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 & 14 others 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

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)2006-2015
Number of pages15
JournalThe journal of infectious diseases
Volume218
Issue number12
Early online date7 Aug 2018
DOIs
Publication statusPublished - 15 Dec 2018

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KIR Receptors
HLA Antigens
Neoplasms
Alleles
Linkage Disequilibrium
Single Nucleotide Polymorphism

Keywords

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

Cite this

Bao, X., Hanson, A. L., Madeleine, M. M., Wang, S. S., Schwartz, S. M., Newell, F., ... 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

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

In: The journal of infectious diseases, Vol. 218, No. 12, 15.12.2018, p. 2006-2015.

Research output: Contribution to journalArticle

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
Bao X, Hanson AL, Madeleine MM, Wang SS, Schwartz SM, Newell F et al. HLA and KIR Associations of Cervical Neoplasia. The journal of infectious diseases. 2018 Dec 15;218(12):2006-2015. https://doi.org/10.1093/infdis/jiy483
Bao, Xiao ; Hanson, Aimee L ; Madeleine, Margaret M ; Wang, Sophia S ; Schwartz, Stephen M ; Newell, Felicity ; Pettersson-Kymmer, Ulrika ; Hemminki, Kari ; Tiews, Sven ; Steinberg, Winfried ; Rader, Janet S ; Castro, Felipe ; Safaeian, Mahboobeh ; Franco, Eduardo L ; Coutlée, François ; Ohlsson, Claes ; Cortes, Adrian ; Marshall, Mhairi ; Mukhopadhyay, Pamela ; Cremin, Katie ; Johnson, Lisa G ; Garland, Suzanne M ; Tabrizi, Sepehr N ; Wentzensen, Nicolas ; Sitas, Freddy ; Trimble, Cornelia ; Little, Julian ; Cruickshank, Maggie ; Frazer, Ian H ; Hildesheim, Allan ; Brown, Matthew A ; Duncan, Emma L ; Sun, YingPu ; Leo, Paul J. / HLA and KIR Associations of Cervical Neoplasia. In: The journal of infectious diseases. 2018 ; Vol. 218, No. 12. pp. 2006-2015.
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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{\cc}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}",
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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 -