Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Lin, Wei‐Yu; Fordham, Sarah E.; Hungate, Eric; Sunter, Nicola J.; Elstob, Claire; Xu, Yaobo; Park, Catherine; Quante, Anne S.; Strauch, Konstantin; Gieger, Christian; Skol, Andrew D.; Rahman, Thahira; Sucheston‐Campbell, Lara E.; Wang, Junke; Hahn, Theresa; Clay-Gilmour, Alyssa; Jones, Gail; Marr, Helen; Jackson, Graham; Menne, Tobias; Collin, Mathew; Ivey, Adam; Hills, Robert Kerrin; Burnett, Alan Kenneth; Russell, Nigel H.; Fitzgibbon, Jude; Larson, Richard A.; Beau, Michelle M. Le; Stock, Wendy; Heidenreich, Olaf; Alharbi, Abrar; Allsup, David; Houlston, Richard S.; Norden, Jean; Dickinson, Anne; Douglas, Elisabeth; Lendrem, Clare; Daly, Ann K.; Palm, Louise; Piechocki, Kim; Jeffries, Sally; Bornhäuser, Martin; Röllig, Christoph; Altmann, Heidi; Ruhnke, Leo; Kunadt, Desireé; Wagenführ, Lisa; Cordell, Heather J.; Darlay, Rebecca; Andersen, Mette Klarskov; Fontana, Maria Chiara; Martinelli, Giovanni; Marconi, Giovanni; Sanz, Miguel Á.; Cervera, José; Gómez-Seguí, Inés; Cluzeau, Thomas; Moreilhon, Chimène; Raynaud, Sophie; Sill, Heinz; Voso, Maria Teresa; Dombret, Hervé; Cheok, Meyling; Preudhomme, Claude; Gale, Rosemary E.; Linch, David C.; Gaal-Wesinger, Julia; Masszi, András; Nowak, Daniel; Hofmann, Wolf‐Karsten; Gilkes, Amanda F.; Porkka, Kimmo; Feenstra, Jelena D. Milosevic; Královics, Róbert; Grimwade, David; Meggendorfer, Manja; Haferlach, Torsten; Krizsán, Szilvia; Bödör, Csaba; Stölzel, Friedrich; Onel, Kenan; Allan, James M.

doi:10.1038/s41467-021-26551-x

Cited by 22 publications

(10 citation statements)

References 81 publications

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“…In addition, we found that most HLA-related genes and PDCD1 expressed at higher levels in the high-risk group, which was in accordance with the current increasing evidence regarding solid tumors suggesting that more HLA presentation increased the recognition of tumor-associated antigens in HLA and in turn increased the success of immune checkpoint inhibitor therapy ( Rizvi et al, 2015 ; Lin W. Y. et al, 2021 ). Therefore, patients with high-risk scores for AML might benefit more from immunotherapy, especially with immune checkpoint inhibitors PD-1.…”

Section: Discussionsupporting

confidence: 89%

The pyroptosis-related gene signature predicts prognosis and reveals characterization of the tumor immune microenvironment in acute myeloid leukemia

Zhou

Qian

et al. 2022

Front. Pharmacol.

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Background: Pyroptosis is a novel inflammatory form of programmed cell death and a prospective target for cancer therapy. Nevertheless, little is known about the association between pyroptosis-related genes (PRGs) and acute myeloid leukemia (AML) prognosis. Herein, we systematically investigated the specific functions and clinical prognostic value of multiple PRGs in AML.Methods: Univariate and LASSO Cox regression analyses based on TCGA and GTEx databases were used to generate the PRG signature, whose predictive efficacy of survival was evaluated using survival analysis, ROC, univariate and multivariate Cox analyses as well as subgroup analysis. The BeatAML cohort was used for data validation. The association between risk score and immune cell infiltration, HLA, immune checkpoints, cancer stem cell (CSC), tumor mutation burden (TMB), and therapeutic drug sensitivity were also analyzed.Results: Six -PRG signatures, namely, CASP3, ELANE, GSDMA, NOD1, PYCARD, and VDR were generated. The high-risk score represented a poorer prognosis and the PRG risk score was also validated as an independent predictor of prognosis. A nomogram including the cytogenetic risk, age, and risk score was constructed for accurate prediction of 1-, 3-, and 5-year survival probabilities. Meanwhile, this risk score was significantly associated with the tumor immune microenvironment (TIME). A high-risk score is characterized by high immune cell infiltration, HLA, and immune checkpoints, as well as low CSC and TMB. In addition, patients with low-risk scores presented significantly lower IC50 values for ATRA, cytarabine, midostaurin, doxorubicin, and etoposide.Conclusion: Our findings might contribute to further understanding of PRGs in the prognosis and development of AML and provide novel and reliable biomarkers for its precise prevention and treatment.

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Section: Discussionsupporting

confidence: 89%

The pyroptosis-related gene signature predicts prognosis and reveals characterization of the tumor immune microenvironment in acute myeloid leukemia

Zhou

Qian

et al. 2022

Front. Pharmacol.

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“…It is a highly effective method for collecting information from highly correlated, complex and multiple traits through dimension reduction. Many studies have already been done which support the use of PC based GWAS for complex traits 18 , 62 – 64 . A comparison between the trait and PC based GWAS models suggested the use of PC based GWAS for efficient and high throughput deliverables.…”

Section: Resultsmentioning

confidence: 99%

Single trait versus principal component based association analysis for flowering related traits in pigeonpea

Kumar

Anjoy

Sahu

et al. 2022

Sci Rep

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Pigeonpea, a tropical photosensitive crop, harbors significant diversity for days to flowering, but little is known about the genes that govern these differences. Our goal in the current study was to use genome wide association strategy to discover the loci that regulate days to flowering in pigeonpea. A single trait as well as a principal component based association study was conducted on a diverse collection of 142 pigeonpea lines for days to first and fifty percent of flowering over 3 years, besides plant height and number of seeds per pod. The analysis used seven association mapping models (GLM, MLM, MLMM, CMLM, EMLM, FarmCPU and SUPER) and further comparison revealed that FarmCPU is more robust in controlling both false positives and negatives as it incorporates multiple markers as covariates to eliminate confounding between testing marker and kinship. Cumulatively, a set of 22 SNPs were found to be associated with either days to first flowering (DOF), days to fifty percent flowering (DFF) or both, of which 15 were unique to trait based, 4 to PC based GWAS while 3 were shared by both. Because PC1 represents DOF, DFF and plant height (PH), four SNPs found associated to PC1 can be inferred as pleiotropic. A window of ± 2 kb of associated SNPs was aligned with available transcriptome data generated for transition from vegetative to reproductive phase in pigeonpea. Annotation analysis of these regions revealed presence of genes which might be involved in floral induction like Cytochrome p450 like Tata box binding protein, Auxin response factors, Pin like genes, F box protein, U box domain protein, chromatin remodelling complex protein, RNA methyltransferase. In summary, it appears that auxin responsive genes could be involved in regulating DOF and DFF as majority of the associated loci contained genes which are component of auxin signaling pathways in their vicinity. Overall, our findings indicates that the use of principal component analysis in GWAS is statistically more robust in terms of identifying genes and FarmCPU is a better choice compared to the other aforementioned models in dealing with both false positive and negative associations and thus can be used for traits with complex inheritance.

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“…Recently, a rare NDUFS8 R2C complex I variant in the germline of two AML patients was identified as heterozygous, exhibiting a decreased basal and maximal oxygen consumption rate [90]. By testing AML blood samples, 47 genes were annotated within 500 Kb of the association signal and the sentinel variant is a significant expression quantitative trait locus for 12 of these, including NDUFS8 (PBH = 1.69 × 10 −4 ) [91].…”

Section: Ndufs8 and Cancermentioning

confidence: 99%

Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases

et al. 2022

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NADH:ubiquinone oxidoreductase core subunit S8 (NDUFS8) is an essential core subunit and component of the iron-sulfur (FeS) fragment of mitochondrial complex I directly involved in the electron transfer process and energy metabolism. Pathogenic variants of the NDUFS8 are relevant to infantile-onset and severe diseases, including Leigh syndrome, cancer, and diabetes mellitus. With over 1000 nuclear genes potentially causing a mitochondrial disorder, the current diagnostic approach requires targeted molecular analysis, guided by a combination of clinical and biochemical features. Currently, there are only several studies on pathogenic variants of the NDUFS8 in Leigh syndrome, and a lack of literature on its precise mechanism in cancer and diabetes mellitus exists. Therefore, NDUFS8-related diseases should be extensively explored and precisely diagnosed at the molecular level with the application of next-generation sequencing technologies. A more distinct comprehension will be needed to shed light on NDUFS8 and its related diseases for further research. In this review, a comprehensive summary of the current knowledge about NDUFS8 structural function, its pathogenic mutations in Leigh syndrome, as well as its underlying roles in cancer and diabetes mellitus is provided, offering potential pathogenesis, progress, and therapeutic target of different diseases. We also put forward some problems and solutions for the following investigations.

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Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Cited by 22 publications

References 81 publications

The pyroptosis-related gene signature predicts prognosis and reveals characterization of the tumor immune microenvironment in acute myeloid leukemia

The pyroptosis-related gene signature predicts prognosis and reveals characterization of the tumor immune microenvironment in acute myeloid leukemia

Single trait versus principal component based association analysis for flowering related traits in pigeonpea

Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases

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