HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes.
Sophia S WangMary CarringtonSonja I BerndtSusan L SlagerPaige M BracciJenna VoutsinasJames R CerhanKarin E SmedbyHenrik HjalgrimJoseph VijaiLindsay M MortonRoel VermeulenOra PaltielClaire M VajdicMartha S LinetAlexandra NietersSilvia de SanjoseWendy CozenElizabeth E BrownJennifer TurnerJohn J SpinelliTongzhang ZhengBrenda M BirmannChristopher R FlowersNikolaus BeckerElizabeth A HollyEleanor KaneDennis WeisenburgerMarc MaynadiePierluigi CoccoDemetrius AlbanesStephanie J WeinsteinLauren R TerasW Ryan DiverStephanie J LaxRuth C TravisRudolph KaaksElio RiboliYolanda BenaventePaul BrennanJames McKayMarie-Hélène Delfau-LarueBrian K LinkCorrado MagnaniMaria Grazia EnnasGiancarlo LatteAndrew L FeldmanNicole Wong DooGraham G GilesMelissa C SoutheyRoger L MilneKenneth OffitJacob MusinskyAlan A ArslanMark P PurdueHans-Olov AdamiMads MelbyeBengt GlimeliusLucia CondeNicola J CampMartha GlennKaren CurtinJacqueline ClavelAlain MonnereauDavid G CoxHervé GhesquièresGilles SallesPaulo BofettaLenka ForetovaAnthony StainesScott DavisRichard K SeversonQing LanAngela Brooks-WilsonMartyn T SmithEve RomanAnne KrickerYawei ZhangPeter KraftStephen J ChanockNathaniel RothmanPatricia HartgeChristine F SkibolaPublished in: Cancer research (2018)
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 (P 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.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086-96. ©2018 AACR.