Allan JM

Bartram CR

da Silva MI

Eisele L

Fiege B

Greaves M

Harrison CJ

Hemminki K

Henrion M

Hoffmann P

Holroyd A

Houlston RS

Irving JA

Kinsey SE

Koehler R

Kumar R

Lightfoot T

Moorman AV

Muhleisen TW

Nothen MM

Roman E

Schrappe M

Sheridan E

Stanulla M

Thompson PD

Thomsen H

Vijayakrishnan J

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 x 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

Newcastle University E-Prints

English

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

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

Abstract

Similar works

Full text

Available Versions

Newcastle University E-Prints