| 1. |
- Archambault, Alexi N., et al.
(författare)
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Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer
- 2020
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1274-1286.e12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 x 10(-5)). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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| 2. |
- Dorigo, Wouter, et al.
(författare)
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The International Soil Moisture Network : Serving Earth system science for over a decade
- 2021
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Ingår i: Hydrology and Earth System Sciences. - : Copernicus GmbH. - 1027-5606 .- 1607-7938. ; 25:11, s. 5749-5804
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Forskningsöversikt (refereegranskat)abstract
- In 2009, the International Soil Moisture Network (ISMN) was initiated as a community effort, funded by the European Space Agency, to serve as a centralised data hosting facility for globally available in situ soil moisture measurements . The ISMN brings together in situ soil moisture measurements collected and freely shared by a multitude of organisations, harmonises them in terms of units and sampling rates, applies advanced quality control, and stores them in a database. Users can freely retrieve the data from this database through an online web portal (https://ismn.earth/en/, last access: 28 October 2021). Meanwhile, the ISMN has evolved into the primary in situ soil moisture reference database worldwide, as evidenced by more than 3000 active users and over 1000 scientific publications referencing the data sets provided by the network. As of July 2021, the ISMN now contains the data of 71 networks and 2842 stations located all over the globe, with a time period spanning from 1952 to the present. The number of networks and stations covered by the ISMN is still growing, and approximately 70 % of the data sets contained in the database continue to be updated on a regular or irregular basis. The main scope of this paper is to inform readers about the evolution of the ISMN over the past decade, including a description of network and data set updates and quality control procedures. A comprehensive review of the existing literature making use of ISMN data is also provided in order to identify current limitations in functionality and data usage and to shape priorities for the next decade of operations of this unique community-based data repository.
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| 3. |
- Guo, Xingyi, et al.
(författare)
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Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects
- 2020
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Ingår i: Gastroenterology. - : Elsevier. - 0016-5085 .- 1528-0012. ; 160:4, s. 1164-1178
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.Methods: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.Results: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.Conclusions: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
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| 4. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 5. |
- Huyghe, Jeroen R, et al.
(författare)
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Genetic architectures of proximal and distal colorectal cancer are partly distinct
- 2021
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Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:7, s. 1325-1334
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Tidskriftsartikel (refereegranskat)abstract
- Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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| 6. |
- Kacerovsky-Bielesz, Gertrud, et al.
(författare)
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A Single Nucleotide Polymorphism Associates With the Response of Muscle ATP Synthesis to Long-Term Exercise Training in Relatives of Type 2 Diabetic Humans
- 2012
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 35:2, s. 350-357
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Myocellular ATP synthesis (fATP) associates with insulin sensitivity in first-degree relatives of subjects with type 2 diabetes. Short-term endurance training can modify their fATP and insulin sensitivity. This study examines the effects of moderate long-term exercise using endurance or resistance training in this cohort. RESEARCH DESIGN AND METHODS-A randomized, parallel-group trial tested 16 glucose-tolerant nonobese relatives (8 subjects in the endurance training group and 8 subjects in the resistance training group) before and after 26 weeks of endurance or resistance training. Exercise performance was assessed from power output and oxygen uptake (VO2) during incremental tests and from maximal torque of knee flexors (MaxT(flex)) and extensors (MaxT(ext)) using isokinetic dynamometry. fATP and ectopic lipids were measured with H-1/P-31 magnetic resonance spectroscopy. RESULTS Endurance training increased power output and VO2 by 44 and 30%, respectively (both P < 0.001), whereas resistance training increased MaxT(ext) and MaxT(flex) by 23 and 40%, respectively (both P < 0.001). Across all groups, insulin sensitivity (382 +/- 90 vs. 389 +/- 40 mL.min.m(-2)) and ectopic lipid contents were comparable after exercise training. However, 8 of 16 relatives had 26% greater fATP, increasing from 9.5 +/- 2.3 to 11.9 +/- 2.4 mu mol.mL(-1).m(-1) (P < 0.05). Six of eight responders were carriers of the G/G single nucleotide polymorphism rs540467 of the NDUFB6 gene (P = 0.019), which encodes a subunit of mitochondrial complex I. CONCLUSIONS-Moderate exercise training for 6 months does not necessarily improve insulin sensitivity but may increase ATP synthase flux. Genetic predisposition can modify the individual response of the ATP synthase flux independently of insulin sensitivity.
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| 7. |
- Kacerovsky-Bielesz, Gertrud, et al.
(författare)
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Short-Term Exercise Training Does Not Stimulate Skeletal Muscle ATP Synthesis in Relatives of Humans With Type 2 Diabetes
- 2009
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 58:6, s. 1333-1341
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-We tested the hypothesis that short-term exercise training improves hereditary insulin resistance by stimulating ATP synthesis and investigated associations With gene polymorphisms. RESEARCH DESIGN AND METHODS-We studied 24 nono-bese first-degree relatives of type 2 diabetic patients and 12 control subjects at rest, and 48 h after three bouts of exercise. In addition to measurements of oxygen uptake and insulin sensitivity (oral glucose tolerance test), ectopic lipids and mitochondrial ATP synthesis were assessed using H-1 and P-31 magnetic resonance spectroscopy, respectively. They were genotyped for polymorphisms in genes regulating mitochondrial function, PPARGC1A (rs8192678) and NDUFB6 (rs540467). RESULTS-Relatives had slightly lower (P = 0.012) insulin sensitivity than control subjects. In control subjects, ATP synthase flux rose by 18% (P = 0.0001), being 23% higher (P = 0.002) than that in relatives after exercise training. Relatives responding to exercise training with increased ATP synthesis (+19%, P = 0.009) showed improved insulin sensitivity (P = 0.009) compared with those whose insulin sensitivity did not improve. A polymorphism in the NDUFB6 gene from respiratory chain complex I related to ATP synthesis (P = 0.02) and insulin Sensitivity response to exercise training (P = 0.05). ATP synthase flux correlated with O-2 uptake and insulin sensitivity. CONCLUSIONS-The ability of short-term exercise to stimulate ATP production distinguished individuals with improved insulin sensitivity from those whose insulin sensitivity did not improve. lit addition, the NDUFB6 gene polymorphism appeared to modulate this adaptation. This finding suggests that genes involved in mitochondrial function contribute to the response of ATP synthesis to exercise training. Diabetes 58:1333-1341, 2009
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| 8. |
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| 9. |
- Marz, Manja, et al.
(författare)
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Animal snoRNAs and scaRNAs with exceptional structures
- 2011
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Ingår i: RNA Biology. - : Informa UK Limited. - 1547-6286 .- 1555-8584. ; 8:6, s. 938-946
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Tidskriftsartikel (refereegranskat)abstract
- The overwhelming majority of small nucleolar RNAs (snoRNAs) fall into two clearly defined classes characterized by distinctive secondary structures and sequence motifs. A small group of diverse ncRNAs, however, shares the hallmarks of one or both classes of snoRNAs but differs substantially from the norm in some respects. Here, we compile the available information on these exceptional cases, conduct a thorough homology search throughout the available metazoan genomes, provide improved and expanded alignments, and investigate the evolutionary histories of these ncRNA families as well as their mutual relationships.
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| 10. |
- Palmtag, Juri, 1980-
(författare)
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Landscape partitioning and burial processes of soil organic carbon in contrasting areas of continuous permafrost
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Recent studies have shown that permafrost soils in the northern circumpolar region store almost twice as much carbon as the atmosphere. Since soil organic carbon (SOC) pools have large regional and landscape-level variability, detailed SOC inventories from across the northern permafrost region are needed to assess potential remobilization of SOC with permafrost degradation and to quantify the permafrost carbon-climate feedback on global warming.This thesis provides high-resolution data on SOC storage in five study areas located in undersampled regions of the continuous permafrost zone (Zackenberg in NE Greenland; Shalaurovo and Cherskiy in NE Siberia; Ary-Mas and Logata in Taymyr Peninsula). The emphasis throughout the five different study areas is put on SOC partitioning within the landscape and soil horizon levels as well as on soil forming processes under periglacial conditions. Our results indicate large differences in mean SOC 0–100 cm storage among study areas, ranging from 4.8 to 30.0 kg C m-2, highlighting the need to consider numerous factors as topography, geomorphology, land cover, soil texture, soil moisture, etc. in the assessment of landscape-level and regional SOC stock estimates.In the high arctic mountainous area of Zackenberg, the mean SOC storage is low due to the high proportion of bare grounds. The geomorphology based upscaling resulted in a c. 40% lower estimate compared to a land cover based upscaling (4.8 vs 8.3 kg C m-2, respectively). A landform approach provides a better tool for identifying hotspots of SOC burial in the landscape, which in this area corresponds to alluvial fan deposits in the foothills of the mountains. SOC burial by cryoturbation was much more limited and largely restricted to soils in the lower central valley. In the lowland permafrost study areas of Russia the mean SOC 0–100 cm storage ranged from 14.8 to 30.0 kg C m-2. Cryoturbation is the main burial process of SOC, storing on average c. 30% of the total landscape SOC 0–100 cm in deeper C-enriched pockets in all study areas. In Taymyr Peninsula, the mean SOC storage between the Ary-Mas and Logata study areas differed by c. 40% (14.8 vs 20.8 kg C m-2, respectively). We ascribe this mainly to the finer soil texture in the latter study area. Grain size analyses show that cryoturbation is most prominent in silt loam soils with high coarse silt to very fine sand fractions. However, in profiles and samples not affected by C-enrichment, C concentrations and densities were higher in silt loam soils with higher clay to medium silt fractions.
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