Variation in ERAP2 has opposing effects on severe respiratory infection and autoimmune disease

Fergus W Hamilton; Alexander J Mentzer; Tom Parks; J Kenneth Baillie; George Davey Smith; Peter Ghazal; Nicholas J Timpson

doi:10.1016/j.ajhg.2023.02.008

Variation in ERAP2 has opposing effects on severe respiratory infection and autoimmune disease

Fergus W Hamilton^*
, Alexander J Mentzer
, Tom Parks
, J Kenneth Baillie
, George Davey Smith
, Peter Ghazal
, Nicholas J Timpson

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

21 Citations (Scopus)

62 Downloads (Pure)

Abstract

ERAP2 is an aminopeptidase involved in immunological antigen presentation. Genotype data in human samples from before and after the Black Death, an epidemic due to Yersinia pestis, have marked changes in allele frequency of the single-nucleotide polymorphism (SNP) rs2549794, with the T allele suggested to be deleterious during this period, while ERAP2 is also implicated in autoimmune diseases. This study explored the association between variation at ERAP2 and (1) infection, (2) autoimmune disease, and (3) parental longevity. Genome-wide association studies (GWASs) of these outcomes were identified in contemporary cohorts (UK Biobank, FinnGen, and GenOMICC). Effect estimates were extracted for rs2549794 and rs2248374, a haplotype tagging SNP. Additionally, cis expression and protein quantitative trait loci (QTLs) for ERAP2 were used in Mendelian randomization (MR) analyses. Consistent with decreased survival in the Black Death, the T allele of rs2549794 showed evidence of association with respiratory infection (odds ratio; OR for pneumonia 1.03; 95% CI 1.01–1.05). Effect estimates were larger for more severe phenotypes (OR for critical care admission with pneumonia 1.08; 95% CI 1.02–1.14). In contrast, opposing effects were identified for Crohn disease (OR 0.86; 95% CI 0.82–0.90). This allele was shown to associate with decreased ERAP2 expression and protein levels, independent of haplotype. MR analyses suggest that ERAP2 expression may be mediating disease associations. Decreased ERAP2 expression is associated with severe respiratory infection with an opposing association with autoimmune diseases. These data support the hypothesis of balancing selection at this locus driven by autoimmune and infectious disease.

Original language	English
Pages (from-to)	691-702
Number of pages	12
Journal	American Journal of Human Genetics
Volume	110
Issue number	4
Early online date	7 Mar 2023
DOIs	https://doi.org/10.1016/j.ajhg.2023.02.008
Publication status	Published - 6 Apr 2023

Bibliographical note

Funding Information:
F.H.’s time was funded by the GW4-CAT Wellcome Doctoral Fellowship Scheme (222894/Z/21/Z). UK Biobank was funded by the Wellcome Trust, the Medical Research Council, the NIHR, and a variety of other charities (https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/our-funding). FinnGen is a public-private partnership (https://www.finngen.fi/en/access_results) funded by multiple institutions across Finland. The authors want to acknowledge the participants and investigators of the FinnGen study. A.J.M. is a NIHR Academic Clinical Lecturer and supported by the Oxford Biomedical Research Centre (BRC). J.K.B. gratefully acknowledges funding support from a Wellcome Trust Senior Research Fellowship (223164/Z/21/Z), UKRI grants MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1, and MC_PC_20029, Sepsis Research (Fiona Elizabeth Agnew Trust), a BBSRC Institute Strategic Program Grant to the Roslin Institute (BB/P013732/1, BB/P013759/1), and the UK Intensive Care Society. We gratefully acknowledge the support of Baillie Gifford and the Baillie Gifford Science Pandemic Hub at the University of Edinburgh. P.G.’s time was funded by the Ser Cymru programme, the Welsh Government, and the EU-ERDF. N.J.T. is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Center (BRC-1215-2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011/1), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). T.P. was funded by the Wellcome Trust Clinical Career Development Fellowship (222098/Z/20/Z). G.D.S. works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). This research was funded in whole, or in part, by the Wellcome Trust (222894/Z/21/Z). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. No authors declare any conflicts of interest.

Funding Information:
F.H.’s time was funded by the GW4-CAT Wellcome Doctoral Fellowship Scheme ( 222894/Z/21/Z ). UK Biobank was funded by the Wellcome Trust , the Medical Research Council , the NIHR , and a variety of other charities ( https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/our-funding ). FinnGen is a public-private partnership ( https://www.finngen.fi/en/access_results ) funded by multiple institutions across Finland. The authors want to acknowledge the participants and investigators of the FinnGen study. A.J.M. is a NIHR Academic Clinical Lecturer and supported by the Oxford Biomedical Research Centre (BRC). J.K.B. gratefully acknowledges funding support from a Wellcome Trust Senior Research Fellowship ( 223164/Z/21/Z ), UKRI grants MC_PC_20004 , MC_PC_19025 , MC_PC_1905 , MRNO2995X/1 , and MC_PC_20029 , Sepsis Research ( Fiona Elizabeth Agnew Trust ), a BBSRC Institute Strategic Program Grant to the Roslin Institute ( BB/P013732/1 , BB/P013759/1 ), and the UK Intensive Care Society . We gratefully acknowledge the support of Baillie Gifford and the Baillie Gifford Science Pandemic Hub at the University of Edinburgh . P.G.’s time was funded by the Ser Cymru programme , the Welsh Government , and the EU-ERDF . N.J.T. is a Wellcome Trust Investigator ( 202802/Z/16/Z ), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z ), is supported by the University of Bristol NIHR Biomedical Research Center ( BRC-1215-2001 ) and the MRC Integrative Epidemiology Unit ( MC_UU_00011/1 ), and works within the CRUK Integrative Cancer Epidemiology Programme ( C18281/A29019 ). T.P. was funded by the Wellcome Trust Clinical Career Development Fellowship ( 222098/Z/20/Z ). G.D.S. works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council ( MC_UU_00011/1 ).

Funding Information:
This research was funded in whole, or in part, by the Wellcome Trust ( 222894/Z/21/Z ). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

Publisher Copyright:
© 2023 The Author(s)

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Bristol Population Health Science Institute

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This is the accepted author manuscript (AAM). The final published version (version of record) is available online via Cell Press at https://doi.org/10.1016/j.ajhg.2023.02.008. Please refer to any applicable terms of use of the publisher.
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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

Cite this

@article{96c95d6462134b33b74d7bd3ca1e7750,

title = "Variation in ERAP2 has opposing effects on severe respiratory infection and autoimmune disease",

abstract = "ERAP2 is an aminopeptidase involved in immunological antigen presentation. Genotype data in human samples from before and after the Black Death, an epidemic due to Yersinia pestis, have marked changes in allele frequency of the single-nucleotide polymorphism (SNP) rs2549794, with the T allele suggested to be deleterious during this period, while ERAP2 is also implicated in autoimmune diseases. This study explored the association between variation at ERAP2 and (1) infection, (2) autoimmune disease, and (3) parental longevity. Genome-wide association studies (GWASs) of these outcomes were identified in contemporary cohorts (UK Biobank, FinnGen, and GenOMICC). Effect estimates were extracted for rs2549794 and rs2248374, a haplotype tagging SNP. Additionally, cis expression and protein quantitative trait loci (QTLs) for ERAP2 were used in Mendelian randomization (MR) analyses. Consistent with decreased survival in the Black Death, the T allele of rs2549794 showed evidence of association with respiratory infection (odds ratio; OR for pneumonia 1.03; 95\% CI 1.01–1.05). Effect estimates were larger for more severe phenotypes (OR for critical care admission with pneumonia 1.08; 95\% CI 1.02–1.14). In contrast, opposing effects were identified for Crohn disease (OR 0.86; 95\% CI 0.82–0.90). This allele was shown to associate with decreased ERAP2 expression and protein levels, independent of haplotype. MR analyses suggest that ERAP2 expression may be mediating disease associations. Decreased ERAP2 expression is associated with severe respiratory infection with an opposing association with autoimmune diseases. These data support the hypothesis of balancing selection at this locus driven by autoimmune and infectious disease.",

author = "Hamilton, \{Fergus W\} and Mentzer, \{Alexander J\} and Tom Parks and Baillie, \{J Kenneth\} and Smith, \{George Davey\} and Peter Ghazal and Timpson, \{Nicholas J\}",

note = "Funding Information: F.H.{\textquoteright}s time was funded by the GW4-CAT Wellcome Doctoral Fellowship Scheme (222894/Z/21/Z). UK Biobank was funded by the Wellcome Trust, the Medical Research Council, the NIHR, and a variety of other charities (https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/our-funding). FinnGen is a public-private partnership (https://www.finngen.fi/en/access\_results) funded by multiple institutions across Finland. The authors want to acknowledge the participants and investigators of the FinnGen study. A.J.M. is a NIHR Academic Clinical Lecturer and supported by the Oxford Biomedical Research Centre (BRC). J.K.B. gratefully acknowledges funding support from a Wellcome Trust Senior Research Fellowship (223164/Z/21/Z), UKRI grants MC\_PC\_20004, MC\_PC\_19025, MC\_PC\_1905, MRNO2995X/1, and MC\_PC\_20029, Sepsis Research (Fiona Elizabeth Agnew Trust), a BBSRC Institute Strategic Program Grant to the Roslin Institute (BB/P013732/1, BB/P013759/1), and the UK Intensive Care Society. We gratefully acknowledge the support of Baillie Gifford and the Baillie Gifford Science Pandemic Hub at the University of Edinburgh. P.G.{\textquoteright}s time was funded by the Ser Cymru programme, the Welsh Government, and the EU-ERDF. N.J.T. is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC \& WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Center (BRC-1215-2001) and the MRC Integrative Epidemiology Unit (MC\_UU\_00011/1), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). T.P. was funded by the Wellcome Trust Clinical Career Development Fellowship (222098/Z/20/Z). G.D.S. works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC\_UU\_00011/1). This research was funded in whole, or in part, by the Wellcome Trust (222894/Z/21/Z). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. No authors declare any conflicts of interest. Funding Information: F.H.{\textquoteright}s time was funded by the GW4-CAT Wellcome Doctoral Fellowship Scheme ( 222894/Z/21/Z ). UK Biobank was funded by the Wellcome Trust , the Medical Research Council , the NIHR , and a variety of other charities ( https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/our-funding ). FinnGen is a public-private partnership ( https://www.finngen.fi/en/access\_results ) funded by multiple institutions across Finland. The authors want to acknowledge the participants and investigators of the FinnGen study. A.J.M. is a NIHR Academic Clinical Lecturer and supported by the Oxford Biomedical Research Centre (BRC). J.K.B. gratefully acknowledges funding support from a Wellcome Trust Senior Research Fellowship ( 223164/Z/21/Z ), UKRI grants MC\_PC\_20004 , MC\_PC\_19025 , MC\_PC\_1905 , MRNO2995X/1 , and MC\_PC\_20029 , Sepsis Research ( Fiona Elizabeth Agnew Trust ), a BBSRC Institute Strategic Program Grant to the Roslin Institute ( BB/P013732/1 , BB/P013759/1 ), and the UK Intensive Care Society . We gratefully acknowledge the support of Baillie Gifford and the Baillie Gifford Science Pandemic Hub at the University of Edinburgh . P.G.{\textquoteright}s time was funded by the Ser Cymru programme , the Welsh Government , and the EU-ERDF . N.J.T. is a Wellcome Trust Investigator ( 202802/Z/16/Z ), is the PI of the Avon Longitudinal Study of Parents and Children (MRC \& WT 217065/Z/19/Z ), is supported by the University of Bristol NIHR Biomedical Research Center ( BRC-1215-2001 ) and the MRC Integrative Epidemiology Unit ( MC\_UU\_00011/1 ), and works within the CRUK Integrative Cancer Epidemiology Programme ( C18281/A29019 ). T.P. was funded by the Wellcome Trust Clinical Career Development Fellowship ( 222098/Z/20/Z ). G.D.S. works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council ( MC\_UU\_00011/1 ). Funding Information: This research was funded in whole, or in part, by the Wellcome Trust ( 222894/Z/21/Z ). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = apr,

day = "6",

doi = "10.1016/j.ajhg.2023.02.008",

language = "English",

volume = "110",

pages = "691--702",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

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TY - JOUR

T1 - Variation in ERAP2 has opposing effects on severe respiratory infection and autoimmune disease

AU - Hamilton, Fergus W

AU - Mentzer, Alexander J

AU - Parks, Tom

AU - Baillie, J Kenneth

AU - Smith, George Davey

AU - Ghazal, Peter

AU - Timpson, Nicholas J

N1 - Funding Information: F.H.’s time was funded by the GW4-CAT Wellcome Doctoral Fellowship Scheme (222894/Z/21/Z). UK Biobank was funded by the Wellcome Trust, the Medical Research Council, the NIHR, and a variety of other charities (https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/our-funding). FinnGen is a public-private partnership (https://www.finngen.fi/en/access_results) funded by multiple institutions across Finland. The authors want to acknowledge the participants and investigators of the FinnGen study. A.J.M. is a NIHR Academic Clinical Lecturer and supported by the Oxford Biomedical Research Centre (BRC). J.K.B. gratefully acknowledges funding support from a Wellcome Trust Senior Research Fellowship (223164/Z/21/Z), UKRI grants MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1, and MC_PC_20029, Sepsis Research (Fiona Elizabeth Agnew Trust), a BBSRC Institute Strategic Program Grant to the Roslin Institute (BB/P013732/1, BB/P013759/1), and the UK Intensive Care Society. We gratefully acknowledge the support of Baillie Gifford and the Baillie Gifford Science Pandemic Hub at the University of Edinburgh. P.G.’s time was funded by the Ser Cymru programme, the Welsh Government, and the EU-ERDF. N.J.T. is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Center (BRC-1215-2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011/1), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). T.P. was funded by the Wellcome Trust Clinical Career Development Fellowship (222098/Z/20/Z). G.D.S. works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). This research was funded in whole, or in part, by the Wellcome Trust (222894/Z/21/Z). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. No authors declare any conflicts of interest. Funding Information: F.H.’s time was funded by the GW4-CAT Wellcome Doctoral Fellowship Scheme ( 222894/Z/21/Z ). UK Biobank was funded by the Wellcome Trust , the Medical Research Council , the NIHR , and a variety of other charities ( https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/our-funding ). FinnGen is a public-private partnership ( https://www.finngen.fi/en/access_results ) funded by multiple institutions across Finland. The authors want to acknowledge the participants and investigators of the FinnGen study. A.J.M. is a NIHR Academic Clinical Lecturer and supported by the Oxford Biomedical Research Centre (BRC). J.K.B. gratefully acknowledges funding support from a Wellcome Trust Senior Research Fellowship ( 223164/Z/21/Z ), UKRI grants MC_PC_20004 , MC_PC_19025 , MC_PC_1905 , MRNO2995X/1 , and MC_PC_20029 , Sepsis Research ( Fiona Elizabeth Agnew Trust ), a BBSRC Institute Strategic Program Grant to the Roslin Institute ( BB/P013732/1 , BB/P013759/1 ), and the UK Intensive Care Society . We gratefully acknowledge the support of Baillie Gifford and the Baillie Gifford Science Pandemic Hub at the University of Edinburgh . P.G.’s time was funded by the Ser Cymru programme , the Welsh Government , and the EU-ERDF . N.J.T. is a Wellcome Trust Investigator ( 202802/Z/16/Z ), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z ), is supported by the University of Bristol NIHR Biomedical Research Center ( BRC-1215-2001 ) and the MRC Integrative Epidemiology Unit ( MC_UU_00011/1 ), and works within the CRUK Integrative Cancer Epidemiology Programme ( C18281/A29019 ). T.P. was funded by the Wellcome Trust Clinical Career Development Fellowship ( 222098/Z/20/Z ). G.D.S. works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council ( MC_UU_00011/1 ). Funding Information: This research was funded in whole, or in part, by the Wellcome Trust ( 222894/Z/21/Z ). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: © 2023 The Author(s)

PY - 2023/4/6

Y1 - 2023/4/6

N2 - ERAP2 is an aminopeptidase involved in immunological antigen presentation. Genotype data in human samples from before and after the Black Death, an epidemic due to Yersinia pestis, have marked changes in allele frequency of the single-nucleotide polymorphism (SNP) rs2549794, with the T allele suggested to be deleterious during this period, while ERAP2 is also implicated in autoimmune diseases. This study explored the association between variation at ERAP2 and (1) infection, (2) autoimmune disease, and (3) parental longevity. Genome-wide association studies (GWASs) of these outcomes were identified in contemporary cohorts (UK Biobank, FinnGen, and GenOMICC). Effect estimates were extracted for rs2549794 and rs2248374, a haplotype tagging SNP. Additionally, cis expression and protein quantitative trait loci (QTLs) for ERAP2 were used in Mendelian randomization (MR) analyses. Consistent with decreased survival in the Black Death, the T allele of rs2549794 showed evidence of association with respiratory infection (odds ratio; OR for pneumonia 1.03; 95% CI 1.01–1.05). Effect estimates were larger for more severe phenotypes (OR for critical care admission with pneumonia 1.08; 95% CI 1.02–1.14). In contrast, opposing effects were identified for Crohn disease (OR 0.86; 95% CI 0.82–0.90). This allele was shown to associate with decreased ERAP2 expression and protein levels, independent of haplotype. MR analyses suggest that ERAP2 expression may be mediating disease associations. Decreased ERAP2 expression is associated with severe respiratory infection with an opposing association with autoimmune diseases. These data support the hypothesis of balancing selection at this locus driven by autoimmune and infectious disease.

AB - ERAP2 is an aminopeptidase involved in immunological antigen presentation. Genotype data in human samples from before and after the Black Death, an epidemic due to Yersinia pestis, have marked changes in allele frequency of the single-nucleotide polymorphism (SNP) rs2549794, with the T allele suggested to be deleterious during this period, while ERAP2 is also implicated in autoimmune diseases. This study explored the association between variation at ERAP2 and (1) infection, (2) autoimmune disease, and (3) parental longevity. Genome-wide association studies (GWASs) of these outcomes were identified in contemporary cohorts (UK Biobank, FinnGen, and GenOMICC). Effect estimates were extracted for rs2549794 and rs2248374, a haplotype tagging SNP. Additionally, cis expression and protein quantitative trait loci (QTLs) for ERAP2 were used in Mendelian randomization (MR) analyses. Consistent with decreased survival in the Black Death, the T allele of rs2549794 showed evidence of association with respiratory infection (odds ratio; OR for pneumonia 1.03; 95% CI 1.01–1.05). Effect estimates were larger for more severe phenotypes (OR for critical care admission with pneumonia 1.08; 95% CI 1.02–1.14). In contrast, opposing effects were identified for Crohn disease (OR 0.86; 95% CI 0.82–0.90). This allele was shown to associate with decreased ERAP2 expression and protein levels, independent of haplotype. MR analyses suggest that ERAP2 expression may be mediating disease associations. Decreased ERAP2 expression is associated with severe respiratory infection with an opposing association with autoimmune diseases. These data support the hypothesis of balancing selection at this locus driven by autoimmune and infectious disease.

U2 - 10.1016/j.ajhg.2023.02.008

DO - 10.1016/j.ajhg.2023.02.008

M3 - Article (Academic Journal)

C2 - 36889308

SN - 0002-9297

VL - 110

SP - 691

EP - 702

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

Variation in ERAP2 has opposing effects on severe respiratory infection and autoimmune disease

Abstract

Bibliographical note

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

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