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Genetic Variants in Apoptosis and Immunoregulation-Related Genes Are Associated with Risk of Chronic Lymphocytic Leukemia

¹ Hematopathology Section, Department of Anatomic Pathology, and ² Department of Hematology, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona; ³ Unit of Infections and Cancer, Cancer Epidemiology Research Programme, Catalan Institut of Oncology, Institut d'Investigació Biomèdica de Bellvitge, CIBER en Epidemiología y Salud Pública, L'Hospitalet; ⁴ Biostatistics and Bioinformatics Unit, and Translational Research Laboratory, Catalan Institut of Oncology, L'Hospitalet, Barcelona, Spain; ⁵ Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Leioa, Bizkaia, Spain; and ⁶ Hospital Txagorritxu, Vitoria, Alava, Spain

Requests for reprints: Elias Campo, Hematopathology Section, Hospital Clínic, Villarroel 170, 08036-Barcelona, Spain. Phone: 34-93-227-5450; Fax: 34-93-227-5717; E-mail: ecampo{at}clinic.ub.es.

Key Words: Chronic lymphocytic leukemia • genetic variation • single-nucleotide polymorphism • genetic risk • haplotypes

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. [Cancer Res 2008;68(24):10178–86]

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