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Genetic Variation in DNA Repair Pathways and Risk of Non-Hodgkin's Lymphoma
Molecular and genetic evidence suggests that DNA repair pathways may contribute to lymphoma susceptibility. Several studies have examined the association of DNA repair genes with lymphoma risk, but the findings from these reports have been inconsistent. Here we provide the results of a focused analysis of genetic variation in DNA repair genes and their association with the risk of non-Hodgkin's lymphoma (NHL). With a population of 1,297 NHL cases and 1,946 controls, we have performed a two-stage case/control association analysis of 446 single nucleotide polymorphisms (SNPs) tagging the genetic variation in 81 DNA repair genes. We found the most significant association with NHL risk in the ATM locus for rs227060 (OR = 1.27, 95% CI: 1.13–1.43, p = 6.77×10−5), which remained significant after adjustment for multiple testing. In a subtype-specific analysis, associations were also observed for the ATM locus among both diffuse large B-cell lymphomas (DLBCL) and small lymphocytic lymphomas (SLL), however there was no association observed among follicular lymphomas (FL). In addition, our study provides suggestive evidence of an interaction between SNPs in MRE11A and NBS1 associated with NHL risk (OR = 0.51, 95% CI: 0.34–0.77, p = 0.0002). Finally, an imputation analysis using the 1,000 Genomes Project data combined with a functional prediction analysis revealed the presence of biologically relevant variants that correlate with the observed association signals. While the findings generated here warrant independent validation, the results of our large study suggest that ATM may be a novel locus associated with the risk of multiple subtypes of NHL
Susceptibility Loci Associated with Specific and Shared Subtypes of Lymphoid Malignancies
<div><p>The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near <em>LPXN</em>, (P<sub>LYM</sub> = 3.89×10<sup>−8</sup>, OR = 1.29) and rs948562 (P<sub>LYM</sub> = 5.85×10<sup>−7</sup>, OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, P<sub>NHL</sub> = 5.72×10<sup>−7</sup>) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (P<sub>FL</sub> = 2.69×10<sup>−12</sup>, OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.</p> </div
Association analysis of genetic variants in DNA repair genes with the risk of major NHL subtypes.
<p>DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; SLL/CLL = small lymphocytic lymphoma/chronic lymphocytic leukemia; OR = odds ratio; CI = confidence interval.</p
Putatively functional SNPs imputed from the ATM locus associated with the risk of NHL.
<p>OR = odds ratio; CI = confidence interval; TFBS = transcription factor binding site; UTR = untranslated region.</p><p>*Correlated tSNP for rs228595 is rs611646; all other SNPs are correlated with the tSNP rs419716.</p
The results of association analysis, displayed as Manhattan plot, after imputation of 28 SNPs genotyped in both stage 1 and 2, which tag 11 DNA repair genes that showed association with NHL risk in our study.
<p>The SNPs and genes are ordered by chromosomal position (x-axis). The associations are displayed as –log<sub>10</sub>(p-value) for each SNP. Red dots represent fifteen tagging SNPs that were genotyped in our study and were associated with NHL risk. Green dots represent tagging SNPs that were genotyped in our study and that showed no association with NHL. Blue markers represent SNPs imputed by IMPUTE from 1KG. The red dotted line defines the threshold of p-value <0.05. * indicates an associated SNP with a putatively functional impact; non-synonymous coding change or SNP mapping in: transcription factor binding site, H3K4Me1 chromatin mark, DNaseI hypersensitivity cluster, 5′UTR, 3′UTR.</p
Association analysis of rs1805812 x rs625245 interactions between <i>MRE11A</i> and <i>NBS1</i> with the risk of NHL.
<p>OR = odds ratio; CI = confidence interval.</p
Association analysis of genetic variants in DNA repair genes with the risk of NHL.
<p>OR = odds ratio; CI = confidence interval.</p