KIR genotypic diversity can track ancestries in heterogeneous populations: a potential confounder for disease association studies

Abstract

Killer cell immunoglobulin-like receptors (KIR) are encoded by highly polymorphic genes that regulate the activation of natural killer (NK) cells and other lymphocyte subsets, and likely play key roles in innate and adaptive immunity. Association studies increasingly implicate KIR in disease predisposition and outcome but could be confounded by unknown KIR genetic structure in heterogeneous populations. To examine this we characterized the diversity of 16 KIR genes in 712 Northern Californians (NC) stratified by selfassigned ethnicities, and compared the profiles of KIR polymorphism with other US and global populations using a reference database. Sixty-eight distinct KIR genotypes were characterized: 58 in 457 Caucasians (NCC); 17 in 47 African Americans (NCAA); 21 in 80 Asians (NCA); 20 in 74 Hispanics (NCH) and 18 in 54 “other” ethnicities (NCO). KIR genotype patterns and frequencies in the 4 defined ethnicities were compared with each other and with 34 global populations by phylogenetic analysis. Although there were no population-specific genotypes, the KIR genotype frequency patterns faithfully traced the ancestry of NCC, NCAA and NCA but not of NCH whose ancestries are known to be more heterogeneous. KIR genotype frequencies can therefore track ethnic ancestries in modern urban populations. Our data emphasize the importance of selecting ethnically matched controls in KIR based studies to avert spurious associations.

Diversity in immunogenomics: the value and the challenge

“…Furthermore, AIRR-seq data provides information on expression profiles; germline V, D and J gene usage; complementarity-determining region (CDR) diversity; and, in the case of immunoglobulin repertoires, somatic hypermutation levels. There have been extensive efforts to explore the genetic diversity of the HLA and KIR systems 13,14 , and the knowledge gained from these efforts could be integrated into the AIRR-seq studies of TCR and immunoglobulin germline gene diversity.…”

HLA-A29 and Birdshot Uveitis: Further Down the Rabbit Hole

“…Among these may also be additional factors of the antigen presentation pathway, including the autophagy gene TECPR2 previously reported ( 34 ) or Killer immunoglobulin-Like Recepto r (KIR) (KIRs) genes ( 133 ). KIR genes have been associated with BU, however, the allele frequencies of controls used in a study of BU patients may not be representative for European populations and stringent correction for multiple testing is required to avoid false-positives, which may influence the outcomes of KIR associations in BU ( 133 , 134 ). Regardless, KIRs are important receptors for T cells, but also Natural Killer (NK) cells , an understudied immune cell in the context of non-infectious uveitis that is decreased in the circulation of BU patients ( 135 ).…”