PMC

Genome-wide association analysis of 502 514 single-nucleotide polymorphisms (SNPs) in 1200 classical Hodgkin lymphoma patients and 6417 control subjects. Multiple logistic regression analysis was performed assuming a log-additive genetic model and adjusting for sex (male or female), country (eight indicator variables after excluding one country as the reference: France, Germany, Spain, Czech Republic, Ireland, United Kingdom, Denmark, Sweden, and the Netherlands), and eight principal components analysis eigenvectors. The −log₁₀ (P value) for each SNP is plotted against their chromosomal position. All statistical tests were two-sided. The horizontal dotted line represents the genome-wide significance threshold level (P < 1 × 10⁻⁷). The regions in which SNPs associated with classical Hodgkin lymphoma are located include 5q31 in the vicinity of the IL13 and IL4 genes, and 6p21 within the major histocompatibility complex (MHC) region.

Genome-wide association study results in total classical Hodgkin lymphoma for single-nucleotide polymorphisms (SNPs) within a 300-kb flanking region of rs20541 at chromosome 5q31 (left) and rs27524 at chromosome 5q15 (right). Multiple logistic regression was performed assuming a log-additive genetic model and adjusting for sex (male or female), country (eight indicator variables after excluding one country as the reference: France, Germany, Spain, Czech Republic, Ireland, United Kingdom, Denmark, Sweden, and the Netherlands), and eight principal components analysis eigenvectors. The −log₁₀ (P value) for each SNP are plotted against their chromosomal position. All statistical tests were two-sided. The black triangle indicates the reported associated SNP and the colors of the dots represent the degree of linkage disequilibrium (based on r²) in relation to that index SNP. Recombination rates (cM/Mb) overlay the plots and are based on HapMap phase I and II data (http://hapmap.ncbi.nlm.nih.gov). cM/Mb = centiMorgans/megabase.

Investigation of the association between genetic variants and total classical Hodgkin lymphoma (cHL), Epstein–Barr virus (EBV)–positive cHL and EBV-negative cHL within an approximately 6.5 Mb region of the extended major histocompatibility complex located at 6p21. Overlayed plots of the −log₁₀ (P values) for 1973 single-nucleotide polymorphisms (SNPs) by their chromosomal position resulting from three separate analyses of all patients who have cHL (total cHL, in gray), patients who have EBV-positive cHL (in blue), and patients who have EBV-negative cHL (in red) are shown. Multiple logistic regression analysis was performed assuming a log-additive genetic model and adjusting for sex (male or female), country (up to eight indicator variables after excluding one country as the reference, depending on the analysis: France, Germany, Spain, Czech Republic, Ireland, United Kingdom, Denmark, Sweden, and the Netherlands), and eight principal components analysis eigenvectors. All statistical tests were two-sided. Arrows indicate cHL-associated regions indexed by five SNPs.

Stratified and subgroup analyses of five single-nucleotide polymorphisms (SNPs) within the major histocompatibility complex region, which were independently associated with classical Hodgkin lymphoma (cHL). Results are shown for A) rs2248462 (class I region, MICB), B) rs2395185 (class II region, HLA-DRA), C) rs2734986 (class I region, HLA-A), D) rs6904029 (class I region, HCG9), and E) rs6903608 (class II region, HLA-DRA). Odds ratios (ORs, represented by boxes with the area of each box inversely proportional to the variance of the estimate) and 95% confidence intervals (CIs, error bars) were derived using multiple logistic regression assuming a log-additive genetic model and adjusting for sex (male or female), country (up to eight indicator variables after excluding one country as the reference, depending on the analysis: France, Germany, Spain, Czech Republic, Ireland, United Kingdom, Denmark, Sweden, and the Netherlands), and eight principal components analysis eigenvectors for the genome-wide association study (GWAS) analyses only. The dashed vertical line represents the OR of the SNP in the analysis of total cHL among all subjects, and the width of the diamond is the corresponding 95% CI. In the analysis stratified by study, the GWAS included the EPILYMPH study (EPILYMH-GWAS), Scandinavian Lymphoma Etiology Study (SCALE-GWAS), the Scotland and Newcastle Lymphoma Group, and Young Adult Hodgkin Case–Control Study analyzed together (referred to as the UK Studies-GWAS), and the Northern Dutch Hodgkin Lymphoma Study (Netherlands-GWAS). The independent replication was done with data from the EPILYMPH study (EPILYMPH - Replication), and the Scotland and Newcastle Lymphoma Group, Young Adult Hodgkin Case–Control Study, and Epidemiology and Genetics Lymphoma Case–Control Study analyzed together (referred to as the UK Studies-Replication). P_homogeneity was on the basis of the Cochran Q test statistic and was used to evaluate between-study heterogeneity in results. Associations between the SNPs and cHL subgroups (including histological subtype, EBV status, and age) were performed, and P values (P_homogeneity) for the χ² test of homogeneity are presented to indicate differences in the OR between subgroup analyses. For rs2248462 (A) and rs 2395185 (B), results were derived from a combined analysis of the GWAS and independent replication phase results using an inverse variance weighting meta-analysis. All statistical tests were two-sided. Ca = case patients; Chr = chromosome; Co = control subjects; MCHL = mixed cellularity Hodgkin lymphoma; NSHL = nodular sclerosis Hodgkin lymphoma.