title: Genetic variants in apoptosis and immunoregulation-related genes are associated with risk of chronic lymphocytic leukemia.
abstract: To identify low-penetrance susceptibility alleles for chronic lymphocytic leukemia (CLL), we performed a case-control study genotyping 768 single-nucleotide polymorphisms (SNP) in 692 cases of CLL and 738 controls. We investigated nonsynonymous SNPs, SNPs with potential functional effect, and tag SNPs in regulatory gene regions in a total of 172 genes involved in cancer biology. After adjustment for multiple testing, we found a strong association between CLL risk and six genetic variants: CCNH (rs2266690, V270A), APAF1 (rs17028658, 3'region), IL16 (rs4505265, first intron), CASP8 (rs1045485, D302H), NOS2A (rs2779251, promoter), and CCR7 (rs3136687, intron 1). We found association with CLL susceptibility and 22 haplotypes in APAF1, IL6, TNFRSF13B, IL16, CASP3, CCR7, LTA/TNF, BAX, BCL2, CXCL12, CASP10/CASP8, CASP1, CCL2, BAK1, and IL1A candidate genes. Finally, we evaluated using public data sets the potential functional effect on gene expression levels of the CLL associated genetic variants detected in regulatory regions. Minor alleles for APAF1 and IL16 were associated with lower mRNA levels; no expression differences were observed for CCR7, whereas NOS2A could not be assessed. This study suggests that common genetic variation in apoptosis- and immunoregulation-related genes is associated with the CLL risk.
authors.affiliation: Department of Anatomic Pathology, Hematopathology Section, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Enjuanes
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Benavente
authors.forename: Francesc
authors.initials: F
authors.lastname: Bosch
authors.forename: Idoia
authors.initials: I
authors.lastname: Martín-Guerrero
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
authors.forename: Susana
authors.initials: S
authors.lastname: Pérez-Alvarez
authors.forename: Oscar
authors.initials: O
authors.lastname: Reina
authors.forename: Maria T
authors.initials: MT
authors.lastname: Ardanaz
authors.forename: Pedro
authors.initials: P
authors.lastname: Jares
authors.forename: Africa
authors.initials: A
authors.lastname: García-Orad
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pujana
authors.forename: Emili
authors.initials: E
authors.lastname: Montserrat
authors.forename: Silvia
authors.initials: S
authors.lastname: de Sanjosé
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
mesh_terms: D000368:Aged; D000483:Alleles; D017209:Apoptosis / Q000235:genetics*; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007109:Immunity / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013030:Spain / Q000453:epidemiology