Identification of genetic variants associated with skeletal muscle function deficit in childhood acute lymphoblastic leukemia survivors
Geneviève Nadeau,1 Erika Ouimet-Grennan,1 Michelle Aaron,1 Simon Drouin,2 Laurence Bertout,2 Albert Shalmiev,2 Patrick Beaulieu,2 Pascal St-Onge,2 Louis-Nicolas Veilleux,3 Frank Rauch,3 Kateryna Petrykey,1,2 Caroline Laverdière,1–2,4 Daniel Sinnett,1–2,4 Nat...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2019-04-01
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| Series: | Pharmacogenomics and Personalized Medicine |
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| Online Access: | https://www.dovepress.com/identification-of-genetic-variants-associated-with-skeletal-muscle-fun-peer-reviewed-article-PGPM |
| _version_ | 1819052895314640896 |
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| author | Nadeau G Ouimet-Grennan E Aaron M Drouin S Bertout L Shalmiev A Beaulieu P St-Onge P Veilleux LN Rauch F Petrykey K Laverdière C Sinnett D Alos N Krajinovic M |
| author_facet | Nadeau G Ouimet-Grennan E Aaron M Drouin S Bertout L Shalmiev A Beaulieu P St-Onge P Veilleux LN Rauch F Petrykey K Laverdière C Sinnett D Alos N Krajinovic M |
| author_sort | Nadeau G |
| collection | DOAJ |
| description | Geneviève Nadeau,1 Erika Ouimet-Grennan,1 Michelle Aaron,1 Simon Drouin,2 Laurence Bertout,2 Albert Shalmiev,2 Patrick Beaulieu,2 Pascal St-Onge,2 Louis-Nicolas Veilleux,3 Frank Rauch,3 Kateryna Petrykey,1,2 Caroline Laverdière,1–2,4 Daniel Sinnett,1–2,4 Nathalie Alos,1–2,5* Maja Krajinovic1–2,4*1Department of Medicine, University of Montreal, Montreal, QC, Canada; 2Sainte-Justine University Hospital Research Centre, Montreal, QC, Canada; 3Division of paediatrics, Montreal Shriners Hospital for Children, Montreal, QC, Canada; 4Division of Hemato-Oncology, Sainte-Justine University Hospital Centre, Montreal, QC, Canada; 5Division of Endocrinology, Sainte-Justine University Hospital Centre, Montreal, QC, Canada *These authors contributed equally to this workBackground: Although 80% of childhood acute lymphoblastic leukemia (ALL) cases are cured with current treatment protocols, exposure to chemotherapeutics or radiation therapy during a vulnerable period of child development has been associated with a high frequency of late adverse effects (LAE). Previous observations suggest important skeletal muscle size, density and function deficits in ALL survivors.Purpose: Given that only a fraction of all patients will suffer from this particular complication, we investigated whether it could be predicted by genetic markers. Patients and methods: We analysed associations between skeletal muscle force (Fmax) and power (Pmax) and germline genetic variants from 1039 genes derived through whole-exome sequencing. Top-ranking association signals retained after correction for multiple testing were confirmed through genotyping, and further analysed through stratified analyses and multivariate models. Results: Our results show that skeletal muscle function deficit is associated with two common single nucleotide polymorphisms (SNPs) (rs2001616DUOX2, P=0.0002 (Pmax) and rs41270041ADAMTS4, P=0.02 (Fmax)) and two rare ones located in the ALOX15 gene (P=0.001 (Pmax)). These associations were further modulated by sex, body mass index and risk groups, which reflected glucocorticoid dose and radiation therapy (P≤0.02). Conclusion: Occurrence of muscle function deficit in childhood ALL is thus strongly modulated by variations in the DUOX2, ADAMTS4 and ALOX15 genes, which could lead to personalized prevention strategies in childhood ALL survivors.Keywords: acute lymphoblastic leukemia, late adverse effects, skeletal muscle deficit, genetic association study, whole exome sequencing |
| first_indexed | 2024-12-21T12:27:06Z |
| format | Article |
| id | doaj.art-38377ad8a6854cb2b34ee39918bfbf61 |
| institution | Directory Open Access Journal |
| issn | 1178-7066 |
| language | English |
| last_indexed | 2024-12-21T12:27:06Z |
| publishDate | 2019-04-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Pharmacogenomics and Personalized Medicine |
| spelling | doaj.art-38377ad8a6854cb2b34ee39918bfbf612022-12-21T19:04:09ZengDove Medical PressPharmacogenomics and Personalized Medicine1178-70662019-04-01Volume 12334545057Identification of genetic variants associated with skeletal muscle function deficit in childhood acute lymphoblastic leukemia survivorsNadeau GOuimet-Grennan EAaron MDrouin SBertout LShalmiev ABeaulieu PSt-Onge PVeilleux LNRauch FPetrykey KLaverdière CSinnett DAlos NKrajinovic MGeneviève Nadeau,1 Erika Ouimet-Grennan,1 Michelle Aaron,1 Simon Drouin,2 Laurence Bertout,2 Albert Shalmiev,2 Patrick Beaulieu,2 Pascal St-Onge,2 Louis-Nicolas Veilleux,3 Frank Rauch,3 Kateryna Petrykey,1,2 Caroline Laverdière,1–2,4 Daniel Sinnett,1–2,4 Nathalie Alos,1–2,5* Maja Krajinovic1–2,4*1Department of Medicine, University of Montreal, Montreal, QC, Canada; 2Sainte-Justine University Hospital Research Centre, Montreal, QC, Canada; 3Division of paediatrics, Montreal Shriners Hospital for Children, Montreal, QC, Canada; 4Division of Hemato-Oncology, Sainte-Justine University Hospital Centre, Montreal, QC, Canada; 5Division of Endocrinology, Sainte-Justine University Hospital Centre, Montreal, QC, Canada *These authors contributed equally to this workBackground: Although 80% of childhood acute lymphoblastic leukemia (ALL) cases are cured with current treatment protocols, exposure to chemotherapeutics or radiation therapy during a vulnerable period of child development has been associated with a high frequency of late adverse effects (LAE). Previous observations suggest important skeletal muscle size, density and function deficits in ALL survivors.Purpose: Given that only a fraction of all patients will suffer from this particular complication, we investigated whether it could be predicted by genetic markers. Patients and methods: We analysed associations between skeletal muscle force (Fmax) and power (Pmax) and germline genetic variants from 1039 genes derived through whole-exome sequencing. Top-ranking association signals retained after correction for multiple testing were confirmed through genotyping, and further analysed through stratified analyses and multivariate models. Results: Our results show that skeletal muscle function deficit is associated with two common single nucleotide polymorphisms (SNPs) (rs2001616DUOX2, P=0.0002 (Pmax) and rs41270041ADAMTS4, P=0.02 (Fmax)) and two rare ones located in the ALOX15 gene (P=0.001 (Pmax)). These associations were further modulated by sex, body mass index and risk groups, which reflected glucocorticoid dose and radiation therapy (P≤0.02). Conclusion: Occurrence of muscle function deficit in childhood ALL is thus strongly modulated by variations in the DUOX2, ADAMTS4 and ALOX15 genes, which could lead to personalized prevention strategies in childhood ALL survivors.Keywords: acute lymphoblastic leukemia, late adverse effects, skeletal muscle deficit, genetic association study, whole exome sequencinghttps://www.dovepress.com/identification-of-genetic-variants-associated-with-skeletal-muscle-fun-peer-reviewed-article-PGPMAcute lymphoblastic leukemialate adverse effectsskeletal muscle deficitsgenetic association studywhole exome sequencing |
| spellingShingle | Nadeau G Ouimet-Grennan E Aaron M Drouin S Bertout L Shalmiev A Beaulieu P St-Onge P Veilleux LN Rauch F Petrykey K Laverdière C Sinnett D Alos N Krajinovic M Identification of genetic variants associated with skeletal muscle function deficit in childhood acute lymphoblastic leukemia survivors Pharmacogenomics and Personalized Medicine Acute lymphoblastic leukemia late adverse effects skeletal muscle deficits genetic association study whole exome sequencing |
| title | Identification of genetic variants associated with skeletal muscle function deficit in childhood acute lymphoblastic leukemia survivors |
| title_full | Identification of genetic variants associated with skeletal muscle function deficit in childhood acute lymphoblastic leukemia survivors |
| title_fullStr | Identification of genetic variants associated with skeletal muscle function deficit in childhood acute lymphoblastic leukemia survivors |
| title_full_unstemmed | Identification of genetic variants associated with skeletal muscle function deficit in childhood acute lymphoblastic leukemia survivors |
| title_short | Identification of genetic variants associated with skeletal muscle function deficit in childhood acute lymphoblastic leukemia survivors |
| title_sort | identification of genetic variants associated with skeletal muscle function deficit in childhood acute lymphoblastic leukemia survivors |
| topic | Acute lymphoblastic leukemia late adverse effects skeletal muscle deficits genetic association study whole exome sequencing |
| url | https://www.dovepress.com/identification-of-genetic-variants-associated-with-skeletal-muscle-fun-peer-reviewed-article-PGPM |
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