chromosome 5 (with a maximum LOD score of 2.14 in multipoint linkage analyses), Xp22 at the marker DXS1060, and Xq25 at DXS1001 on the X chromosome (with LOD scores of 1.95 and 1.91, respectively, in two-point linkage analyses). Noticeably, Xp22 happens to be the very region where a newly identified gene underlying idiopathic short stature, SHOX, maps. Based on our findings, further confirmation and fine-mapping studies are to be pursued on expanded samples and/or with denser markers for eventual identification of major functional genes involved in human height variation.
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