To investigate whether a bias toward the presence of genes coding for activating KIRs were present in patients with NK-type lymphoproliferative disease of granular lymphocytes (NK-LDGL), by multiplex PCR analysis in this study we evaluated the KIR genotype in 35 patients with NK-LDGL and in 50 normal subjects. According to the published data in the Caucasian population, all individuals were positively scored for the framework loci (KIR2DL4+, KIR3DL2+ and KIR3DL3+). All genotypes were characterized by a gene encoding a group 1 HLA-C-specific inhibitory KIR, which was either KIR2DL1, KIR2DL2 or KIR2DL3 and at least contained one activating KIR gene. The KIR genotype analysis revealed that patients genotypes were largely represented by type B haplotype (34/35) that is characterized by the presence of multiple activating KIRs. The same KIR genotype was often shared between NK-LDGL patients. These genotypic profiles were not present in the group of controls and are infrequent (1,2%) or not still found in the Caucasian population. In contrast with literature data reporting that the frequency of haplotype A in homozigous state represents the most common condition in the Caucasian population (accounting for 1/3 of normal individuals), we surprisingly found that also almost all the controls studied (49/50) were equipped with the type B haplotype.

When the genotypic frequency was considered, the most frequently gene content found was 9 in controls and 11 or 14 in patients, indicating that patients genotypes contained a higher number of genes than controls. This picture was almost entirely due to the high variability of the activating genes number. As far as the activating genes are concerned, although the number of control individuals analyzed was still low, the frequency of KIR2DS1, KIR2DS2, KIR2DS4, KIR1D and KIR3DS1 was found to be higher in patients than in controls. This indicates that genotypic profiles of NK-LDGL patients are characterized by an increased presence of activating KIRs.

Consistent with these findings, the analysis of the KIR genes repertoire in NK-LDGL patients clearly indicates that the susceptibility to this disease is influenced by the KIR genotype and in particular by the presence of a considerable number of activating KIR genes. Moreover, we observed that healthy individuals scored as controls (all coming from the north-east of Italy) showed genotypes with a higher number of activating genes as compared to other Caucasian populations. This observation suggests that a genetic predisposition to development of NK-type LDGL might occur among the population of north-east of Italy and in turn this could explain the high frequency of NK-type LDGL in this Italian region.

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