Defining the genetic susceptibility to cervical neoplasia - a genome-wide association study

Paul J. Leo; Margaret M. Madeleine; Sophia Wang; Stephen M. Schwartz; Felicity Newell; Ulrika Kymmer; Kari Hemminki; Goran Hallmans; Sven Tiews; Winfried Steinberg; Janet S. Rader; Felipe Castro; Mahboobeh Safaeian; Eduardo L. Franco; Francois Coutlee; Claes Ohlsson; Adrian Cortes; Mhairi Marshall; Pamela Mukhopadhyay; Katie Cremin; Lisa G. Johnson; Suzanne Garland; Sepehr N. Tabrizi; Nicolas Wentzensen; Freddy Sitas; Julian Little; Maggie Cruickshank; Ian H. Frazer; Allan Hildesheim; Matthew A. Brown

doi:10.1371/journal.pgen.1006866

Defining the genetic susceptibility to cervical neoplasia - a genome-wide association study

Paul J. Leo, Margaret M. Madeleine, Sophia Wang, Stephen M. Schwartz, Felicity Newell, Ulrika Kymmer, Kari Hemminki, Goran Hallmans, Sven Tiews, Winfried Steinberg, Janet S. Rader, Felipe Castro, Mahboobeh Safaeian, Eduardo L. Franco, Francois Coutlee, Claes Ohlsson, Adrian Cortes, Mhairi Marshall, Pamela Mukhopadhyay, Katie CreminLisa G. Johnson, Suzanne Garland, Sepehr N. Tabrizi, Nicolas Wentzensen, Freddy Sitas, Julian Little, Maggie Cruickshank, Ian H. Frazer, Allan Hildesheim, Matthew A. Brown (Corresponding Author)

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Abstract

A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.

Original language	English
Article number	1006866
Number of pages	20
Journal	PLoS Genetics
Volume	13
Issue number	8
Early online date	14 Aug 2017
DOIs	https://doi.org/10.1371/journal.pgen.1006866 https://doi.org/10.1371/journal.pgen.1007257
Publication status	Published - 2017

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10.1371/journal.pgen.1007257Licence: CC BY

Defining the genetic susceptibility to cervical neoplasia—A genome-wide association study
Copyright: © 2017 Leo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. https://creativecommons.org/licenses/by/4.0/
Final published version, 2.98 MBLicence: CC BY
Correction: Defining the genetic susceptibility to cervical neoplasia A genome-wide association studyFinal published version, 219 KBLicence: CC BY

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Leo, P. J., Madeleine, M. M., Wang, S., Schwartz, S. M., Newell, F., Kymmer, U., Hemminki, K., Hallmans, G., Tiews, S., Steinberg, W., Rader, J. S., Castro, F., Safaeian, M., Franco, E. L., Coutlee, F., Ohlsson, C., Cortes, A., Marshall, M., Mukhopadhyay, P., ... Brown, M. A. (2017). Defining the genetic susceptibility to cervical neoplasia - a genome-wide association study. PLoS Genetics, 13(8), [1006866]. https://doi.org/10.1371/journal.pgen.1006866, https://doi.org/10.1371/journal.pgen.1007257

Leo, PJ, Madeleine, MM, Wang, S, Schwartz, SM, Newell, F, Kymmer, U, Hemminki, K, Hallmans, G, Tiews, S, Steinberg, W, Rader, JS, Castro, F, Safaeian, M, Franco, EL, Coutlee, F, Ohlsson, C, Cortes, A, Marshall, M, Mukhopadhyay, P, Cremin, K, Johnson, LG, Garland, S, Tabrizi, SN, Wentzensen, N, Sitas, F, Little, J, Cruickshank, M, Frazer, IH, Hildesheim, A & Brown, MA 2017, 'Defining the genetic susceptibility to cervical neoplasia - a genome-wide association study', PLoS Genetics, vol. 13, no. 8, 1006866. https://doi.org/10.1371/journal.pgen.1006866, https://doi.org/10.1371/journal.pgen.1007257

@article{450b495fd8c841e784c37d278821111e,

title = "Defining the genetic susceptibility to cervical neoplasia - a genome-wide association study",

abstract = "A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.",

author = "Leo, {Paul J.} and Madeleine, {Margaret M.} and Sophia Wang and Schwartz, {Stephen M.} and Felicity Newell and Ulrika Kymmer and Kari Hemminki and Goran Hallmans and Sven Tiews and Winfried Steinberg and Rader, {Janet S.} and Felipe Castro and Mahboobeh Safaeian and Franco, {Eduardo L.} and Francois Coutlee and Claes Ohlsson and Adrian Cortes and Mhairi Marshall and Pamela Mukhopadhyay and Katie Cremin and Johnson, {Lisa G.} and Suzanne Garland and Tabrizi, {Sepehr N.} and Nicolas Wentzensen and Freddy Sitas and Julian Little and Maggie Cruickshank and Frazer, {Ian H.} and Allan Hildesheim and Brown, {Matthew A.}",

note = "Funding: MAB was funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship. Support was also received from the Australian Cancer Research Foundation. JL holds a Tier 1 Canada Research Chair in Human Genome Epidemiology. The Seattle study was supported by the following grants: NIH, National Cancer Institute grants P01CA042792 and R01CA112512. Cervical Health Study (from which the NSW component was obtained) was funded by NHMRC Grant 387701, and CCNSW core grant. The Montreal study was funded by the Canadian Institutes of Health Research (grant MOP-42532) and sample processing was funded by the Reseau FRQS SIDA-MI. The Swedish Research Council, the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg and Ume{\aa}, the Lundberg Foundation, the Torsten and Ragnar Soderberg{\textquoteright}s Foundation, the Novo Nordisk Foundation, and the European Commission grant HEALTH-F2-2008-201865-GEFOS, BBMRI.se, the Swedish Society of Medicine, the KempeFoundation (JCK-1021), the Medical Faculty of Ume{\aa} University, the County Council of Vasterbotten (Spjutspetsanslag VLL:159:33-2007). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript",

year = "2017",

doi = "10.1371/journal.pgen.1006866",

language = "English",

volume = "13",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

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TY - JOUR

T1 - Defining the genetic susceptibility to cervical neoplasia - a genome-wide association study

AU - Leo, Paul J.

AU - Madeleine, Margaret M.

AU - Wang, Sophia

AU - Schwartz, Stephen M.

AU - Newell, Felicity

AU - Kymmer, Ulrika

AU - Hemminki, Kari

AU - Hallmans, Goran

AU - Tiews, Sven

AU - Steinberg, Winfried

AU - Rader, Janet S.

AU - Castro, Felipe

AU - Safaeian, Mahboobeh

AU - Franco, Eduardo L.

AU - Coutlee, Francois

AU - Ohlsson, Claes

AU - Cortes, Adrian

AU - Marshall, Mhairi

AU - Mukhopadhyay, Pamela

AU - Cremin, Katie

AU - Johnson, Lisa G.

AU - Garland, Suzanne

AU - Tabrizi, Sepehr N.

AU - Wentzensen, Nicolas

AU - Sitas, Freddy

AU - Little, Julian

AU - Cruickshank, Maggie

AU - Frazer, Ian H.

AU - Hildesheim, Allan

AU - Brown, Matthew A.

N1 - Funding: MAB was funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship. Support was also received from the Australian Cancer Research Foundation. JL holds a Tier 1 Canada Research Chair in Human Genome Epidemiology. The Seattle study was supported by the following grants: NIH, National Cancer Institute grants P01CA042792 and R01CA112512. Cervical Health Study (from which the NSW component was obtained) was funded by NHMRC Grant 387701, and CCNSW core grant. The Montreal study was funded by the Canadian Institutes of Health Research (grant MOP-42532) and sample processing was funded by the Reseau FRQS SIDA-MI. The Swedish Research Council, the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg and Umeå, the Lundberg Foundation, the Torsten and Ragnar Soderberg’s Foundation, the Novo Nordisk Foundation, and the European Commission grant HEALTH-F2-2008-201865-GEFOS, BBMRI.se, the Swedish Society of Medicine, the KempeFoundation (JCK-1021), the Medical Faculty of Umeå University, the County Council of Vasterbotten (Spjutspetsanslag VLL:159:33-2007). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

PY - 2017

Y1 - 2017

N2 - A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.

AB - A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.

U2 - 10.1371/journal.pgen.1006866

DO - 10.1371/journal.pgen.1006866

M3 - Article

VL - 13

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 8

M1 - 1006866

ER -

Defining the genetic susceptibility to cervical neoplasia - a genome-wide association study

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