| 101. |
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| 102. |
- Parsa, Afshin, et al.
(author)
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Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function
- 2013
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In: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 24:12, s. 2105-2117
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Journal article (peer-reviewed)abstract
- Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
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| 103. |
- Pattaro, Cristian, et al.
(author)
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Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function
- 2012
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:3, s. e1002584-
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Journal article (peer-reviewed)abstract
- Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genomewide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
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| 104. |
- Prokopenko, Inga, et al.
(author)
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Variants in MTNR1B influence fasting glucose levels
- 2009
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 77-81
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Journal article (peer-reviewed)abstract
- To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.
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| 105. |
- Saleheen, Danish, et al.
(author)
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Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions
- 2017
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In: Circulation. - 0009-7322 .- 1524-4539. ; 135:24, s. 2336-2353
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Journal article (peer-reviewed)abstract
- BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk.METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of < 1.0x10-3 (Bonferroni correction for 50 tests).RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P= 1.3x10(-16)) in comparison with 5% in ever-smokers (P= 2.5x10-4), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value= 8.7x10-5). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7.CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.
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| 106. |
- Smith, Gustav, et al.
(author)
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Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure
- 2016
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 12:5
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Journal article (peer-reviewed)abstract
- Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.
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| 107. |
- Teo, K., et al.
(author)
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Prevalence of a healthy lifestyle among individuals with cardiovascular disease in high-, middle- and low-income countries: The Prospective Urban Rural Epidemiology (PURE) study
- 2013
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In: Journal of the American Medical Association. - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 309:15, s. 1613-21
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Journal article (peer-reviewed)abstract
- IMPORTANCE: Little is known about adoption of healthy lifestyle behaviors among individuals with a coronary heart disease (CHD) or stroke event in communities across a range of countries worldwide. OBJECTIVE: To examine the prevalence of avoidance or cessation of smoking, eating a healthy diet, and undertaking regular physical activities by individuals with a CHD or stroke event. DESIGN, SETTING, AND PARTICIPANTS: Prospective Urban Rural Epidemiology (PURE) was a large, prospective cohort study that used an epidemiological survey of 153,996 adults, aged 35 to 70 years, from 628 urban and rural communities in 3 high-income countries (HIC), 7 upper-middle-income countries (UMIC), 3 lower-middle-income countries (LMIC), and 4 low-income countries (LIC), who were enrolled between January 2003 and December 2009. MAIN OUTCOME MEASURES: Smoking status (current, former, never), level of exercise (low, <600 metabolic equivalent task [MET]-min/wk; moderate, 600-3000 MET-min/wk; high, >3000 MET-min/wk), and diet (classified by the Food Frequency Questionnaire and defined using the Alternative Healthy Eating Index). RESULTS: Among 7519 individuals with self-reported CHD (past event: median, 5.0 [interquartile range {IQR}, 2.0-10.0] years ago) or stroke (past event: median, 4.0 [IQR, 2.0-8.0] years ago), 18.5% (95% CI, 17.6%-19.4%) continued to smoke; only 35.1% (95% CI, 29.6%-41.0%) undertook high levels of work- or leisure-related physical activity, and 39.0% (95% CI, 30.0%-48.7%) had healthy diets; 14.3% (95% CI, 11.7%-17.3%) did not undertake any of the 3 healthy lifestyle behaviors and 4.3% (95% CI, 3.1%-5.8%) had all 3. Overall, 52.5% (95% CI, 50.7%-54.3%) quit smoking (by income country classification: 74.9% [95% CI, 71.1%-78.6%] in HIC; 56.5% [95% CI, 53.4%-58.6%] in UMIC; 42.6% [95% CI, 39.6%-45.6%] in LMIC; and 38.1% [95% CI, 33.1%-43.2%] in LIC). Levels of physical activity increased with increasing country income but this trend was not statistically significant. The lowest prevalence of eating healthy diets was in LIC (25.8%; 95% CI, 13.0%-44.8%) compared with LMIC (43.2%; 95% CI, 30.0%-57.4%), UMIC (45.1%, 95% CI, 30.9%-60.1%), and HIC (43.4%, 95% CI, 21.0%-68.7%). CONCLUSION AND RELEVANCE: Among a sample of patients with a CHD or stroke event from countries with varying income levels, the prevalence of healthy lifestyle behaviors was low, with even lower levels in poorer countries.
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| 108. |
- Waschitz, Y., et al.
(author)
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Independent isotopic fission yields of Cf-252 spontaneous fission via mass measurements at the FRS Ion Catcher
- 2023
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In: 15th International Conference on Nuclear Data for Science and Technology, ND2022. - : EDP Sciences.
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Conference paper (peer-reviewed)abstract
- We present first preliminary results of a novel method for measuring independent isotopic fission yields (IIFYs) of spontaneous fission (SF) via direct mass measurements, at the FRS Ion Catcher (FRS -IC) at GSI. Fission products were generated from a Cf-252 source installed in a cryogenic stopping cell, and were identified and counted with the multiple-reflection time-of-flight mass spectrometer (MR-TOR-MS) of the FRS-IC, utilizing well-established measurement and data analysis methods. The MR-TOR-MS resolves isobars unambiguously, even with limited statistics, and its non-scanning nature ensures minimal relative systematic uncertainties amongst fission products. The analysis for extracting IIFYs includes isotope-dependent efficiency corrections for all components of the FRS -IC. In particular, we applied a self-consistent technique that takes into account the element-dependent survival efficiencies in the CSC, due to chemical reactions with the buffer gas. Our IIFY results, which cover several tens of fission products in the less -accessible high-mass peak (Z = 56 to 63) down to fission yields at the level of 10(-5), are generally similar to those of the nuclear database ENDF/B-VII.O. Nevertheless, they reveal some structures that are not observed in the database smooth trends. These are the first results of a planned campaign to investigate IIFY distributions of spontaneous fission at the FRS-IC. Upcoming experiments will extend our results to wider Z and N ranges, lower fission yields, and other spontaneously-fissioning actinides.
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| 109. |
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| 110. |
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