Association of Killer Cell Immunoglobulin-Like Receptor Genes with Hodgkin's Lymphoma in a Familial Study

Caroline Besson,Josette Brière,Christophe Ferme,Danielle Canioni,Jacqueline Clavel,Martine Raphael,Eric Vivier,Corinne Amiel,Sophie Roetynck,Fionnuala Williams,Patrice Carde,Derek Middleton,Catherine Lependeven,Olivier Hermine,Laurent Orsi,Jean-Claude Nicolas,Pauline Brice,Laurent Abel,Guillemette Antoni

doi:10.1371/journal.pone.0000406

Abstract

BackgroundEpstein-Barr virus (EBV) is the major environmental factor associated with Hodgkin's lymphoma (HL), a common lymphoma in young adults. Natural killer (NK) cells are key actors of the innate immune response against viruses. The regulation of NK cell function involves activating and inhibitory Killer cell Immunoglobulin-like receptors (KIRs), which are expressed in variable numbers on NK cells. Various viral and virus-related malignant disorders have been associated with the presence/absence of certain KIR genes in case/control studies. We investigated the role of the KIR cluster in HL in a family-based association study.MethodologyWe included 90 families with 90 HL index cases (age 16–35 years) and 255 first-degree relatives (parents and siblings). We developed a procedure for reconstructing full genotypic information (number of gene copies) at each KIR locus from the standard KIR gene content. Out of the 90 collected families, 84 were informative and suitable for further analysis. An association study was then carried out with specific family-based analysis methods on these 84 families.Principal FindingsFive KIR genes in strong linkage disequilibrium were found significantly associated with HL. Refined haplotype analysis showed that the association was supported by a dominant protective effect of KIR3DS1 and/or KIR2DS1, both of which are activating receptors. The odds ratios for developing HL in subjects with at least one copy of KIR3DS1 or KIR2DS1 with respect to subjects with neither of these genes were 0.44[95% confidence interval 0.23–0.85] and 0.42[0.21–0.85], respectively. No significant association was found in a tentative replication case/control study of 68 HL cases (age 18–71 years). In the familial study, the protective effect of KIR3DS1/KIR2DS1 tended to be stronger in HL patients with detectable EBV in blood or tumour cells.ConclusionsThis work defines a template for family-based association studies based on full genotypic information for the KIR cluster, and provides the first evidence that activating KIRs can have a protective role in HL.

Highlights

Hodgkin’s lymphoma (HL) differs from other lymphomas in terms of both specific pathological and epidemiological features
As our analysis focuses on the genotypes of each of the nine variable Killer cell Immunoglobulin-like receptors (KIRs) genes shown in figure 1 (KIR2DS2, KIR2DL2/ 2DL3, KIR2DL1, KIR3DS1/3DL1, KIR2DL5, KIR2DS3, KIR2DS5, KIR2DS1, KIR2DS4), we first reconstructed the genotypes from the KIR gene content results
We report here the first family-based association study to show an association between a disease and genes of the KIR cluster

Summary

Introduction

Hodgkin’s lymphoma (HL) differs from other lymphomas in terms of both specific pathological and epidemiological features. HL is one of the most common forms of lymphoma occurring in young adults in developed countries, with an annual incidence of around 3 per 100,000 [2,3]. Both genetic and environmental factors are thought to be involved in the pathogenesis of HL [2]. The protective effect of KIR3DS1/KIR2DS1 tended to be stronger in HL patients with detectable EBV in blood or tumour cells. This work defines a template for family-based association studies based on full genotypic information for the KIR cluster, and provides the first evidence that activating KIRs can have a protective role in HL

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Conclusion