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11.
Erin N. Smith Wei Chen Mika K?h?nen Johannes Kettunen Terho Lehtim?ki Leena Peltonen Olli T. Raitakari Rany M. Salem Nicholas J. Schork Marian Shaw Sathanur R. Srinivasan Eric J. Topol Jorma S. Viikari Gerald S. Berenson Sarah S. Murray 《PLoS genetics》2010,6(9)
Cardiovascular disease (CVD) is the leading cause of death worldwide. Recent genome-wide association (GWA) studies have pinpointed many loci associated with CVD risk factors in adults. It is unclear, however, if these loci predict trait levels at all ages, if they are associated with how a trait develops over time, or if they could be used to screen individuals who are pre-symptomatic to provide the opportunity for preventive measures before disease onset. We completed a genome-wide association study on participants in the longitudinal Bogalusa Heart Study (BHS) and have characterized the association between genetic factors and the development of CVD risk factors from childhood to adulthood. We report 7 genome-wide significant associations involving CVD risk factors, two of which have been previously reported. Top regions were tested for replication in the Young Finns Study (YF) and two associations strongly replicated: rs247616 in CETP with HDL levels (combined P = 9.7×10−24), and rs445925 at APOE with LDL levels (combined P = 8.7×10−19). We show that SNPs previously identified in adult cross-sectional studies tend to show age-independent effects in the BHS with effect sizes consistent with previous reports. Previously identified variants were associated with adult trait levels above and beyond those seen in childhood; however, variants with time-dependent effects were also promising predictors. This is the first GWA study to evaluate the role of common genetic variants in the development of CVD risk factors in children as they advance through adulthood and highlights the utility of using longitudinal studies to identify genetic predictors of adult traits in children. 相似文献
12.
Anu Loukola Jadwiga Buchwald Richa Gupta Teemu Palviainen Jenni H?llfors Emmi Tikkanen Tellervo Korhonen Miina Ollikainen Antti-Pekka Sarin Samuli Ripatti Terho Lehtim?ki Olli Raitakari Veikko Salomaa Richard J. Rose Rachel F. Tyndale Jaakko Kaprio 《PLoS genetics》2015,11(9)
Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on the rate of nicotine metabolism. Our objective was to use nicotine metabolite ratio (NMR), an established biomarker of nicotine metabolism rate, in a genome-wide association study (GWAS) to identify novel genetic variants influencing nicotine metabolism. A heritability estimate of 0.81 (95% CI 0.70–0.88) was obtained for NMR using monozygotic and dizygotic twins of the FinnTwin cohort. We performed a GWAS in cotinine-verified current smokers of three Finnish cohorts (FinnTwin, Young Finns Study, FINRISK2007), followed by a meta-analysis of 1518 subjects, and annotated the genome-wide significant SNPs with methylation quantitative loci (meQTL) analyses. We detected association on 19q13 with 719 SNPs exceeding genome-wide significance within a 4.2 Mb region. The strongest evidence for association emerged for CYP2A6 (min p = 5.77E-86, in intron 4), the main metabolic enzyme for nicotine. Other interesting genes with genome-wide significant signals included CYP2B6, CYP2A7, EGLN2, and NUMBL. Conditional analyses revealed three independent signals on 19q13, all located within or in the immediate vicinity of CYP2A6. A genetic risk score constructed using the independent signals showed association with smoking quantity (p = 0.0019) in two independent Finnish samples. Our meQTL results showed that methylation values of 16 CpG sites within the region are affected by genotypes of the genome-wide significant SNPs, and according to causal inference test, for some of the SNPs the effect on NMR is mediated through methylation. To our knowledge, this is the first GWAS on NMR. Our results enclose three independent novel signals on 19q13.2. The detected CYP2A6 variants explain a strikingly large fraction of variance (up to 31%) in NMR in these study samples. Further, we provide evidence for plausible epigenetic mechanisms influencing NMR. 相似文献
13.
Ohlsson C Wallaschofski H Lunetta KL Stolk L Perry JR Koster A Petersen AK Eriksson J Lehtimäki T Huhtaniemi IT Hammond GL Maggio M Coviello AD;EMAS Study Group Ferrucci L Heier M Hofman A Holliday KL Jansson JO Kähönen M Karasik D Karlsson MK Kiel DP Liu Y Ljunggren O Lorentzon M Lyytikäinen LP Meitinger T Mellström D Melzer D Miljkovic I Nauck M Nilsson M Penninx B Pye SR Vasan RS Reincke M Rivadeneira F Tajar A Teumer A Uitterlinden AG Ulloor J Viikari J Völker U Völzke H Wichmann HE Wu TS 《PLoS genetics》2011,7(10):e1002313
Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone''s high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10−41 and rs6258, p = 2.3×10−22). Subjects with ≥3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10−16). The rs6258 polymorphism in exon 4 of SHBG affected SHBG''s affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation. 相似文献
14.
Jylhävä J Lyytikäinen LP Kähönen M Hutri-Kähönen N Kettunen J Viikari J Raitakari OT Lehtimäki T Hurme M 《PloS one》2012,7(4):e35426
Introduction
Circulating cell-free DNA (cf-DNA) is a useful indicator of cell death, and it can also be used to predict outcomes in various clinical disorders. Several innate immune mechanisms are known to be involved in eliminating DNA and chromatin-related material as part of the inhibition of potentially harmful autoimmune responses. However, the exact molecular mechanism underlying the clearance of circulating cf-DNA is currently unclear.Methods
To examine the mechanisms controlling serum levels of cf-DNA, we carried out a genome-wide association analysis (GWA) in a cohort of young adults (aged 24–39 years; n = 1841; 1018 women and 823 men) participating in the Cardiovascular Risk in Young Finns Study. Genotyping was performed with a custom-built Illumina Human 670 k BeadChip. The Quant-iTTM high sensitivity DNA assay was used to measure cf-DNA directly from serum.Results
The results revealed that 110 single nucleotide polymorphisms (SNPs) were associated with serum cf-DNA with genome-wide significance (p<5×10−8). All of these significant SNPs were localised to chromosome 2q37, near the UDP-glucuronosyltransferase 1 (UGT1) family locus, and the most significant SNPs localised within the UGT1 polypeptide A1 (UGT1A1) gene region.Conclusion
The UGT1A1 enzyme catalyses the detoxification of several drugs and the turnover of many xenobiotic and endogenous compounds by glucuronidating its substrates. These data indicate that UGT1A1-associated processes are also involved in the regulation of serum cf-DNA concentrations. 相似文献15.
Levula M Oksala N Airla N Zeitlin R Salenius JP Järvinen O Venermo M Partio T Saarinen J Somppi T Suominen V Virkkunen J Hautalahti J Laaksonen R Kähönen M Mennander A Kytömäki L Soini JT Parkkinen J Pelto-Huikko M Lehtimäki T 《PloS one》2012,7(4):e33787
Background
Atherosclerosis is a complex disease with hundreds of genes influencing its progression. In addition, the phenotype of the disease varies significantly depending on the arterial bed.Methodology/Principal Findings
We characterized the genes generally involved in human advanced atherosclerotic (AHA type V–VI) plaques in carotid and femoral arteries as well as aortas from 24 subjects of Tampere Vascular study and compared the results to non-atherosclerotic internal thoracic arteries (n=6) using genome-wide expression array and QRT-PCR. In addition we determined genes that were typical for each arterial plaque studied. To gain a comprehensive insight into the pathologic processes in the plaques we also analyzed pathways and gene sets dysregulated in this disease using gene set enrichment analysis (GSEA). According to the selection criteria used (>3.0 fold change and p-value <0.05), 235 genes were up-regulated and 68 genes down-regulated in the carotid plaques, 242 genes up-regulated and 116 down-regulated in the femoral plaques and 256 genes up-regulated and 49 genes down-regulated in the aortic plaques. Nine genes were found to be specifically induced predominantly in aortic plaques, e.g., lactoferrin, and three genes in femoral plaques, e.g., chondroadherin, whereas no gene was found to be specific for carotid plaques. In pathway analysis, a total of 28 pathways or gene sets were found to be significantly dysregulated in atherosclerotic plaques (false discovery rate [FDR] <0.25).Conclusions
This study describes comprehensively the gene expression changes that generally prevail in human atherosclerotic plaques. In addition, site specific genes induced only in femoral or aortic plaques were found, reflecting that atherosclerotic process has unique features in different vascular beds. 相似文献16.
Gaál EI Salo P Kristiansson K Rehnström K Kettunen J Sarin AP Niemelä M Jula A Raitakari OT Lehtimäki T Eriksson JG Widen E Günel M Kurki M von und Zu Fraunberg M Jääskeläinen JE Hernesniemi J Järvelin MR Pouta A;International Consortium for Blood Pressure Genome-Wide Association Studies Newton-Cheh C Salomaa V Palotie A Perola M 《PLoS genetics》2012,8(3):e1002563
Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n(FIN) = 11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n = 19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p(FIN) = 3.01E-05, p(ICBP-GWAS) = 0.0007, p(ALL) = 8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance. 相似文献
17.
Novel method for cell debris removal in the flow cytometric cell cycle analysis using carboxy-fluorescein diacetate succinimidyl ester. 总被引:1,自引:0,他引:1
BACKGROUND: Cell cycle analysis with flow cytometry using propidium iodide (PI) can be difficult in some cases because of the cell debris. Here, we introduce debris removal using intranuclear protein staining (DRIPS), a novel method for separating intact nuclei and cell debris to different populations using carboxy-fluorescein diacetate succinimidyl ester (CFSE). METHODS: To study the apoptosis-sensitivity, chicken DT40 B cell lymphoma cell line was gamma irradiated. After the irradiation, the cells were incubated up to 8 h and the stages of the cell cycle were followed with flow cytometry. RESULTS: CFSE staining, done simultaneously with PI, stained the cell debris brighter than intact nuclei and could be excluded from the histogram with a simple gating procedure. The method is reliable and reproducible and can be executed within 15 min. CONCLUSIONS: DRIPS-method greatly enhances the analysis of difficult cell cycle samples. 相似文献
18.
Although clutch size variation has been a key target for studies of avian life history theory, most empirical work has only focused on the ability of parents to raise their altricial young. In this study, we test the hypothesis that costs incurred during incubation may be an additional factor constraining clutch size in altricial birds. In the pied flycatcher (Ficedula hypoleuca), we manipulated the incubation effort of the female by enlarging and reducing clutch sizes. To manipulate incubation effort only, the original clutch sizes were restored shortly after hatching. We found that fledging success was lower among broods whose clutches were enlarged during incubation. There was, however, no effect of manipulation on female body condition or on their ability to mount a humoral immune response to diphtheria or tetanus toxoid during the incubation or nestling provisioning period. Instead, we found that the original clutch size was related to the immune response so that females with seven eggs had significantly lower primary antibody responses against tetanus compared to those with six eggs. Our results suggest that incubating females are not willing to jeopardise their own condition and immune function, but instead pay the costs of incubating a larger clutch by lower offspring production. The results support the view that costs of producing and incubating eggs may be substantial and hence that these costs are likely to contribute to shaping the optimal clutch size in altricial birds. 相似文献
19.
20.
Lyzel S. Elias-Sonnenschein Seppo Helisalmi Teemu Natunen Anette Hall Teemu Paajanen Sanna-Kaisa Herukka Marjo Laitinen Anne M. Remes Anne M. Koivisto Kari M. Mattila Terho Lehtim?ki Frans R. J. Verhey Pieter Jelle Visser Hilkka Soininen Mikko Hiltunen 《PloS one》2013,8(4)