Non-del(5q) myelodysplastic syndromes-associated loci detected by SNP-array genome-wide association meta-analysis
Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-a...
| Auteurs principaux: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Langue: | English |
| Publié: |
American Society for Hematology
2019
|
| _version_ | 1826307312355115008 |
|---|---|
| author | McGraw, KL Cheng, C-H Chen, YA Hou, H-A Nilsson, B Genovese, G Cluzeau, T Pellagatti, A Przychodzen, BP Mallo, M Arenillas, L Mohamedali, A Adès, L Sallman, DA Padron, E Sokol, L Moreilhon, C Raynaud, S Tien, H-F Boultwood, J Ebert, BL Sole, F Fenaux, P Mufti, GJ Maciejewski, JP |
| author_facet | McGraw, KL Cheng, C-H Chen, YA Hou, H-A Nilsson, B Genovese, G Cluzeau, T Pellagatti, A Przychodzen, BP Mallo, M Arenillas, L Mohamedali, A Adès, L Sallman, DA Padron, E Sokol, L Moreilhon, C Raynaud, S Tien, H-F Boultwood, J Ebert, BL Sole, F Fenaux, P Mufti, GJ Maciejewski, JP |
| author_sort | McGraw, KL |
| collection | OXFORD |
| description | Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS. |
| first_indexed | 2024-03-07T07:01:19Z |
| format | Journal article |
| id | oxford-uuid:57f18e2b-7c35-40bb-add7-0abb954fe4b4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:01:19Z |
| publishDate | 2019 |
| publisher | American Society for Hematology |
| record_format | dspace |
| spelling | oxford-uuid:57f18e2b-7c35-40bb-add7-0abb954fe4b42022-03-29T17:16:44ZNon-del(5q) myelodysplastic syndromes-associated loci detected by SNP-array genome-wide association meta-analysisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:57f18e2b-7c35-40bb-add7-0abb954fe4b4EnglishSymplectic Elements at OxfordAmerican Society for Hematology2019McGraw, KLCheng, C-HChen, YAHou, H-ANilsson, BGenovese, GCluzeau, TPellagatti, APrzychodzen, BPMallo, MArenillas, LMohamedali, AAdès, LSallman, DAPadron, ESokol, LMoreilhon, CRaynaud, STien, H-FBoultwood, JEbert, BLSole, FFenaux, PMufti, GJMaciejewski, JPMyelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS. |
| spellingShingle | McGraw, KL Cheng, C-H Chen, YA Hou, H-A Nilsson, B Genovese, G Cluzeau, T Pellagatti, A Przychodzen, BP Mallo, M Arenillas, L Mohamedali, A Adès, L Sallman, DA Padron, E Sokol, L Moreilhon, C Raynaud, S Tien, H-F Boultwood, J Ebert, BL Sole, F Fenaux, P Mufti, GJ Maciejewski, JP Non-del(5q) myelodysplastic syndromes-associated loci detected by SNP-array genome-wide association meta-analysis |
| title | Non-del(5q) myelodysplastic syndromes-associated loci detected by SNP-array genome-wide association meta-analysis |
| title_full | Non-del(5q) myelodysplastic syndromes-associated loci detected by SNP-array genome-wide association meta-analysis |
| title_fullStr | Non-del(5q) myelodysplastic syndromes-associated loci detected by SNP-array genome-wide association meta-analysis |
| title_full_unstemmed | Non-del(5q) myelodysplastic syndromes-associated loci detected by SNP-array genome-wide association meta-analysis |
| title_short | Non-del(5q) myelodysplastic syndromes-associated loci detected by SNP-array genome-wide association meta-analysis |
| title_sort | non del 5q myelodysplastic syndromes associated loci detected by snp array genome wide association meta analysis |
| work_keys_str_mv | AT mcgrawkl nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT chengch nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT chenya nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT houha nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT nilssonb nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT genoveseg nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT cluzeaut nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT pellagattia nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT przychodzenbp nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT mallom nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT arenillasl nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT mohamedalia nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT adesl nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT sallmanda nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT padrone nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT sokoll nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT moreilhonc nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT raynauds nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT tienhf nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT boultwoodj nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT ebertbl nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT solef nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT fenauxp nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT muftigj nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis AT maciejewskijp nondel5qmyelodysplasticsyndromesassociatedlocidetectedbysnparraygenomewideassociationmetaanalysis |