HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes

Abstract

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci ( trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. HLA gene diversity reduces risk for non-Hodgkin lymphoma. .

Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts

“…The HLA region is critical for innate and adaptive immune response and has a complex relationship with cancer risk. Heterogeneous associations with HLA haplotypes have been reported for different subtypes of NHL 44 and lung cancer 45 , suggesting that relevant risk variants are likely to differ within, as well as between, cancers. Studies have further demonstrated that somatic mutation profiles are associated with HLA class I (ref.…”

The role of HLA variation in lymphoma aetiology and survival

“…An initial evaluation of HLA zygosity based on allelotyping data reported increased risk of DLBCL with HLA class I zygosity among a U.S. Caucasian population of 163 DLBCL patients (Table ) . A GWAS‐based evaluation of HLA zygosity which leveraged imputed HLA data with 3,617 DLBCL patients confirmed the elevation of DLBCL risk with increasing number of HLA class I alleles and further observed increasing DLBCL risk associated with HLA class II alleles as well as zygosity across HLA‐B , HLA‐C , HLA‐DRB1 and HLA‐DQB1 . However, among transplant recipients, Hussain and colleagues reported no association among HLA class I or II zygosity .…”

“…Only one report of zygosity has been reported to date for FL risk, reporting increased FL risk for zygosity in HLA class II alleles, both overall across alleles ( P ‐trend < 0.0001) and individually ( HLA‐DRB1 : OR = 1.54, 95% CI = 1.31–1.82; HLA‐DQB1 : OR = 1.42, 95% CI = 1.23–1.65; HLA‐DPB1 : OR = 1.24, 95% CI = 1.10–1.40) (Table ) . Although conducted among 2686 FL patients and 8,753 controls, replication of these results is needed.…”

“…Only one study to date has reported associations between HLA zygosity and MZL, based on imputed GWAS data from 741 MZL patients that were part of the international GWAS effort and imputed for HLA (Table ). An increasing number of HLA class I and class II loci were associated with increased MZL risk, with specific MZL risk increases noted for homozygosity at HLA‐B (OR = 1.34, 95% CI = 1.01–1.78), HLA‐C (OR = 1.33, 95% CI = 1.04–1.70) and HLA‐DRB1 (OR = 1.45, 95% CI = 1.12–1.89) loci . Replication of these results is needed, as are larger populations to permit the evaluation of associations by MZL subtypes.…”

“…HLA-C (OR = 1.33, 95% CI = 1.04-1.70) and HLA-DRB1 (OR = 1.45, 95% CI = 1.12-1.89) loci [37]. Replication of these results is needed, as are larger populations to permit the evaluation of associations by MZL subtypes.…”