A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia

Abstract

We conducted a genome-wide association study of 299,983 tagging SNPs for chronic lymphocytic leukemia (CLL) and performed validation in two additional series totaling 1,529 cases and 3,115 controls. We identified six previously unreported CLL risk loci at 2q13 (rs17483466; P = 2.36 x 10(-10)), 2q37.1 (rs13397985, SP140; P = 5.40 x 10(-10)), 6p25.3 (rs872071, IRF4; P = 1.91 x 10(-20)), 11q24.1 (rs735665; P = 3.78 x 10(-12)), 15q23 (rs7176508; P = 4.54 x 10(-12)) and 19q13.32 (rs11083846, PRKD2; P = 3.96 x 10(-9)). These data provide the first evidence for the existence of common, low-penetrance susceptibility to a hematological malignancy and new insights into disease causation in CLL.

Variant IRF4/MUM1 associates with CD38 status and treatment-free survival in chronic lymphocytic leukaemia

“…1 Given a putative role for IRF4 in the aetiology of CLL and a role in regulating B-cell development, we hypothesised that genetic variation in this gene also has a role in determining prognosis in CLL.…”

Germline copy number variation associated with Mendelian inheritance of CLL in two families

“…We found a significant decrease in IRF4 expression in the CLLs with the gain (P-value o0.0001; Figure 2e), whereas the other three genes were unchanged. Although the risk allele identified by GWAS at rs872071 has been previously associated with reduced IRF4 expression, 12 we see if anything a trend toward increased IRF4 expression with the GG risk allele (Figure 2e). These findings have been further confirmed by quantitative PCR (P ¼ 0.006; Figure 2f).…”

“…14 Mice lacking IRF4 have a block at a late stage of B-cell maturation and develop generalized lymphadenopathy. 15 These data together with the GWAS findings and fine mapping 11,12 suggest that germline gain of the IRF4 locus may predispose individuals in this family to CLL.…”

“…To identify mutations in these loci, we sequenced the coding regions of all four genes in this family and 84 other familial CLLs, and found no somatic mutations or novel germline variants. As the 3 0 UTR of IRF4 has been implicated in CLL risk by genome wide association study (GWAS), 11,12 we also sequenced the 5 0 and 3 0 UTRs of IRF4 in this family and six other CLLs, yet found no somatic mutations or novel SNPs (data not shown).…”

Association of TAP1 and TAP2 Gene Polymorphisms with Hematological Malignancies

“…The frequency of TAP2-565 heterozygous genotype GA was found to be significantly high in CLL cases compared to the control group (p<0.05) suggesting that this genotype could be a risk factor for the development of CLL. Genome wide association study conducted in CLL patients resulted in the identification of low-penetrance susceptibility loci but TAP genes were not defined as susceptibility loci for CLL (Di Bernardo et al, 2008). It could be argued that the clinical significance of these polymorphisms may likely vary depending on the disease context as well as on the allele distribution in a particular population.…”