Common genetic variation at 15q25.2 impacts on chronic lymphocytic leukaemia risk

Abstract

Summary A genome‐wide association study of chronic lymphocytic leukaemia (CLL) suggested that common variants at 15q25.2 (rs783540) and 18q21.1 (rs1036935) influence CLL. To validate these associations and explore their relationship with CLL risk we genotyped case‐control datasets from Poland, UK and Italy totalling 1428 cases and 1920 controls. Combined data from these and previously genotyped series (2503 cases and 5789 controls) provided evidence for an association between 15q25.2 and 18q21.1 loci and CLL risk (Pcombined = 1·10 × 10−7 and 1·30 × 10−5 respectively). These data provide further evidence for the involvement of common genetic variants in CLL risk and insight into the biological basis of disease development.

Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia

“…Recent genome-wide association studies (GWAS) of CLL have provided evidence that the coinheritance of multiple low-risk variants located on chromosomes 2q37.1, 2q37.3, 2q13, 6p21.3, 6p25.3, 8q24.21, 11q24.1, 15q21.3, 15q23, 15q25.2, 16q24.1, and 19q13.32 contributes to the heritability of CLL. [3][4][5][6] The statistical power of individual GWAS has been limited by the modest effect sizes of individual genetic variants, the need to establish stringent statistical significance thresholds, and financial constraints on the number of variants that can be followed up. Meta-analysis of existing GWAS data therefore offers the opportunity to discover additional CLL susceptibility loci.…”

Single nucleotide polymorphisms and inherited risk of chronic lymphocytic leukemia among African Americans

“…§African American control RAF were pooled from HapMap data (n ϭ 56-57) and genotypes from African American controls participating in a prostate cancer genome-wide SNP association study (n ϭ 474). 20,21 ʈComparison of RAF from pooled Duke and CRC African American CLL cohorts with pooled African American control CLL RAF.…”

“…CLL risk allele frequencies were compared with pooled results from previously published white CLL patients. 9,10,[12][13][14]20,21 Control African American allele frequencies were obtained from published GWA data (474 African American patients from MD Anderson 18,19 ) and from the HapMap database 15 (http://hapmap.ncbi.nlm.nih.gov/). Control allele frequencies were not available for rs1050979.…”

Inherited Susceptibility to CLL

“…These associations are robust, having been replicated in multiple independent case-control series [46][47][48]. Importantly, none of the genes implicated by these GWAS have previously been evaluated in targeted association studies, emphasising that the candidate gene approach was severely limited by inadequate knowledge of the biology of CLL.…”