Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes

Aimee L. Hanson; Joanne Sahhar; Gene Siew Ngian; Janet Roddy; Jennifer Walker; Wendy Stevens; Mandana Nikpour; Shervin Assassi; Susanna Proudman; Maureen D. Mayes; Tony J. Kenna; Matthew A. Brown

doi:10.3389/fgene.2022.913196

Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes

Aimee L. Hanson, Joanne Sahhar, Gene Siew Ngian, Janet Roddy, Jennifer Walker, Wendy Stevens, Mandana Nikpour, Shervin Assassi, Susanna Proudman, Maureen D. Mayes, Tony J. Kenna, Matthew A. Brown^*

^*Corresponding author for this work

Medical & Molecular Genetics

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

11 Citations (Scopus)

Abstract

Systemic sclerosis (SSc) is an autoinflammatory, fibrotic condition of unknown aetiology. The presence of detectable autoantibodies against diverse nuclear antigens, as well as strong HLA associations with disease, suggest autoimmune involvement, however the links between endogenous and exogenous risk factors and SSc pathology remain undetermined. We have conducted a genetic analysis of HLA inheritance in two independent and meta-analysed cohorts of 1,465 SSc cases and 13,273 controls, including stratified association analyses in clinical and autoantibody positive subgroups of disease. Additionally, we have used patient genotypes to impute gene dosages across the KIR locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of KIR-HLA epistatic interactions in SSc to date. We confirm previous Class II HLA associations with SSc risk and report a new Class I association with haplotype HLA-B*44:03-HLA-C*16:01 at genome-wide significance (GWS). We further report statistically significant HLA associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of HLA-DRB1*15:01, previously shown to bind topoisomerase-1 derived peptides, with anti-topoisomerase (ATA) positive disease. Finally, we identify genetic epistasis between KIRs and HLA class I ligands, suggesting genetic modulation of lymphocyte activation may further contribute to an individual’s underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.

Original language	English
Article number	913196
Journal	Frontiers in Genetics
Volume	13
DOIs	https://doi.org/10.3389/fgene.2022.913196
Publication status	Published - 8 Jun 2022

Keywords

HLA association and disease
human disease genetics
immunogenetics
killer immunoglobulin like receptor (KIR)
systemic sclerosis (scleroderma)

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10.3389/fgene.2022.913196

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Hanson, A. L., Sahhar, J., Ngian, G. S., Roddy, J., Walker, J., Stevens, W., Nikpour, M., Assassi, S., Proudman, S., Mayes, M. D., Kenna, T. J., & Brown, M. A. (2022). Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes. Frontiers in Genetics, 13, Article 913196. https://doi.org/10.3389/fgene.2022.913196

@article{83c023370aa841d49d2cc534f8d1d59e,

title = "Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes",

abstract = "Systemic sclerosis (SSc) is an autoinflammatory, fibrotic condition of unknown aetiology. The presence of detectable autoantibodies against diverse nuclear antigens, as well as strong HLA associations with disease, suggest autoimmune involvement, however the links between endogenous and exogenous risk factors and SSc pathology remain undetermined. We have conducted a genetic analysis of HLA inheritance in two independent and meta-analysed cohorts of 1,465 SSc cases and 13,273 controls, including stratified association analyses in clinical and autoantibody positive subgroups of disease. Additionally, we have used patient genotypes to impute gene dosages across the KIR locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of KIR-HLA epistatic interactions in SSc to date. We confirm previous Class II HLA associations with SSc risk and report a new Class I association with haplotype HLA-B*44:03-HLA-C*16:01 at genome-wide significance (GWS). We further report statistically significant HLA associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of HLA-DRB1*15:01, previously shown to bind topoisomerase-1 derived peptides, with anti-topoisomerase (ATA) positive disease. Finally, we identify genetic epistasis between KIRs and HLA class I ligands, suggesting genetic modulation of lymphocyte activation may further contribute to an individual{\textquoteright}s underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.",

keywords = "HLA association and disease, human disease genetics, immunogenetics, killer immunoglobulin like receptor (KIR), systemic sclerosis (scleroderma)",

author = "Hanson, {Aimee L.} and Joanne Sahhar and Ngian, {Gene Siew} and Janet Roddy and Jennifer Walker and Wendy Stevens and Mandana Nikpour and Shervin Assassi and Susanna Proudman and Mayes, {Maureen D.} and Kenna, {Tony J.} and Brown, {Matthew A.}",

note = "Funding Information: This work was in part supported by the National Health and Medical Research Council (NHMRC) Grant GNT1162767. The Australian Scleroderma Cohort Study is supported by Scleroderma Victoria, Scleroderma Australia, Arthritis Australia, Australian Rheumatology Association, philanthropic donations, Janssen, and GSK. MN is supported by an NHMRC Investigator Grant (GNT1176538). Publisher Copyright: Copyright {\textcopyright} 2022 Hanson, Sahhar, Ngian, Roddy, Walker, Stevens, Nikpour, Assassi, Proudman, Mayes, Kenna and Brown.",

year = "2022",

month = jun,

day = "8",

doi = "10.3389/fgene.2022.913196",

language = "English",

volume = "13",

journal = "Frontiers in Genetics",

issn = "1664-8021",

publisher = "Frontiers Media S.A.",

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TY - JOUR

T1 - Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes

AU - Hanson, Aimee L.

AU - Sahhar, Joanne

AU - Ngian, Gene Siew

AU - Roddy, Janet

AU - Walker, Jennifer

AU - Stevens, Wendy

AU - Nikpour, Mandana

AU - Assassi, Shervin

AU - Proudman, Susanna

AU - Mayes, Maureen D.

AU - Kenna, Tony J.

AU - Brown, Matthew A.

N1 - Funding Information: This work was in part supported by the National Health and Medical Research Council (NHMRC) Grant GNT1162767. The Australian Scleroderma Cohort Study is supported by Scleroderma Victoria, Scleroderma Australia, Arthritis Australia, Australian Rheumatology Association, philanthropic donations, Janssen, and GSK. MN is supported by an NHMRC Investigator Grant (GNT1176538). Publisher Copyright: Copyright © 2022 Hanson, Sahhar, Ngian, Roddy, Walker, Stevens, Nikpour, Assassi, Proudman, Mayes, Kenna and Brown.

PY - 2022/6/8

Y1 - 2022/6/8

N2 - Systemic sclerosis (SSc) is an autoinflammatory, fibrotic condition of unknown aetiology. The presence of detectable autoantibodies against diverse nuclear antigens, as well as strong HLA associations with disease, suggest autoimmune involvement, however the links between endogenous and exogenous risk factors and SSc pathology remain undetermined. We have conducted a genetic analysis of HLA inheritance in two independent and meta-analysed cohorts of 1,465 SSc cases and 13,273 controls, including stratified association analyses in clinical and autoantibody positive subgroups of disease. Additionally, we have used patient genotypes to impute gene dosages across the KIR locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of KIR-HLA epistatic interactions in SSc to date. We confirm previous Class II HLA associations with SSc risk and report a new Class I association with haplotype HLA-B*44:03-HLA-C*16:01 at genome-wide significance (GWS). We further report statistically significant HLA associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of HLA-DRB1*15:01, previously shown to bind topoisomerase-1 derived peptides, with anti-topoisomerase (ATA) positive disease. Finally, we identify genetic epistasis between KIRs and HLA class I ligands, suggesting genetic modulation of lymphocyte activation may further contribute to an individual’s underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.

AB - Systemic sclerosis (SSc) is an autoinflammatory, fibrotic condition of unknown aetiology. The presence of detectable autoantibodies against diverse nuclear antigens, as well as strong HLA associations with disease, suggest autoimmune involvement, however the links between endogenous and exogenous risk factors and SSc pathology remain undetermined. We have conducted a genetic analysis of HLA inheritance in two independent and meta-analysed cohorts of 1,465 SSc cases and 13,273 controls, including stratified association analyses in clinical and autoantibody positive subgroups of disease. Additionally, we have used patient genotypes to impute gene dosages across the KIR locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of KIR-HLA epistatic interactions in SSc to date. We confirm previous Class II HLA associations with SSc risk and report a new Class I association with haplotype HLA-B*44:03-HLA-C*16:01 at genome-wide significance (GWS). We further report statistically significant HLA associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of HLA-DRB1*15:01, previously shown to bind topoisomerase-1 derived peptides, with anti-topoisomerase (ATA) positive disease. Finally, we identify genetic epistasis between KIRs and HLA class I ligands, suggesting genetic modulation of lymphocyte activation may further contribute to an individual’s underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.

KW - HLA association and disease

KW - human disease genetics

KW - immunogenetics

KW - killer immunoglobulin like receptor (KIR)

KW - systemic sclerosis (scleroderma)

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U2 - 10.3389/fgene.2022.913196

DO - 10.3389/fgene.2022.913196

M3 - Article

AN - SCOPUS:85133306348

SN - 1664-8021

VL - 13

JO - Frontiers in Genetics

JF - Frontiers in Genetics

M1 - 913196

ER -

Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes

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