Allele imputation for the killer cell immunoglobulin-like receptor KIR3DL1/S1

Abstract

Highly polymorphic interaction of KIR3DL1 and KIR3DS1 with HLA class I ligands modulates the effector functions of natural killer (NK) cells and some T cells. This genetically determined diversity affects severity of infections, immune-mediated diseases, and some cancers, and impacts the course of immunotherapies, including transplantation. KIR3DL1 is an inhibitory receptor, and KIR3DS1 is an activating receptor encoded by the KIR3DL1/S1 gene that has more than 200 diverse and divergent alleles. Determination of KIR3DL1/S1 genotypes for medical application is hampered by complex sequence and structural variation, requiring targeted approaches to generate and analyze high-resolution allele data. To overcome these obstacles, we developed and optimized a model for imputing KIR3DL1/S1 alleles at high-resolution from whole-genome SNP data. We designed the model to represent a substantial component of human genetic diversity. Our Global imputation model is effective at genotyping KIR3DL1/S1 alleles with an accuracy ranging from 88% in Africans to 97% in East Asians, with mean specificity of 99% and sensitivity of 95% for alleles >1% frequency. We used the established algorithm of the HIBAG program, in a modification named Pulling Out Natural killer cell Genomics (PONG). Because HIBAG was designed to impute HLA alleles also from whole-genome SNP data, PONG allows combinatorial diversity of KIR3DL1/S1 with HLA-A and -B to be analyzed using complementary techniques on a single data source. The use of PONG thus negates the need for targeted sequencing data in very large-scale association studies where such methods might not be tractable.

Combined flow cytometry natural killer immunophenotyping and KIR/HLA-C genotyping reveal remarkable differences in acute myeloid leukemia patients, but suggest an overall impairment of the natural killer response

“…KIR individual haplotypes present an impressive diversity due to allelic polymorphism and inheritance of different genes encoding activating and inhibitory receptors, which are known to bind HLA class I molecules ( 49 ). For instance, KIR2DL1 (CD158a) and KIR2DL2/2DL3 (CD158b) bind to HLA-C, while KIR3DL1 (CD158e1) binds to HLA-A and HLA-B ( 20 ). The absence of such molecules on the surface of a particular cell (generally described as “missing self”) ( 7 ) makes it a target for the NK attack.…”

“…KIR2DL1 bind to HLA-C2, while KIR2DL2 and KIR2DL3 bind to HLA-C1. KIR3DL1 binds to the Bw4 epitope of the HLA-A and B molecules ( 20 ). NKG2A (CD159a) pairs with CD94 to make an inhibitory receptor that binds to HLA-E, a non-classical MHC ( 21 ).…”

Evaluation of KIR3DL1/KIR3DS1 allelic polymorphisms in Kenyan children with endemic Burkitt lymphoma

“…KIR3DL1 is a highly polymorphic KIR whose locus encodes inhibitory (KIR3DL1) and activating (KIR3DS1) allotypes (IPD-KIR sequence database: http://www.ebi.ac.uk/ipd/kir/ ) [ 26 ]. The KIR3DL1/3DS1 gene has over 200 alleles [ 27 ]; which can be classified into three genotypes 3DL1 / 3DL1 , 3DL1 / 3DS1 , or 3DS1 / 3DS1 [ 28 ]. Considering the different patterns of expression and homology, the alleles can be categorized into functionally distinct KIR3DL1*High , KIR3DL1*Low , KIR3DL1*Null , and KIR3DS1 (3DS1) genotypes [ 29 , 30 ].…”

HLA-B*57:01 Complexed to a CD8 T-Cell Epitope from the HSV-2 ICP22 Protein Binds NK and T Cells through KIR3DL1

“…Along with other HLA allelic variants sharing the Bw4 determinant, HLA-B*57:01 appears to have specificity for KIR3DL1. Most persons possess one or two functional copies of either KIR3DL1 , [ 9 , 10 , 11 ] or KIR3DS1 , an activating variant of KIR3DL1 that can occur at the same location in the KIR locus on human chromosome 19 [ 12 ]. KIR3DL1 has many allelic variants that encode different protein sequences with differing expression levels on the cell surface, which impacts the strength of NK cell inhibition [ 9 , 13 ].…”