INSIG2 gene rs7566605 polymorphism is associated with severe obesity in Japanese

The single nucleotide polymorphism (SNP) rs7566605 in the upstream region of the insulin-induced gene 2 (INSIG2) is associated with the obesity phenotype in many Caucasian populations. In Japanese, this association with the obesity phenotype is not clear. To investigate the relationship between rs7566605 and obesity in Japanese, we genotyped rs7566605 from severely obese subjects [n = 908, body mass index (BMI) ≥ 30 kg/m2] and normal-weight control subjects (n = 1495, BMI < 25 kg/m2). A case–control association analysis revealed that rs7566605 was significantly associated with obesity in Japanese. The P value in the minor allele recessive mode was 0.00020, and the odds ratio (OR) adjusted for gender and age was 1.61 [95% confidential interval (CI) = 1.24–2.09]. Obesity-associated phenotypes, which included the level of BMI, plasma glucose, hemoglobin A1c, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and blood pressure, were not associated with the rs7566605 genotype. Thus, rs7566605 in the upstream region of the INSIG2 gene was found to be associated with obesity, i.e., severe obesity, in Japanese

Protein kinase C (PKC)-mediated phosphorylation of PACSIN2 triggers the removal of caveolae from the plasma membrane

PACSIN2, a membrane-sculpting BAR domain protein, localizes to caveolae. Here, we found that protein kinase C (PKC) phosphorylates PACSIN2 at serine 313, thereby decreasing its membrane binding and tubulation capacities. Concomitantly, phosphorylation decreased the time span for which caveolae could be tracked at the plasma membrane (the ‘tracking duration’). Analyses of the phospho-mimetic S313E mutant suggested that PACSIN2 phosphorylation was sufficient to reduce caveolar-tracking durations. Both hypotonic treatment and isotonic drug-induced PKC activation increased PACSIN2 phosphorylation at serine 313 and shortened caveolar-tracking durations. Caveolar-tracking durations were also reduced upon the expression of other membrane-binding-deficient PACSIN2 mutants or upon RNA interference (RNAi)-mediated PACSIN2 depletion, pointing to a role for PACSIN2 levels in modulating the lifetime of caveolae. Interestingly, the decrease in membrane-bound PACSIN2 was inversely correlated with the recruitment and activity of dynamin 2, a GTPase that mediates membrane scission. Furthermore, expression of EHD2, which stabilizes caveolae and binds to PACSIN2, restored the tracking durations of cells with reduced PACSIN2 levels. These findings suggest that the PACSIN2 phosphorylation decreases its membrane-binding activity, thereby decreasing its stabilizing effect on caveolae and triggering dynamin-mediated removal of caveolae

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

BACKGROUND: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P&lt;5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P&lt;10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P&lt;10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P&lt;0.005). CONCLUSIONS: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.</p

Radiocarbon Wiggle-Matching of Japanese Historical Materials with a Possible Systematic Age Offset

From the 19th International Radiocarbon Conference held in Keble College, Oxford, England, April 3-7, 2006.Progress in radiocarbon accelerator mass spectrometry (AMS) techniques enables much more access to wiggle-matching techniques for high-precision 14C dating with relatively low costs than before. Recently, we have applied wiggle-matching for a number of wood samples where dendrochronology is difficult because of various limitations imposed for dendro-dating. In most cases, wiggle-matching gave rather unambiguous calendar ages, but we found that in some cases the calibrated date was very sensitive to a systematic error of the 14C date. Here, we present a wooden artifact from the Ujishigai archaeological site as a case where the highest wiggle-matched date did not agree with the date given by dendrochronology. An age with lower probability agreed with the tree-ring age of AD 389, which marked the beginning of the production of Sue ware (unglazed stoneware) in Japan. We show that systematic errors must be carefully taken into account while interpreting 14C wiggle-matching results, whether they are due to instrumental errors (statistical) or due to a regional offset from the IntCal04 (Reimer et al. 2004) calibration curve.The Radiocarbon archives are made available by Radiocarbon and the University of Arizona Libraries. Contact [email protected] for further information.Migrated from OJS platform February 202

Radiocarbon Wiggle-Matching of Japanese Historical Materials with a Possible Systematic Age Offset

From the 19th International Radiocarbon Conference held in Keble College, Oxford, England, April 3-7, 2006.Progress in radiocarbon accelerator mass spectrometry (AMS) techniques enables much more access to wiggle-matching techniques for high-precision 14C dating with relatively low costs than before. Recently, we have applied wiggle-matching for a number of wood samples where dendrochronology is difficult because of various limitations imposed for dendro-dating. In most cases, wiggle-matching gave rather unambiguous calendar ages, but we found that in some cases the calibrated date was very sensitive to a systematic error of the 14C date. Here, we present a wooden artifact from the Ujishigai archaeological site as a case where the highest wiggle-matched date did not agree with the date given by dendrochronology. An age with lower probability agreed with the tree-ring age of AD 389, which marked the beginning of the production of Sue ware (unglazed stoneware) in Japan. We show that systematic errors must be carefully taken into account while interpreting 14C wiggle-matching results, whether they are due to instrumental errors (statistical) or due to a regional offset from the IntCal04 (Reimer et al. 2004) calibration curve.The Radiocarbon archives are made available by Radiocarbon and the University of Arizona Libraries. Contact [email protected] for further information.Migrated from OJS platform February 202