Fine-scale mapping of the 6p25.3 chronic lymphocytic leukaemia susceptibility locus

• Published in: Human molecular genetics 2010-05, Vol.19 (9), p.1840-1845
• Main Authors: Crowther-Swanepoel, Dalemari, Broderick, Peter, Ma, Yussanne, Robertson, Lindsay, Pittman, Alan M., Price, Amy, Twiss, Philip, Vijayakrishnan, Jayaram, Qureshi, Mobshra, Dyer, Martin J. S., Matutes, Estella, Dearden, Claire, Catovsky, Daniel, Houlston, Richard S.
• Format: Article
• Language: English
• Subjects: 3' Untranslated regions; 3' Untranslated Regions - genetics; Base Sequence; Biological and medical sciences; Case-Control Studies; chromosome 6; Chromosome Mapping; Chromosomes, Human, Pair 6 - genetics; Chronic lymphatic leukemia; Classical genetics, quantitative genetics, hybrids; Computational Biology; DNA; European Continental Ancestry Group - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene mapping; Genetic Predisposition to Disease - genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Hematologic and hematopoietic diseases; Humans; Interferon regulatory factor 4; Interferon Regulatory Factors - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Methods, theories and miscellaneous; Molecular and cellular biology; Molecular Sequence Data; Polymorphism, Single Nucleotide - genetics; Sequence Analysis, DNA; Single-nucleotide polymorphism; Susceptibility; Utah
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddq044

A recent genome-wide association study of chronic lymphocytic leukaemia (CLL) has identified a susceptibility locus on 6p25.3 associated with a modest but highly significant increase in CLL risk. Using a set of single nucleotide polymorphism (SNP) markers, we generated a fine-scale map and narrowed the association signal to a 18 kb DNA segment within the 3′-untranslated region (UTR) of the IRF4 (interferon regulatory factor 4) gene. Resequencing this segment in European subjects identified 55 common polymorphisms, including 13 highly correlated candidate causal variants. In a large case–control study, it was shown that all but four variants could be excluded with 95% confidence. These four SNPs map to a 3 kb region of the 3′-UTR of IRF4, consistent with the causal basis of the association being mediated through differential IRF4 expression.