A Meta-Analysis of Nodular Sclerosis Hodgkin Lymphoma Identifies Risk Loci at 6p21.32

Abstract 2686

Nodular sclerosis Hodgkin lymphoma (NSHL) is epidemiologically and pathologically distinct from other Hodgkin lymphoma subtypes. It is highly heritable and is the most common form of HL in young adults. In a combined analysis of results from two genome-wide association scans (one undertaken at the University of Southern California using the Illumina Human610-Quad beadchip and the other at the University of Chicago using the Affymetrix Genome-Wide Human SNP Array 6.0) of 395 European-origin NSHL patients and 3,245 controls, we identified two single nucleotide polymorphisms (SNPs) at chromosome 6p21.32 directly genotyped in both scans associated with disease risk at genome-wide levels of significance (rs9268542: p=8.2×10⁻¹⁰, odds ratio (OR)= 1.63, 95% Confidence Interval (CI) = 1.40–1.91; and rs204999: p=2.3×10^-9, OR= 0.54, 95% CI: 0.44=0.66). These SNPs are located in distinct haplotype blocks and are in only weak linkage disequilibrium (LD) (r²=0.06). Joint analysis revealed that each SNP was independently associated with disease risk, with the global likelihood ratio test remaining statistically significant for each group (p-value for 2 df test USC = 7.46 × 10^-9 and UC=.3.51 × 10^-6). Neither SNP is in a known gene or microRNA. rs9268542 is in LD with SNPs in the HLA-DRA gene (r²=0.92-0.93) and is a cis-acting expression QTL (eQTL) for several HLA Class II genes (HLA-DRB1-HLA-DRB5; HLA-DQB1-HLA-DQB2; all p=1×10^-5). Of note, rs6903608, an imputed SNP in the same region also surpassing genome-wide significance for association with NSHL, is an eQTL for these same HLA Class II genes at p=1×10^-20. rs204999 is in LD with SNPs in the nearby PRRT1 (r²=0.82) and EGFL8 (r²=0.81) genes, for which function remains poorly defined. Thus, we identified one SNP on chromosome 6p21.32 associated with NSHL that, by eQTL analysis, may be implicated in the transcriptional regulation of HLA-class II genes, a known susceptibly region for NSHL, and one SNP in the genomic region that appears to be independently-associated with NSHL, but which does not appear to be linked to the HLA locus.