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

Association analysis of genetic variants in DNA repair genes with the risk of NHL.

<p>OR = odds ratio; CI = confidence interval.</p

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_LYM = 3.89×10⁻⁸, OR = 1.29) and rs948562 (P_LYM = 5.85×10⁻⁷, OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, P_NHL = 5.72×10⁻⁷) 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_FL = 2.69×10⁻¹², 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

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 –log₁₀(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

Heterogeneity test.

<p>(P) BD is the asymptotic p-value of Breslow-Day statistic for the heterogeneity test.</p

Quantile–quantile plots.

<p>Quantile–quantile (QQ) plots for (A) LYM, (B) NHL, (C) FL, (D) DLBCL. The X-axis represents expected −log₁₀(P) and the Y-axis represents −log₁₀(P) from logistic regression. Genomic inflation factor λ for LYM, NHL, FL and DLBCL was 1.09, 1.07, 1.04 and 1.04 respectively.</p

Summary statistics for the analyses in all three stages.

<p>Association with all lymphoma subtypes (LYM), all non-Hodgkin's lymphomas (NHL), and subtypes of follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) and all non-follicular or non-diffuse subtypes (NFD), RA = Risk allele.</p

The Chr6p21.32 locus depicting the novel loci near the HLA II locus.

<p>SNPs marked in blue are novel SNPs that are significant in LYM, NHL or FL. The two SNPs previously reported are rs7755224 and rs10484561 (in black).</p