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

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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 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.

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Acknowledgments

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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Authors and Affiliations

  1. Kalmanovitz Liver Immunology Laboratory, California Pacific Medical Center & Research Institute, 2340 Clay Street, 3rd floor, San Francisco, CA, 94115, USA

    Komal Manpreet Singh, Yume T. Phung, Mohamed S. Kohla, Diana L. Suen, Sahar Murad, Shana Rheault, Sofie Dohil, Adil E. Wakil & Stewart L. Cooper

  2. Division of Hepatology, California Pacific Medical Center & Sutter Pacific Medical Foundation, San Francisco, CA, USA

    Adil E. Wakil & Stewart L. Cooper

  3. Department of Transplantation, California Pacific Medical Center, San Francisco, CA, USA

    Sahar Murad, Robert W. Osorio, Adil E. Wakil & Stewart L. Cooper

  4. UCSF Liver Center, San Francisco, CA, USA

    Sandy Feng & Stewart L. Cooper

  5. Department of Transplantation, University of California, San Francisco, San Francisco, CA, USA

    Billy Y-A Lan, Sharon Chan & Sandy Feng

  6. Department of Epidemiology, University of California, San Francisco, San Francisco, CA, USA

    Peter Davidson, Jennifer Evans & Kimberly Page

  7. The National Liver Institute, Menoufiya, Egypt

    Mohamed S. Kohla

  8. https://sourceforge.net/users/manpsing

    Manpreet Singh

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  1. Komal Manpreet Singh
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  2. Yume T. Phung
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Correspondence to Stewart L. Cooper.

Additional information

The study was conducted in a multi-ethnic cohort from Northern California. Our analysis shows the potential of KIR genotype frequency polymorphism to trace populations to their native ancestries and to foil disease association studies if ethnicity is ignored. The present study focuses on the importance of defining underlying population structure in conducting KIR association studies and highlights KIR genotype polymorphism itself as a useful tool in population structure analysis. The work describes a new dataset and novel analysis. None of the material has been published or is under consideration for publication elsewhere.

Electronic supplementary material

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Supplementary Figure 1

Phylogenetic tree constructed using KIR genotype frequencies of major ethnicities sampled in Northern California (PDF 95.3 kb)

Supplementary Figure 2

Individual KIR Gene Frequencies in California (PDF 116 kb)

Supplementary Table 1

KIR genotype analysis within California (PDF 122 kb)

Supplementary Table 2

KIR alleles potentially undetected by the typing system (PDF 131 kb)

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Singh, K.M., Phung, Y.T., Kohla, M.S. et al. KIR genotypic diversity can track ancestries in heterogeneous populations: a potential confounder for disease association studies. Immunogenetics 64, 97–109 (2012). https://doi.org/10.1007/s00251-011-0569-x

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