We found evidence for 6 out of the 7 previously implicated SNPs for CLL risk in an independent sample of US Caucasians. Even after using a Bonferroni correction of 6 independent regions (i.e., correcting for 6 independent tests), 4 SNPs still remained significant in our sample. There was suggestive evidence that the associations of the SNPs differed by family history status of CLL. A next step would be to evaluate whether these variants co-segregate with relatives who have CLL.
We were unable to replicate the association between CLL risk and rs11083846 located on 19q13. Limited statistical power may be an explanation. Assuming a 5% type I error rate and a 1.35 effect size (reported in Di Bernardo et al.), we have between 67% to 74% power to find this effect size with allele frequency between 0.22 and 0.28. Alternatively, this could be related to inherent differences in the populations under study. Our allele frequency of this SNP was greater in the controls compared to that of Di Bernardo et al., resulting in less allele frequency difference between cases and controls.
As reported in Di Bernardo et al
., three of replicated SNPs are located within genes, including rs872071 within the 3′ UTR of IRF4
, rs17483466 located in intron 10 of ACOXL
, and rs13397985 located in intron 1 of SP140
. The SNP rs9378805 is about 10 kb from 3′ end of IRF4
is of great interest because of its role in lymphocyte development and previous associations with other lymphomas(12
The strength of this study includes the well-characterized CLL cases and controls, as well as a fairly comparable number of CLL cases to that in each of the three phases of Di Bernardo et al.. This study has several limitations. First, genotyped data were pulled from two on-going separate genotype studies. As a result, not all subjects were genotyped across the 5 typed SNPs. The impact of this, however, was minor because even with fewer subjects genotyped, we were still able to identify all the SNPs but one with comparable effect sizes as those previously reported, yet with reduced statistical power. Second, two previously implicated SNPs were not typed in our study. To overcome this limitation, we imputed genotypes at these SNPs; we also evaluated associations of neighboring genotyped SNPs in high LD with the implicated SNPs. Both the observed genotype data at neighboring SNPs and the imputed data at the previously implicated SNPs were consistent with each other for each of the two regions on chromosomes 15 and 19. Further our imputation results had high accuracy. Thus, although we did not have actual data for these SNPs, surrogate information was available and reliable.
In conclusion, this study confirms the previously reported associations of CLL risk and SNPs located on chromosomes 2q13, 2q37.1, 6p25.3, 11q24.1, and 15q23. Candidate genes have been identified in or near the regions of interest, so further work is needed to identify the causal SNPs, as well as the biological mechanisms by which CLL risk is increased.