Fine-scale mapping of the 6p25.3 chronic lymphocytic leukaemia susceptibility locus.
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.
Crowther-Swanepoel
Dalemari
D
Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
Broderick
Peter
P
Ma
Yussanne
Y
Robertson
Lindsay
L
Pittman
Alan M
AM
Price
Amy
A
Twiss
Philip
P
Vijayakrishnan
Jayaram
J
Qureshi
Mobshra
M
Dyer
Martin J S
MJ
Matutes
Estella
E
Dearden
Claire
C
Catovsky
Daniel
D
Houlston
Richard S
RS
D020413:3' Untranslated Regions / Q000235:genetics; D001483:Base Sequence; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D019295:Computational Biology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D014589:Utah; D044465:White People / Q000235:genetics; D000099218:Interferon Regulatory Factor-4
D020413:3' Untranslated Regions; D050835:Interferon Regulatory Factors; D000099218:Interferon Regulatory Factor-4