HLA and KIR Associations of Cervical Neoplasia

Xiao Bao; Aimee L Hanson; Margaret M Madeleine; Sophia S Wang; Stephen M Schwartz; Felicity Newell; Ulrika Pettersson-Kymmer; Kari Hemminki; Sven Tiews; Winfried Steinberg; Janet S Rader; Felipe Castro; Mahboobeh Safaeian; Eduardo L Franco; François Coutlée; Claes Ohlsson; Adrian Cortes; Mhairi Marshall; Pamela Mukhopadhyay; Katie Cremin; Lisa G Johnson; Suzanne M Garland; Sepehr N Tabrizi; Nicolas Wentzensen; Freddy Sitas; Cornelia Trimble; Julian Little; Maggie Cruickshank; Ian H Frazer; Allan Hildesheim; Matthew A Brown; Emma L Duncan; YingPu Sun; Paul J Leo

doi:10.1093/infdis/jiy483

HLA and KIR Associations of Cervical Neoplasia

Xiao Bao, Aimee L Hanson, Margaret M Madeleine, Sophia S Wang, Stephen M Schwartz, Felicity Newell, Ulrika Pettersson-Kymmer, Kari Hemminki, Sven Tiews, Winfried Steinberg, Janet S Rader, Felipe Castro, Mahboobeh Safaeian, Eduardo L Franco, François Coutlée, Claes Ohlsson, Adrian Cortes, Mhairi Marshall, Pamela Mukhopadhyay, Katie CreminLisa G Johnson, Suzanne M Garland, Sepehr N Tabrizi, Nicolas Wentzensen, Freddy Sitas, Cornelia Trimble, Julian Little, Maggie Cruickshank, Ian H Frazer, Allan Hildesheim, Matthew A Brown, Emma L Duncan, YingPu Sun^* (Corresponding Author), Paul J Leo

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

BackgroundCervical 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 recognised 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.MethodsHere, we used HLA and KIR dosages imputed from SNP genotype data from 2,143 cervical neoplasia cases and 13,858 healthy controls of European decent.ResultsFour novel HLA alleles were identified in association with cervical neoplasia: HLA-DRB3*9901 (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), due to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles. We also found homozygosity of HLA-C1 group alleles is a protective factor for HPV16-related cervical neoplasia (C1/C1, OR=0.79, P=0.005). This protective association was restricted to carriers of either KIR2DL2 (OR=0.67, P=0.00045) or KIR2DS2 (OR=0.69, P=0.0006).ConclusionsOur findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.

Original language	English
Pages (from-to)	2006-2015
Number of pages	15
Journal	The journal of infectious diseases
Volume	218
Issue number	12
Early online date	7 Aug 2018
DOIs	https://doi.org/10.1093/infdis/jiy483
Publication status	Published - 15 Dec 2018

Keywords

cervical neoplasia
human leukocyte antigens (HLA)
killer immunoglobulin-like receptors (KIRs)
HPV16-related cervical neoplasia

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Accepted Manuscript
This is a pre-copyedited, author-produced version of an article accepted for publication in Journal of Infectious Diseases following peer review. The version of record Xiao Bao, Aimee L Hanson, Margaret M Madeleine, Sophia S Wang, Stephen M Schwartz, Felicity Newell, Ulrika Pettersson-Kymmer, Kari Hemminki, Sven Tiews, Winfried Steinberg, Janet S Rader, Felipe Castro, Mahboobeh Safaeian, Eduardo L Franco, François Coutlée, Claes Ohlsson, Adrian Cortes, Mhairi Marshall, Pamela Mukhopadhyay, Katie Cremin, Lisa G Johnson, Suzanne M Garland, Sepehr N Tabrizi, Nicolas Wentzensen, Freddy Sitas, Cornelia Trimble, Julian Little, Maggie Cruickshank, Ian H Frazer, Allan Hildesheim, Matthew A Brown, Emma L Duncan, Ying Pu Sun, Paul J Leo; HLA and KIR Associations of Cervical Neoplasia, The Journal of Infectious Diseases, Volume 218, Issue 12, 5 November 2018, Pages 2006–2015 is available online at: https://academic.oup.com/jid/article/218/12/2006/5067537
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Cite this

Bao, X., Hanson, A. L., Madeleine, M. M., Wang, S. S., Schwartz, S. M., Newell, F., Pettersson-Kymmer, U., Hemminki, K., Tiews, S., Steinberg, W., Rader, J. S., Castro, F., Safaeian, M., Franco, E. L., Coutlée, F., Ohlsson, C., Cortes, A., Marshall, M., Mukhopadhyay, P., ... Leo, P. J. (2018). HLA and KIR Associations of Cervical Neoplasia. The journal of infectious diseases, 218(12), 2006-2015. https://doi.org/10.1093/infdis/jiy483

Bao, X, Hanson, AL, Madeleine, MM, Wang, SS, Schwartz, SM, Newell, F, Pettersson-Kymmer, U, Hemminki, K, Tiews, S, Steinberg, W, Rader, JS, Castro, F, Safaeian, M, Franco, EL, Coutlée, F, Ohlsson, C, Cortes, A, Marshall, M, Mukhopadhyay, P, Cremin, K, Johnson, LG, Garland, SM, Tabrizi, SN, Wentzensen, N, Sitas, F, Trimble, C, Little, J, Cruickshank, M, Frazer, IH, Hildesheim, A, Brown, MA, Duncan, EL, Sun, Y & Leo, PJ 2018, 'HLA and KIR Associations of Cervical Neoplasia', The journal of infectious diseases, vol. 218, no. 12, pp. 2006-2015. https://doi.org/10.1093/infdis/jiy483

@article{02870b85f41f4763a36ea5d15615d760,

title = "HLA and KIR Associations of Cervical Neoplasia",

abstract = "BackgroundCervical 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 recognised 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.MethodsHere, we used HLA and KIR dosages imputed from SNP genotype data from 2,143 cervical neoplasia cases and 13,858 healthy controls of European decent.ResultsFour novel HLA alleles were identified in association with cervical neoplasia: HLA-DRB3*9901 (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), due to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles. We also found homozygosity of HLA-C1 group alleles is a protective factor for HPV16-related cervical neoplasia (C1/C1, OR=0.79, P=0.005). This protective association was restricted to carriers of either KIR2DL2 (OR=0.67, P=0.00045) or KIR2DS2 (OR=0.69, P=0.0006).ConclusionsOur findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.",

keywords = "cervical neoplasia, human leukocyte antigens (HLA), killer immunoglobulin-like receptors (KIRs), HPV16-related cervical neoplasia",

author = "Xiao Bao and Hanson, {Aimee L} and Madeleine, {Margaret M} and Wang, {Sophia S} and Schwartz, {Stephen M} and Felicity Newell and Ulrika Pettersson-Kymmer and Kari Hemminki and Sven Tiews and Winfried Steinberg and Rader, {Janet S} and Felipe Castro and Mahboobeh Safaeian and Franco, {Eduardo L} and Fran{\c c}ois Coutl{\'e}e and Claes Ohlsson and Adrian Cortes and Mhairi Marshall and Pamela Mukhopadhyay and Katie Cremin and Johnson, {Lisa G} and Garland, {Suzanne M} and Tabrizi, {Sepehr N} and Nicolas Wentzensen and Freddy Sitas and Cornelia Trimble and Julian Little and Maggie Cruickshank and Frazer, {Ian H} and Allan Hildesheim and Brown, {Matthew A} and Duncan, {Emma L} and YingPu Sun and Leo, {Paul J}",

year = "2018",

month = dec,

day = "15",

doi = "10.1093/infdis/jiy483",

language = "English",

volume = "218",

pages = "2006--2015",

journal = "The journal of infectious diseases",

issn = "0022-1899",

publisher = "Oxford University Press",

number = "12",

}

TY - JOUR

T1 - HLA and KIR Associations of Cervical Neoplasia

AU - Bao, Xiao

AU - Hanson, Aimee L

AU - Madeleine, Margaret M

AU - Wang, Sophia S

AU - Schwartz, Stephen M

AU - Newell, Felicity

AU - Pettersson-Kymmer, Ulrika

AU - Hemminki, Kari

AU - Tiews, Sven

AU - Steinberg, Winfried

AU - Rader, Janet S

AU - Castro, Felipe

AU - Safaeian, Mahboobeh

AU - Franco, Eduardo L

AU - Coutlée, François

AU - Ohlsson, Claes

AU - Cortes, Adrian

AU - Marshall, Mhairi

AU - Mukhopadhyay, Pamela

AU - Cremin, Katie

AU - Johnson, Lisa G

AU - Garland, Suzanne M

AU - Tabrizi, Sepehr N

AU - Wentzensen, Nicolas

AU - Sitas, Freddy

AU - Trimble, Cornelia

AU - Little, Julian

AU - Cruickshank, Maggie

AU - Frazer, Ian H

AU - Hildesheim, Allan

AU - Brown, Matthew A

AU - Duncan, Emma L

AU - Sun, YingPu

AU - Leo, Paul J

PY - 2018/12/15

Y1 - 2018/12/15

N2 - BackgroundCervical 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 recognised 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.MethodsHere, we used HLA and KIR dosages imputed from SNP genotype data from 2,143 cervical neoplasia cases and 13,858 healthy controls of European decent.ResultsFour novel HLA alleles were identified in association with cervical neoplasia: HLA-DRB3*9901 (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), due to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles. We also found homozygosity of HLA-C1 group alleles is a protective factor for HPV16-related cervical neoplasia (C1/C1, OR=0.79, P=0.005). This protective association was restricted to carriers of either KIR2DL2 (OR=0.67, P=0.00045) or KIR2DS2 (OR=0.69, P=0.0006).ConclusionsOur findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.

AB - BackgroundCervical 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 recognised 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.MethodsHere, we used HLA and KIR dosages imputed from SNP genotype data from 2,143 cervical neoplasia cases and 13,858 healthy controls of European decent.ResultsFour novel HLA alleles were identified in association with cervical neoplasia: HLA-DRB3*9901 (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), due to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles. We also found homozygosity of HLA-C1 group alleles is a protective factor for HPV16-related cervical neoplasia (C1/C1, OR=0.79, P=0.005). This protective association was restricted to carriers of either KIR2DL2 (OR=0.67, P=0.00045) or KIR2DS2 (OR=0.69, P=0.0006).ConclusionsOur findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.

KW - cervical neoplasia

KW - human leukocyte antigens (HLA)

KW - killer immunoglobulin-like receptors (KIRs)

KW - HPV16-related cervical neoplasia

U2 - 10.1093/infdis/jiy483

DO - 10.1093/infdis/jiy483

M3 - Article

VL - 218

SP - 2006

EP - 2015

JO - The journal of infectious diseases

JF - The journal of infectious diseases

SN - 0022-1899

IS - 12

ER -

HLA and KIR Associations of Cervical Neoplasia

Abstract

Keywords

UN SDGs

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