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The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A.

Vijayakrishnan, Jayaram; Henrion, Marc; Moorman, Anthony V; Fiege, Bettina; Kumar, Rajiv; Inacio da Silva Filho, Miguel; Holroyd, Amy; Koehler, Rolf; Thomsen, Hauke and Irving, Julie A, et al. (2015) In Scientific Reports 5.
Abstract
Genome-wide association studies (GWAS) have provided strong evidence for inherited predisposition to childhood acute lymphoblastic leukaemia (ALL) identifying a number of risk loci. We have previously shown common SNPs at 9p21.3 influence ALL risk. These SNP associations are generally not themselves candidates for causality, but simply act as markers for functional variants. By means of imputation of GWAS data and subsequent validation SNP genotyping totalling 2,177 ALL cases and 8,240 controls, we have shown that the 9p21.3 association can be ascribed to the rare high-impact CDKN2A p.Ala148Thr variant (rs3731249; Odds ratio = 2.42, P = 3.45 × 10(-19)). The association between rs3731249 genotype and risk was not specific to particular... (More)
Genome-wide association studies (GWAS) have provided strong evidence for inherited predisposition to childhood acute lymphoblastic leukaemia (ALL) identifying a number of risk loci. We have previously shown common SNPs at 9p21.3 influence ALL risk. These SNP associations are generally not themselves candidates for causality, but simply act as markers for functional variants. By means of imputation of GWAS data and subsequent validation SNP genotyping totalling 2,177 ALL cases and 8,240 controls, we have shown that the 9p21.3 association can be ascribed to the rare high-impact CDKN2A p.Ala148Thr variant (rs3731249; Odds ratio = 2.42, P = 3.45 × 10(-19)). The association between rs3731249 genotype and risk was not specific to particular subtype of B-cell ALL. The rs3731249 variant is associated with predominant nuclear localisation of the CDKN2A transcript suggesting the functional effect of p.Ala148Thr on ALL risk may be through compromised ability to inhibit cyclin D within the cytoplasm. (Less)
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Scientific Reports
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Nature Publishing Group
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  • pmid:26463672
  • wos:000362715200001
  • scopus:84944706694
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2045-2322
DOI
10.1038/srep15065
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English
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b4b71390-5fdf-4f57-8949-19bc34cf9815 (old id 8152448)
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http://www.ncbi.nlm.nih.gov/pubmed/26463672?dopt=Abstract
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2015-11-03 12:45:53
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@article{b4b71390-5fdf-4f57-8949-19bc34cf9815,
  abstract     = {Genome-wide association studies (GWAS) have provided strong evidence for inherited predisposition to childhood acute lymphoblastic leukaemia (ALL) identifying a number of risk loci. We have previously shown common SNPs at 9p21.3 influence ALL risk. These SNP associations are generally not themselves candidates for causality, but simply act as markers for functional variants. By means of imputation of GWAS data and subsequent validation SNP genotyping totalling 2,177 ALL cases and 8,240 controls, we have shown that the 9p21.3 association can be ascribed to the rare high-impact CDKN2A p.Ala148Thr variant (rs3731249; Odds ratio = 2.42, P = 3.45 × 10(-19)). The association between rs3731249 genotype and risk was not specific to particular subtype of B-cell ALL. The rs3731249 variant is associated with predominant nuclear localisation of the CDKN2A transcript suggesting the functional effect of p.Ala148Thr on ALL risk may be through compromised ability to inhibit cyclin D within the cytoplasm.},
  articleno    = {15065},
  author       = {Vijayakrishnan, Jayaram and Henrion, Marc and Moorman, Anthony V and Fiege, Bettina and Kumar, Rajiv and Inacio da Silva Filho, Miguel and Holroyd, Amy and Koehler, Rolf and Thomsen, Hauke and Irving, Julie A and Allan, James M and Lightfoot, Tracy and Roman, Eve and Kinsey, Sally E and Sheridan, Eamonn and Thompson, Pamela D and Hoffmann, Per and Nöthen, Markus M and Mühleisen, Thomas W and Eisele, Lewin and Bartram, Claus R and Schrappe, Martin and Greaves, Mel and Hemminki, Kari and Harrison, Christine J and Stanulla, Martin and Houlston, Richard S},
  issn         = {2045-2322},
  language     = {eng},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A.},
  url          = {http://dx.doi.org/10.1038/srep15065},
  volume       = {5},
  year         = {2015},
}