KIR genotypic diversity can track ancestries in heterogeneous populations: a potential confounder for disease association studies
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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 self-assigned 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.
KeywordsKIR genotype frequency Polymorphism Northern California population Ethnicity
We thank the subjects who participated in the study. The work was supported by the National Institutes of Health (NIH) grant R01-DK064051 (to SLC). Drs Cooper and Feng would like to acknowledge NIH Grant P30 DK026743 awarded to the UCSF Liver Center. We also thank the “Ibrahim El Hefni Liver Biorepository” at CPMC, especially Adrian Wadley and Dr. Daniel Stone for providing samples and for valuable input in the manuscript, and Catherine Carr for enthusiastically recruiting patients at CPMC liver clinics. We greatly appreciate the support of the other surgeons and hepatologists who dedicated time for patient recruitment and of the exceptional staff in the Department of Transplantation and Division of Hepatology at CPMC and UCSF and those involved with The UFO Study. Our sincere thanks to Dr. Martin Brotman for facilitating a translational research program at CPMC. We also thank Dr. Marcelo Pando, Ms. Susan Perkin and Dr. Dolly Tyan at Stanford Blood Center for testing duplicate samples. We are grateful to Dr. Jason D. Barbour for critically reading the manuscript and to the reviewers, whose suggestions and comments enriched the scientific content. We also extend our profound gratitude to The Ibrahim El-Hefni Technical Training Foundation and the El-Hefni family, The Kalmanovitz Foundation, The Raab Foundation, Mr. Harry Litke, The Unbroken Chain Foundation, and Mr. and Mrs. John Mumford for supporting multiple aspects of this study; it could not have been accomplished otherwise.
Conflict of interest
The authors declare that they have no conflicts of interest with the organizations that funded the research.
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