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; Ying Pu 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, Ying Pu Sun, Paul J. Leo

School of Medicine

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

7 Scopus citations

Abstract

Background. Cervical 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 recognized 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. Methods. Here, we used HLA and KIR dosages imputed from single-nucleotide polymorphism genotype data from 2143 cervical neoplasia cases and 13 858 healthy controls of European decent. Results. The following 4 novel HLA alleles were identified in association with cervical neoplasia, owing to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles: HLA-DRB3*9901 (odds ratio [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). We also found that homozygosity of HLA-C1 group alleles is a protective factor for human papillomavirus type 16 (HPV16)-related cervical neoplasia (C1/C1; OR, 0.79; P = .005). This protective association was restricted to carriers of either KIR2DL2 (OR, 0.67; P = .00045) or KIR2DS2 (OR, 0.69; P = .0006). Conclusions. Our 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 (US)
Pages (from-to)	2006-2015
Number of pages	10
Journal	Journal of Infectious Diseases
Volume	218
Issue number	12
DOIs	https://doi.org/10.1093/infdis/jiy483
State	Published - Nov 5 2018

Keywords

Cervical neoplasia
HPV16-related cervical neoplasia
Human leukocyte antigens (HLA)
Killer immunoglobulin-like receptors (KIRs)

ASJC Scopus subject areas

General Medicine

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10.1093/infdis/jiy483

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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. 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, YP & Leo, PJ 2018, 'HLA and KIR associations of cervical neoplasia', Journal of Infectious Diseases, vol. 218, no. 12, pp. 2006-2015. https://doi.org/10.1093/infdis/jiy483

@article{457ba84d154a4f7e9aeb6f1b10252678,

title = "HLA and KIR associations of cervical neoplasia",

abstract = "Background. Cervical 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 recognized 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. Methods. Here, we used HLA and KIR dosages imputed from single-nucleotide polymorphism genotype data from 2143 cervical neoplasia cases and 13 858 healthy controls of European decent. Results. The following 4 novel HLA alleles were identified in association with cervical neoplasia, owing to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles: HLA-DRB3*9901 (odds ratio [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). We also found that homozygosity of HLA-C1 group alleles is a protective factor for human papillomavirus type 16 (HPV16)-related cervical neoplasia (C1/C1; OR, 0.79; P = .005). This protective association was restricted to carriers of either KIR2DL2 (OR, 0.67; P = .00045) or KIR2DS2 (OR, 0.69; P = .0006). Conclusions. Our 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, HPV16-related cervical neoplasia, Human leukocyte antigens (HLA), Killer immunoglobulin-like receptors (KIRs)",

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 Sun, {Ying Pu} and Leo, {Paul J.}",

year = "2018",

month = nov,

day = "5",

doi = "10.1093/infdis/jiy483",

language = "English (US)",

volume = "218",

pages = "2006--2015",

journal = "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, Ying Pu

AU - Leo, Paul J.

PY - 2018/11/5

Y1 - 2018/11/5

N2 - Background. Cervical 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 recognized 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. Methods. Here, we used HLA and KIR dosages imputed from single-nucleotide polymorphism genotype data from 2143 cervical neoplasia cases and 13 858 healthy controls of European decent. Results. The following 4 novel HLA alleles were identified in association with cervical neoplasia, owing to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles: HLA-DRB3*9901 (odds ratio [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). We also found that homozygosity of HLA-C1 group alleles is a protective factor for human papillomavirus type 16 (HPV16)-related cervical neoplasia (C1/C1; OR, 0.79; P = .005). This protective association was restricted to carriers of either KIR2DL2 (OR, 0.67; P = .00045) or KIR2DS2 (OR, 0.69; P = .0006). Conclusions. Our findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.

AB - Background. Cervical 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 recognized 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. Methods. Here, we used HLA and KIR dosages imputed from single-nucleotide polymorphism genotype data from 2143 cervical neoplasia cases and 13 858 healthy controls of European decent. Results. The following 4 novel HLA alleles were identified in association with cervical neoplasia, owing to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles: HLA-DRB3*9901 (odds ratio [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). We also found that homozygosity of HLA-C1 group alleles is a protective factor for human papillomavirus type 16 (HPV16)-related cervical neoplasia (C1/C1; OR, 0.79; P = .005). This protective association was restricted to carriers of either KIR2DL2 (OR, 0.67; P = .00045) or KIR2DS2 (OR, 0.69; P = .0006). Conclusions. Our 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 - HPV16-related cervical neoplasia

KW - Human leukocyte antigens (HLA)

KW - Killer immunoglobulin-like receptors (KIRs)

UR - http://www.scopus.com/inward/record.url?scp=85056286117&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056286117&partnerID=8YFLogxK

U2 - 10.1093/infdis/jiy483

DO - 10.1093/infdis/jiy483

M3 - Article

C2 - 30099516

AN - SCOPUS:85056286117

SN - 0022-1899

VL - 218

SP - 2006

EP - 2015

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

IS - 12

ER -

HLA and KIR associations of cervical neoplasia

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