| 1. |
|
|
| 2. |
-
- 2019
-
Tidskriftsartikel (refereegranskat)
|
|
| 3. |
|
|
| 4. |
- Chen, Jie, et al.
(författare)
-
Therapeutic targets for inflammatory bowel disease : proteome-wide Mendelian randomization and colocalization analyses
- 2023
-
Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 89
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Identifying new drug targets for inflammatory bowel disease (IBD) is urgently needed. The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) and colocalization analyses to identify possible targets for IBD.Methods: Summary-level data of 4907 circulating protein levels were extracted from a large-scale protein quantitative trait loci study including 35,559 individuals. Genetic associations with IBD and its subtypes were obtained from the Inflammatory Bowel Disease Genetics Consortium (25,024 cases and 34,915 controls), the FinnGen study (7206 cases and 253,199 controls), and the UK Biobank study (7045 cases and 449,282 controls). MR analysis was conducted to estimate the associations between protein and IBD risk. The colocalization analysis was used to examine whether the identified proteins and IBD shared casual variants.Findings: Genetically predicted levels of 3, and 5 circulating proteins were associated with IBD and ulcerative colitis (UC), respectively. With high supporting evidence of colocalization, genetically predicted MST1 (macrophage stim-ulating 1) and HGFAC (hepatocyte growth factor activator) levels were inversely associated with IBD risks. The as-sociations of STAT3 (signal transducer and activator of transcription 3), MST1, CXCL5 (C-X-C motif chemokine ligand 5), and ITPKA (inositol-trisphosphate 3-kinase A) with the risk of UC were supported by colocalization analysis.Interpretation: The proteome-wide MR investigation identified many proteins associated with the risk of IBD. MST1, HGFAC, STAT3, ITPKA, and CXCL5 deserve further investigation as potential therapeutic targets for IBD. 2023;89: Published https://doi.org/10. 1016/j.ebiom.2023. 104494
|
|
| 5. |
|
|
| 6. |
- Ai, Sizhi, et al.
(författare)
-
Causal associations of short and long sleep durations with 12 cardiovascular diseases : linear and nonlinear Mendelian randomization analyses in UK Biobank
- 2021
-
Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 42:34, s. 3349-3357
-
Tidskriftsartikel (refereegranskat)abstract
- Aims Observational studies have suggested strong associations between sleep duration and many cardiovascular diseases (CVDs), but causal inferences have not been confirmed. We aimed to determine the causal associations between genetically predicted sleep duration and 12 CVDs using both linear and nonlinear Mendelian randomization (MR) designs. Methods and results Genetic variants associated with continuous, short (<= 6 h) and long (>= 9 h) sleep durations were used to examine the causal associations with 12 CVDs among 404 044 UK Biobank participants of White British ancestry. Linear MR analyses showed that genetically predicted sleep duration was negatively associated with arterial hypertension, atrial fibrillation, pulmonary embolism, and chronic ischaemic heart disease after correcting for multiple tests (P <0.001). Nonlinear MR analyses demonstrated nonlinearity (L-shaped associations) between genetically predicted sleep duration and four CVDs, including arterial hypertension, chronic ischaemic heart disease, coronary artery disease, and myocardial infarction. Complementary analyses provided confirmative evidence of the adverse effects of genetically predicted short sleep duration on the risks of 5 out of the 12 CVDs, including arterial hypertension, pulmonary embolism, coronary artery disease, myocardial infarction, and chronic ischaemic heart disease (P< 0.001), and suggestive evidence for atrial fibrillation (P < 0.05). However, genetically predicted long sleep duration was not associated with any CVD. Conclusion This study suggests that genetically predicted short sleep duration is a potential causal risk factor of several CVDs, while genetically predicted long steep duration is unlikely to be a causal risk factor for most CVDs. [GRAPHICS] .
|
|
| 7. |
- Kanoni, Stavroula, et al.
(författare)
-
Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
-
Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
|
|
| 8. |
- Menghrajani, Kamal, et al.
(författare)
-
Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML
- 2022
-
Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 6:3, s. 828-847
-
Tidskriftsartikel (refereegranskat)abstract
- Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P < .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P < .001), as was overall survival (HR, 1.32; P < .001, and HR, 1.45; P < .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.
|
|
| 9. |
- Wang, Ningjian, et al.
(författare)
-
Long-term night shift work is associated with the risk of atrial fibrillation and coronary heart disease
- 2021
-
Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 42:40, s. 4180-
-
Tidskriftsartikel (refereegranskat)abstract
- AimsThe aim of this study was to test whether current and past night shift work was associated with incident atrial fibrillation (AF) and whether this association was modified by genetic vulnerability. Its associations with coronary heart disease (CHD), stroke, and heart failure (HF) were measured as a secondary aim.Methods and resultsThis cohort study included 283657 participants in paid employment or self-employed without AF and 276009 participants free of CHD, stroke, and HF at baseline in the UK Biobank. Current and lifetime night shift work information was obtained. Cox proportional hazard models were used. Weighted genetic risk score for AF was calculated. During a median follow-up of 10.4years, 5777 incident AF cases were documented. From 'day workers', 'shift but never/rarely night shifts', and 'some night shifts' to 'usual/permanent night shifts', there was a significant increasing trend in the risk of incident AF (P for trend 0.013). Usual or permanent night shifts were associated with the highest risk [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.02-1.32]. Considering a person's lifetime work schedule and compared with shift workers never working nights, participants with a duration over 10years and an average 3-8 nights/month frequency of night shift work exposure possessed higher AF risk (HR 1.18, 95% CI 0.99-1.40 and HR 1.22, 95% CI 1.02-1.45, respectively). These associations between current and lifetime night shifts and AF were not modified by genetic predisposition to AF. Usual/permanent current night shifts, >= 10years and 3-8 nights/month of lifetime night shifts were significantly associated with a higher risk of incident CHD (HR 1.22, 95% CI 1.11-1.35, HR 1.37, 95% CI 1.20-1.58 and HR 1.35, 95% CI 1.18-1.55, respectively). These associations in stroke and HF were not significant.ConclusionBoth current and lifetime night shift exposures were associated with increased AF risk, regardless of genetic AF risk. Night shift exposure also increased the risk of CHD but not stroke or HF. Whether decreasing night shift work frequency and duration might represent another avenue to improve heart health during working life and beyond warrants further study.
|
|
| 10. |
- Wang, Zhaoming, et al.
(författare)
-
Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
|
|
