Elsevier

Human Immunology

Volume 77, Issue 1, January 2016, Pages 41-46
Human Immunology

Genetic associations of killer immunoglobulin like receptors and class I human leukocyte antigens on childhood acute lymphoblastic leukemia among north Indians

https://doi.org/10.1016/j.humimm.2015.10.009Get rights and content

Abstract

Background

Molecular interactions between KIRs and their cognate HLA class-I ligands, play a central role in the regulation of natural killer (NK) cell responses in malignancies. We aimed to determine the role of KIR genes and their HLA ligands in genetic predisposition of childhood acute lymphoblastic leukemia (ALL).

Methods

Genotyping of 16 KIR genes, along with HLA class-I groups C1/C2 and Bw4 super-type ligands, was carried-out in 137 childhood ALL cases and 274 healthy controls.

Results

We observed an increased incidence of activating KIRs namely; 2DS2 (OR = 2.23, p = <0.001), 2DS3 (OR = 1.74, p = 0.011), 3DS1 (OR = 2.22, p = <0.001), 2DS5 (OR = 2.10, p = 0.001), 2DS1 (OR = 4.42, p = <0.001) and 2DS4 (OR = 2.88, p = <0.001) genes in childhood ALL cases compared to controls. Frequency of BB genotype that possess 2–6 activating KIR genes was predominant in cases compared to controls (OR = 2.55, p = <0.001). KIR-receptor/HLA-ligand combinations analysis revealed a moderate risk of almost 2-fold for activating KIR-ligand combinations namely; KIR2DS1-HLAC2, KIR2DS2-HLAC1 and KIR3DS1-HLABw4 in childhood ALL cases.

Conclusion

Our data suggests the role for KIR genes and their HLA ligands in aetiology of childhood ALL.

Introduction

Childhood acute lymphoblastic leukemia (ALL) (OMIM = 615545) is the most frequent hematopoietic malignancy in children worldwide [1]. Molecular interactions between killer immunoglobulin-like receptors (KIRs) and their cognate HLA class I ligands, play a central role in the regulation of natural killer (NK) cell responses in malignancies including certain types of leukemia [2], [3]. Recently, it has been proposed that the variation in KIR gene content may affect childhood ALL risk [2].

Killer cell immunoglobulin-like receptor (KIR) gene complex is located on chromosome 19q13.4 spanning 150 Kb and consists of 14 gene loci and 2 pseudo-genes [4]. KIR genes are highly polymorphic and interact with equally polymorphic Human leukocyte antigen (HLA) class I molecule. KIR genes are expressed on the surface of natural killer (NK) cells and some T cells, and regulate the development and function of these cells through interaction with their cognate HLA ligands. KIR genes with long cytoplasmic tail (L) transmit inhibitory signals after binding with their cognate HLA ligand and those with short tails (S) transmit activating signals [5], in this way it produces varied effect on NK cell activity. The expression of HLA class-I alleles at the surface of cells enables NK cells to recognize as self and helps them to target the non-self entities, such as cancer cells and some virally infected cells, for lysis [6].

HLA-C is considered as a dominant KIR ligand. On the basis of polymorphic residues within the α  1 extracellular domain, all HLA-C alleles may be grouped as HLA-C group-1 (C1) or group-2 (C2). KIR2DL1 binds with C2 ligands to form a strong inhibitory interaction, whereas both KIR2DL2 and KIR2DL3 bind with C1 ligands to deliver intermediate and weak inhibitory signals respectively [7]. KIR3DL1 is an inhibitory receptor for HLA-Bw4 super-type alleles, which consists of approximately 30–40% of HLA-B alleles [8]. On the contrary; HLA-Bw6 super-type alleles do not binds with KIRs. KIR3DL1/HLA-Bw4 interactions convey weak or strong inhibitory signals to NK cells, depending upon the allelic polymorphisms (variations) within individual HLA-Bw4 ligands [8].

On the basis of KIR gene content, groups of two KIR haplotype A and B, have been recognized [5]. In general, group A and B KIR haplotypes have four framework genes of non-expressed KIR3DL3 located at the centromeric end and KIR3DL2 at the telomeric end, while KIR3DP1 and KIR2DL4 is located in the middle of KIR gene cluster. The non-allelic homologous recombination (deletion and duplication) of KIR genes have led to many different haplotypes [9]. Group A KIR haplotypes are found in all the populations and comprises of five productive inhibitory KIR (KIR2DL3, KIR2DL1, KIR2DL4, KIR3DL1, KIR3DL2), and the stimulatory KIR2DS4, which is normally present in an allelic variant that is not expressed at the cell surface [10]. Group B KIR haplotypes consists of diverse gene content including various genes (KIR2DL2, KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5, and KIR3DS1) which are not found in group A KIR haplotypes. Consequently, the majority of group B KIR haplotypes encode more activating KIRs as compared to group A KIR haplotypes. On the basis of group A and B KIR haplotypes all the individuals may be grouped as having one of two KIR genotypes; (i) A/A, which is homozygous for group A KIR haplotypes, or (ii) B/x, which consists of either one (A/B heterozygotes) or two (B/B homozygotes) group B haplotypes. The incidence of KIR haplotypes or specific KIR genes have been reported with susceptibility to human diseases, like autoimmune disorders [11], [12], [13], recurrent miscarriages [14], [15], infectious diseases [16] and cancers [2], [17].

There are conflicting reports regarding the association of KIR gene polymorphisms with childhood ALL in different ethnic groups [2], [3], [18]. In some studies, KIR gene polymorphisms have been shown to be associated with childhood ALL [2], [3], while other studies have found no association [18]. Most of the studies of KIR gene polymorphisms and childhood ALL have focused on children of European [18] or European American descent [2], [3] . However, till date no study on KIR gene polymorphisms among childhood ALL cases has been reported from Indian subcontinent. We have undertaken the present study to fulfill this gap.

The present study is aimed to determine the role of KIR genes and their cognate HLA ligands in genetic predisposition to childhood ALL.

Section snippets

Ethics statement

The study was approved by the ethics committee of King George’s Medical University (KGMU), Lucknow, India and was performed as per the ethical standards laid down by the Declaration of Helsinki. Informed written consent was obtained from all the individuals prior to their inclusion in the study.

Study population

We registered one hundred and fifty five pediatric cases (men = 128 (82.58%), women = 27 (17.41%)) diagnosed with childhood ALL during December 2011–March 2014. All the cases were recruited from the

Clinical parameters in childhood acute lymphoblastic leukemia cases

Mean haemoglobin at the time of presentation was 6.37 ± 2.26 g/dl. Hemoglobin level was between 5 and 10 g/dl in most of the cases, among them nearly one third cases had severe anemia (Hb < 5 g/dl). Half of the children suffering from ALL had a total leukocyte count less than 20,000 at the time of presentation. Mean absolute neutrophil counts (ANC) was 2081 ± 579 mm3. Severe neutropenia was observed in about one third of the children. Mean platelet count at presentation was 65583 ± 80578 cells/cm3.

Discussion

KIR gene repertoire recognize specific motifs of HLA class I molecules and form array of receptor–ligand interactions, which determines the NK cell response to its target [22]. NK cell interactions are dependent on the combinations of variable KIR and HLA class I gene products. The activation of NK cells is dependent on the equilibrium between the inhibitory and activating receptors. Recently, it has been suggested that the variation in KIR gene content may affect childhood ALL risk [2], [3].

Conflicts of interest

None to declare.

Acknowledgement

We are thankful to the Department of Biotechnology, Government of India, New-Delhi for providing the financial support through Bioinformatics infrastructure facility (BIF) research grant to carry out this work.

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