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. 2013;9(1):e1003220.
doi: 10.1371/journal.pgen.1003220. Epub 2013 Jan 17.

Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies

Joseph Vijai  1 , Tomas Kirchhoff, Kasmintan A Schrader, Jennifer Brown, Ana Virginia Dutra-Clarke, Christopher Manschreck, Nichole Hansen, Rohini Rau-Murthy, Kara Sarrel, Jennifer Przybylo, Sohela Shah, Srujana Cheguri, Zsofia Stadler, Liying Zhang, Ora Paltiel, Dina Ben-Yehuda, Agnes Viale, Carol Portlock, David Straus, Steven M Lipkin, Mortimer Lacher, Mark Robson, Robert J Klein, Andrew Zelenetz, Kenneth Offit
Affiliations

Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies

Joseph Vijai et al. PLoS Genet. 2013.

Abstract

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 LPXN, (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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Manhattan plots.
Manhattan plots for (A) LYM, (B) NHL, (C) FL, (D) DLBCL. The blue line shows suggestive association and the red line genome-wide association. X-axis labels correspond to chromosomes, Y-axis shows −log10(P) from logistic regression.
Figure 2
Figure 2. Quantile–quantile plots.
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.
Figure 3
Figure 3. Regional plots from stage-1 GWAS.
(A) Chr6p23, (B) Chr11q12.1 and (C) Chr 6p21.32. The regions corresponding to LD between lead SNPs and other SNPs are marked on the X axis of the plot.
Figure 4
Figure 4. The Chr6p21.32 locus depicting the novel loci near the HLA II locus.
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).
See this image and copyright information in PMC

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