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Nature Research, Scientific Reports, 1(5), 2015

DOI: 10.1038/srep15065

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

Journal article published in 2015 by Jayaram Vijayakrishnan, Moorman Av, Marc Henrion ORCID, Anthony V. Moorman, Bettina Fiege, Miguel Inacio da Silva Filho, Rajiv Kumar, Amy Holroyd, da Silva Filho Mi, Rolf Koehler, Julie A. Irving, Hauke Thomsen, James M. Allan ORCID, Irving Ja, Allan Jm and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

AbstractGenome-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.