HLA and KIR Associations of Cervical Neoplasia

Abstract

Background: Cervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognized by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflammatory activity. We hypothesized that the inheritance of particular HLA-KIR combinations would increase cervical neoplasia risk.

Methods: Here, we used HLA and KIR dosages imputed from single-nucleotide polymorphism genotype data from 2143 cervical neoplasia cases and 13858 healthy controls of European decent.

Results: The following 4 novel HLA alleles were identified in association with cervical neoplasia, owing to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles: HLA-DRB3*9901 (odds ratio [OR], 1.24; P = 2.49 × 10-9), HLA-DRB5*0101 (OR, 1.29; P = 2.26 × 10-8), HLA-DRB5*9901 (OR, 0.77; P = 1.90 × 10-9), and HLA-DRB3*0301 (OR, 0.63; P = 4.06 × 10-5). We also found that homozygosity of HLA-C1 group alleles is a protective factor for human papillomavirus type 16 (HPV16)-related cervical neoplasia (C1/C1; OR, 0.79; P = .005). This protective association was restricted to carriers of either KIR2DL2 (OR, 0.67; P = .00045) or KIR2DS2 (OR, 0.69; P = .0006).

Conclusions: Our findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.

Figure 1.

Killer immunoglobulin-like receptor (KIR) proteins are classified by the number of extracellular immunoglobulin domains (2D or 3D) and by whether they have a long (L) or short (S) cytoplasmic domain. Inhibitory KIRs and KIR2DL4 have immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic domains. Activating KIRs possess a basic amino acid in the transmembrane domain, which allows interactions with the accessory molecule DAP-12, delivering activating signals through its immunoreceptor tyrosine-based activating (ITAM) motif. The ligands for several KIR proteins are subsets of HLA class I proteins. KIR2DL4 has a charged amino acid and ITIM motifs, and it interacts with the accessory protein FcεRI-γ, which sends an activating signal via its ITAM similar to DAP-12. Note that HLA-Bw6 alleles are not known to be KIR ligands.

Figure 2.

HLA and KIR gene imputation and association tests were performed using genotype data from 2143 cervical neoplasia cases and 13858 healthy controls of European descent. A total of 791 individuals were genotyped using the Illumina OmniExpress BeadChip tool (Omni), and 1352 individuals were genotyped using the Illumina Human660-Quad BeadChip tool (660Q). All 13428 controls were genotyped using the Illumina Immunochip BeadChip tool (Ichip). To avoid imputation bias caused by different numbers of key single-nucleotide polymorphisms (SNPs) between Omni and 660Q, these 2 groups of cases were imputed separately and compared to 2 control groups—Ichip control group 1 (Ichip1; n = 6703) and control group 2 (Ichip2; n = 6725)—obtained by randomly dividing the controls. A total of 77 key SNPs for Omni and Ichip1 and 66 key SNPs for 660Q and Ichip2 were reclustered and used for imputation. Case-control analyses were conducted separately, followed by meta-analysis. QC, quality control.

Figure 3.

Pair-wise linkage disequilibrium (r²) plot of HLA alleles associated with cervical neoplasia. HLA alleles are clustered according to their pair-wise linkage disequilibrium on both the x-axis and y-axis. On the y-axis, alleles are labeled with regard to whether they are risk or protective alleles in the overall cervical neoplasia data set, and on the x-axis, they are labeled according to whether they are HLA class I or II alleles.