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31.
van Vliet-Ostaptchouk JV van Haeften TW Landman GW Reiling E Kleefstra N Bilo HJ Klungel OH de Boer A van Diemen CC Wijmenga C Boezen HM Dekker JM van 't Riet E Nijpels G Welschen LM Zavrelova H Bruin EJ Elbers CC Bauer F Onland-Moret NC van der Schouw YT Grobbee DE Spijkerman AM van der A DL Simonis-Bik AM Eekhoff EM Diamant M Kramer MH Boomsma DI de Geus EJ Willemsen G Slagboom PE Hofker MH 't Hart LM 《PloS one》2012,7(3):e32148
Background
Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients.Methodology
The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp.Principal Findings
We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07–1.35, p = 0.002). The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications.Conclusions
Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism. 相似文献32.
Shiffman D Trompet S Louie JZ Rowland CM Catanese JJ Iakoubova OA Kirchgessner TG Westendorp RG de Craen AJ Slagboom PE Buckley BM Stott DJ Sattar N Devlin JJ Packard CJ Ford I Sacks FM Jukema JW 《PloS one》2012,7(5):e38240
Statin therapy reduces the risk of coronary heart disease (CHD), however, the person-to-person variability in response to statin therapy is not well understood. We have investigated the effect of genetic variation on the reduction of CHD events by pravastatin. First, we conducted a genome-wide association study of 682 CHD cases from the Cholesterol and Recurrent Events (CARE) trial and 383 CHD cases from the West of Scotland Coronary Prevention Study (WOSCOPS), two randomized, placebo-controlled studies of pravastatin. In a combined case-only analysis, 79 single nucleotide polymorphisms (SNPs) were associated with differential CHD event reduction by pravastatin according to genotype (P<0.0001), and these SNPs were analyzed in a second stage that included cases as well as non-cases from CARE and WOSCOPS and patients from the PROspective Study of Pravastatin in the Elderly at Risk/PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease (PROSPER/PHASE), a randomized placebo controlled study of pravastatin in the elderly. We found that one of these SNPs (rs13279522) was associated with differential CHD event reduction by pravastatin therapy in all 3 studies: P = 0.002 in CARE, P = 0.01 in WOSCOPS, P = 0.002 in PROSPER/PHASE. In a combined analysis of CARE, WOSCOPS, and PROSPER/PHASE, the hazard ratio for CHD when comparing pravastatin with placebo decreased by a factor of 0.63 (95% CI: 0.52 to 0.75) for each extra copy of the minor allele (P = 4.8 × 10(-7)). This SNP is located in DnaJ homolog subfamily C member 5B (DNAJC5B) and merits investigation in additional randomized studies of pravastatin and other statins. 相似文献
33.
Shuttling between species for pathways of lifespan regulation: A central role for the vitellogenin gene family? 总被引:3,自引:0,他引:3
Brandt BW Zwaan BJ Beekman M Westendorp RG Slagboom PE 《BioEssays : news and reviews in molecular, cellular and developmental biology》2005,27(3):339-346
Studies to find genes that affect maximum lifespan aim at identifying important determinants of ageing that may be universal across species. Model organisms show insulin signalling can play an important role in ageing. In view of insulin resistance, such loci can also be important in human ageing and health. The study of long-lived humans and their children points to the relevance of lipoprotein profiles and particle size for longevity. If ageing pathways are conserved, then the genes mediating such pathways may also be conserved. Cross-species sequence comparisons of potential longevity loci may reveal whether the pathways that they represent are central themes in lifespan regulation. Using bioinformatic tools, we performed a sequence comparison of the genes involved in lipid metabolism identified in humans as potential longevity loci. This analysis revealed that lipid storage and transport may be a common theme related to longevity in humans, honeybees and nematodes. Here, the vitellogenin family emerges as a potential key connection between lipid metabolism and the insulin/IGF-1 signalling pathway. 相似文献
34.
Reduced insulin/IGF-1 signalling and human longevity 总被引:6,自引:0,他引:6
van Heemst D Beekman M Mooijaart SP Heijmans BT Brandt BW Zwaan BJ Slagboom PE Westendorp RG 《Aging cell》2005,4(2):79-85
Evidence is accumulating that aging is hormonally regulated by an evolutionarily conserved insulin/IGF-1 signalling (IIS) pathway. Mutations in IIS components affect lifespan in Caenorhabditis elegans, Drosophila melanogaster and mice. Most long-lived IIS mutants also show increased resistance to oxidative stress. In D. melanogaster and mice, the long-lived phenotype of several IIS mutants is restricted to females. Here, we analysed the relationship between IIS signalling, body height and longevity in humans in a prospective follow-up study. Based on the expected effects (increased or decreased signalling) of the selected variants in IIS pathway components (GHRHR, GH1, IGF1, INS, IRS1), we calculated composite IIS scores to estimate IIS pathway activity. In addition, we analysed the relative impact on lifespan and body size of the separate variants in multivariate models. In women, lower IIS scores are significantly associated with lower body height and improved old age survival. Multivariate analyses showed that these results were most pronounced for the GH1 SNP, IGF1 CA repeat and IRS1 SNP. In females, for variant allele carriers of the GH1 SNP, body height was 2 cm lower (P = 0.007) and mortality 0.80-fold reduced (P = 0.019) when compared with wild-type allele carriers. Thus, in females, genetic variation causing reduced IIS activation is beneficial for old age survival. This effect was stronger for the GH1 SNP than for variation in the conserved IIS genes that were found to affect longevity in model organisms. 相似文献
35.
A whole-genome scan for 24-hour respiration rate: a major locus at 10q26 influences respiration during sleep
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de Geus EJ Posthuma D Kupper N van den Berg M Willemsen G Beem AL Slagboom PE Boomsma DI 《American journal of human genetics》2005,76(1):100-111
Identification of genes causing variation in daytime and nighttime respiration rates could advance our understanding of the basic molecular processes of human respiratory rhythmogenesis. This could also serve an important clinical purpose, because dysfunction of such processes has been identified as critically important in sleep disorders. We performed a sib-pair-based linkage analysis on ambulatory respiration rate, using the data from 270 sibling pairs who were genotyped at 374 markers on the autosomes, with an average distance of 9.65 cM. Uni- and multivariate variance-components-based multipoint linkage analyses were performed for respiration rate during three daytime periods (morning, afternoon, and evening) and during nighttime sleep. Evidence of linkage was found at chromosomal locations 3q27, 7p22, 10q26, and 22q12. The strongest evidence of linkage was found for respiration rate during sleep, with LOD scores of 2.36 at 3q27, 3.86 at 10q26, and 1.59 at 22q12. In a simultaneous analysis of these three loci, >50% of the variance in sleep respiration rate could be attributed to a quantitative-trait loci near marker D10S1248 at 10q. Genes in this area (GFRA1, ADORA2L, FGR2, EMX2, and HMX2) can be considered promising positional candidates for genetic association studies of respiratory control during sleep. 相似文献
36.
Age‐dependent expression of DNMT1 and DNMT3B in PBMCs from a large European population enrolled in the MARK‐AGE study
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Fabio Ciccarone Marco Malavolta Roberta Calabrese Tiziana Guastafierro Maria Giulia Bacalini Anna Reale Claudio Franceschi Miriam Capri Antti Hervonen Mikko Hurme Beatrix Grubeck‐Loebenstein Bernhard Koller Jürgen Bernhardt Christiane Schn P. Eline Slagboom Olivier Toussaint Ewa Sikora Efstathios S. Gonos Nicolle Breusing Tilman Grune Eugne Jansen Martijn Doll María Moreno‐Villanueva Thilo Sindlinger Alexander Bürkle Michele Zampieri Paola Caiafa 《Aging cell》2016,15(4):755-765
37.
C. M. Middeldorp M. C. T. Slof‐Op ‘t Landt S. E. Medland C. E. M. van Beijsterveldt M. Bartels G. Willemsen J.‐J. Hottenga E. J. C. de Geus H. E. D. Suchiman C. V. Dolan M. C. Neale P. E. Slagboom D. I. Boomsma 《Genes, Brain & Behavior》2010,9(7):808-816
There are two major hypotheses regarding the etiology of anxiety and depression: the mono‐amine hypothesis and the hypothesis of an abnormal stress response acting partly via reduced neurogenesis. Association studies have focused on genes involved in these processes, but with inconclusive results. This study investigated the effect of 45 single nucleotide polymorphisms (SNPs) in genes encoding for serotonin receptors 1A, 1D, 2A, catechol‐O‐methyltransferase (COMT), tryptophane hydroxylase type 2 (TPH2), brain derived neurotrophic factor (BDNF), PlexinA2 and regulators of G‐protein‐coupled signaling (RGS) 2, 4, 16. Anxious depression (A/D) symptoms were assessed five times in 11 years in over 11 000 adults with 1504 subjects genotyped and at age 7, 10, 12 and during adolescence in over 20 000 twins with 1078 subjects genotyped. In both cohorts, a longitudinal model with one latent factor loading on all A/D measures over time was analysed. The genetic association effect modeled at the level of this latent factor was 60% and 70% heritable in the children and adults, respectively, and explained around 50% of the total phenotypic variance. Power analyses showed that the samples contained 80% power to detect an effect explaining between 1.4% and 3.6% of the variance. However, no SNP showed a consistent effect on A/D. To conclude, this longitudinal study in children and adults found no association of SNPs in the serotonergic system or core regulators of neurogenesis with A/D. Overall, there has been no convincing evidence, so far, for a role of genetic variation in these pathways in the development of anxiety and depression. 相似文献
38.
Marjon Stijntjes Anton J. M. de Craen Diana van Heemst Carel G. M. Meskers Mark A. van Buchem Rudi G. J. Westendorp P. Eline Slagboom Andrea B. Maier 《PloS one》2013,8(3)
Background
Decline in cognitive performance is a highly prevalent health condition in elderly. We studied whether offspring of nonagenarian siblings with a familial history of longevity, perform better on cognitive tests compared to their partners as controls. This is relevant since it could provide insights into determinants underlying decline in cognitive performance.Methods
Cross-sectional analysis within the longitudinal cohort of the Leiden Longevity Study consisting of middle-aged offspring of nonagenarian siblings together with their partners (n = 500, mean age (SD) 66.3 (6.1) and 65.7 (7.2) years, respectively) as controls. Memory function, attention and processing speed were tested using the 15-Picture Learning Test, Stroop test and Digit Symbol Substitution Test. Data were analyzed with regression adjusted for age, gender, years of education and additionally for diabetes mellitus, cardiovascular diseases, alcohol use, smoking, inflammatory markers and apolipoprotein E genotype. Robust standard errors were used to account for familial relationships among the offspring.Results
Cognitive performance was worse at higher calendar age (p<0.001, all except Stroop test part 1). The offspring performed better compared to their partners on trial 3 (p = 0.005), the immediate (p = 0.016) and delayed (p = 0.004) recall of the 15-Picture Learning Test as well as on the interference and combined interference score of the Stroop test (p = 0.014 and p = 0.036, respectively) in the fully adjusted model. The difference between offspring and partners was estimated to be more than three years according to the observed difference in calendar age.Conclusions
Offspring of nonagenarian siblings with a familial history of longevity have better cognitive performance compared to the group of their partners of comparable age. This effect is independent of age-related diseases and known possible confounders. Possible explanations might be differences in subclinical vascular pathology between both groups. 相似文献39.