Jin H.-S.,Ajou University |
Kim J.,Ajou University |
Lee S.-J.,Ajou University |
Kim K.,Sookmyung Womens University |
And 13 more authors.
Molecular and Cellular Endocrinology | Year: 2014
Several association studies have implicated the PARK2 gene that encodes parkin - the key molecule orchestrating the mitochondrial quality control system - as a candidate susceptibility gene for diabetes. A total of 7551 unrelated Korean KARE cohort subjects were analyzed to investigate the association between the PARK2 single nucleotide polymorphism (SNP) and quantitative glycemic traits. Two SNPs, rs10455889 and rs9365294, were significantly associated with fasting plasma glucose level (p=~1.2×10-4) and insulin secretion indices (p=~7.4×10-5) in male KARE subjects. Parkin was expressed predominantly in the rat pancreatic islets. Downregulation of the Park2 gene in rat INS-1 β-cells resulted in a significant decrease in the glucose-stimulated insulin secretion, intracellular insulin gene expression, and intracellular ATP level. The Park2-depleted β-cells also exhibited increased mitochondrial fragmentation and ROS production and decreased mitochondrial membrane potential. Both population-based statistical evaluation and experimental evidence demonstrated a fundamental role of the PARK2 gene in the maintenance of β-cell function. © 2013 Elsevier Ireland Ltd.
Olson M.A.,USAMRIID |
Lee M.S.,USAMRIID |
Lee M.S.,Center for Genome Science |
Lee M.S.,U.S. Army
Proteins: Structure, Function and Bioinformatics | Year: 2013
In this study, the application of temperature-based replica-exchange (T-ReX) simulations for structure refinement of decoys taken from the I-TASSER dataset was examined. A set of eight nonredundant proteins was investigated using self-guided Langevin dynamics (SGLD) with a generalized Born implicit solvent model to sample conformational space. For two of the protein test cases, a comparison of the SGLD/T-ReX method with that of a hybrid explicit/implicit solvent molecular dynamics T-ReX simulation model is provided. Additionally, the effect of side-chain placement among the starting decoy structures, using alternative rotamer conformations taken from the SCWRL4 modeling program, was investigated. The simulation results showed that, despite having near-native backbone conformations among the starting decoys, the determinant of their refinement is side-chain packing to a level that satisfies a minimum threshold of native contacts to allow efficient excursions toward the downhill refinement regime on the energy landscape. By repacking using SCWRL4 and by applying the RWplus statistical potential for structure identification, the SGLD/T-ReX simulations achieved refinement to an average of 38% increase in the number of native contacts relative to the original I-TASSER decoy sets and a 25% reduction in values of Cα root-mean-square deviation. The hybrid model succeeded in obtaining a sharper funnel to low-energy states for a modeled target than the implicit solvent SGLD model; yet, structure identification remained roughly the same. Without meeting a threshold of near-native packing of side chains, the T-ReX simulations degrade the accuracy of the decoys, and subsequently, refinement becomes tantamount to the protein folding problem. Proteins 2013. 2012 Published by Wiley Periodicals, Inc. Published 2012 Wiley Periodicals, Inc..
Song Y.-M.,Sungkyunkwan University |
Lee D.-H.,Seoul National University |
Lee M.K.,Seoul National University |
Lee K.,Inje University |
And 5 more authors.
Twin Research and Human Genetics | Year: 2010
Determining valid zygosity is a basic and important requirement in a twin study, because misdiagnosing zygosity leads to biased results. The Healthy Twin Study has collected data from adult like-sex twins and their families since 2005. In the study, a questionnaire to determine zygosity was developed comprising four questions; one concerning the degree of resemblance, and three concerning the degree of confusion by the resemblance. Among 2,761 individuals (624 twin pairs) of twin and their families, 406 pairs of twins (mean age 38.3, 63.5% women) with both questionnaire and genotype information were selected to examine the validity of the zygosity questionnaire using 16 short tandem repeat markers. We first determined individual zygosity including undetermined category, and then decided the zygosity of a twin pair using a decision tree. Sensitivity of questionnaire diagnosis was 98.8% for monozygotic (MZ) and 88.9% for dizygotic (DZ) twins, and positive predictive value was 97.2% for MZ and 95.0% for DZ. When we compared correctly and wrongly diagnosed twin pairs, misdiagnosed DZ twins (nine pairs) showed striking similarity in stature or obesity even exceeding that of true MZ twins. Our finding suggests that a parsimonious questionnaire method of diagnosing the zygosity will be useful, and adding physical or physiological measurements to a questionnaire of zygosity diagnosis will either confound the correct diagnosis or reduce the efficiency of the study compared with using questionnaire alone or with introducing genotyping.
Cho N.H.,Ajou University |
Choi H.S.,Seoul National University |
Kim K.W.,Seoul National University |
Kim H.-L.,Center for Genome Science |
And 7 more authors.
Clinical Endocrinology | Year: 2010
Objective Several population-based studies in iodine-deficient areas have shown an association between smoking and thyroid function. There are no population-based studies about the effects of smoking in iodine-sufficient areas. We examined the effect of smoking on thyroid function and the association with iodine intake in Korea, an area with sufficient iodine intake, much more than recommended by the World Health Organization (WHO). Design Of 5018 subjects in a population-based cohort, we included 3399 who had no history of thyroid disease were not taking thyroid medication and whose blood samples were available for measurement of thyroid function. Measurements Thyroid function test, questionnaire about smoking status and dietary intake. Results Of 3399 subjects, 397(11·7%) had subclinical hypothyroidism (SCH). Female sex was an independent risk factor for SCH. Multivariate analysis in female subjects showed the following were independent risk factors for SCH: older age, positive antithyroid peroxidase (anti-TPO) antibody status and iodine intake, whereas current smoking was inversely related with SCH. However, in male subjects, only age showed a weak association with SCH. When the interaction between smoking and other risk factors was analysed, smoking showed no association with anti-TPO antibody status, whereas it showed a significant negative interaction with iodine intake (odds ratio, 0·930; 95% CI, 0·869-0·996; P = 0·037). Furthermore, the risk for SCH was observed only in the never-smoker group; however, it was abolished in current- and ex-smoker groups. Conclusion Cigarette smoking was associated with a lower prevalence of SCH in a negative interaction with iodine intake. © 2010 Blackwell Publishing Ltd.
Franceschini N.,University of North Carolina at Chapel Hill |
Carty C.,Fred Hutchinson Cancer Research Center |
Buzkova P.,University of Washington |
Reiner A.P.,University of Washington |
And 21 more authors.
Circulation: Cardiovascular Genetics | Year: 2011
Background-Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts. Methods and Results-The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7×10 -41), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7×10 -6), MTHFD1L (rs6922269, P=5.1×10 -10), APOE (rs429358; P=2.7×10 -18), ZNF627 (rs4804611; P=5.0×10 -8), CXCL12 (rs501120; P=1.4×10 -6) and LPL (rs268; P=2.7×10 -17). The 9p21 region showed significant between- study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities. Conclusions-Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations. © 2011 American Heart Association, Inc.