Reevaluation of the interaction between HLA-DRB1 shared epitope alleles, PTPN22, and smoking in determining susceptibility to autoantibody-positive and autoantibody-negative rheumatoid arthritis in a large UK Caucasian population

Yorkshire Early Arthritis Register Consortium, UK Rheumatoid Arthritis Genetics Consortium

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

OBJECTIVE: To define interactions between the HLA-DRB1 shared epitope (SE), PTPN22, and smoking in cyclic citrullinated peptide (CCP) antibody- and rheumatoid factor (RF)-positive and -negative rheumatoid arthritis (RA). METHODS: Data on approximately 5,000 RA patients and approximately 3,700 healthy controls recruited from 6 centers in the UK were analyzed; not all centers had both genotype data and smoking data available for study. The magnitude of association was assessed in autoantibody-positive and -negative subgroups. The effect of smoking on antibody status among cases was assessed following adjustment for year of birth and center, using Mantel-Haenszel analysis. Analyses of the combined effects of PTPN22, HLA-DRB1 SE, and smoking were performed using additive and multiplicative models of interaction within a logistic regression framework. RESULTS: The combined effects of PTPN22, HLA-DRB1 SE, and smoking were defined, with no evidence of departure from a multiplicative model. Within the case population, all 3 factors were independently associated with the generation of CCP antibodies (odds ratio [OR] 11.1, P <0.0001), whereas only HLA-DRB1 SE and smoking were independently associated with RF production (OR 4.4, P <0.0001). There was some evidence of increasing likelihood of antibody positivity with heavier smoking. Finally, we demonstrated that smoking was associated with the generation of both CCP and RF antibodies (OR 1.7, P = 0.0001). CONCLUSION: PTPN22 appears to be primarily associated with anticitrulline autoimmunity, whereas HLA-DRB1 SE is independently associated with RF. This study has confirmed associations of specific gene-environment combinations with a substantially increased risk of developing RA. Further work is needed to determine how these data can be used to inform clinical practice.
Original languageEnglish
Pages (from-to)2565-2576
Number of pages12
JournalArthritis & Rheumatism
Volume60
Issue number9
Early online date27 Aug 2009
DOIs
Publication statusPublished - Sep 2009

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HLA-DRB1 Chains
Autoantibodies
Epitopes
Rheumatoid Arthritis
Smoking
Alleles
Rheumatoid Factor
Population
Antibodies
Odds Ratio
Birthing Centers
Autoimmunity
Logistic Models
Genotype

Keywords

  • adult
  • aged
  • aged, 80 and over
  • alleles
  • arthritis, rheumatoid
  • autoantibodies
  • case-control studies
  • epitopes
  • European continental ancestry group
  • female
  • genetic predisposition to disease
  • Great Britain
  • HLA-DR antigens
  • humans
  • logistic models
  • male
  • middle aged
  • models, genetic
  • peptides, cyclic
  • protein tyrosine phosphatase, non-receptor type 22
  • rheumatoid factor
  • smoking
  • young adult

Cite this

Reevaluation of the interaction between HLA-DRB1 shared epitope alleles, PTPN22, and smoking in determining susceptibility to autoantibody-positive and autoantibody-negative rheumatoid arthritis in a large UK Caucasian population. / Yorkshire Early Arthritis Register Consortium; UK Rheumatoid Arthritis Genetics Consortium.

In: Arthritis & Rheumatism, Vol. 60, No. 9, 09.2009, p. 2565-2576.

Research output: Contribution to journalArticle

@article{1b7314b6e48542afaef4c6b2b70c65c9,
title = "Reevaluation of the interaction between HLA-DRB1 shared epitope alleles, PTPN22, and smoking in determining susceptibility to autoantibody-positive and autoantibody-negative rheumatoid arthritis in a large UK Caucasian population",
abstract = "OBJECTIVE: To define interactions between the HLA-DRB1 shared epitope (SE), PTPN22, and smoking in cyclic citrullinated peptide (CCP) antibody- and rheumatoid factor (RF)-positive and -negative rheumatoid arthritis (RA). METHODS: Data on approximately 5,000 RA patients and approximately 3,700 healthy controls recruited from 6 centers in the UK were analyzed; not all centers had both genotype data and smoking data available for study. The magnitude of association was assessed in autoantibody-positive and -negative subgroups. The effect of smoking on antibody status among cases was assessed following adjustment for year of birth and center, using Mantel-Haenszel analysis. Analyses of the combined effects of PTPN22, HLA-DRB1 SE, and smoking were performed using additive and multiplicative models of interaction within a logistic regression framework. RESULTS: The combined effects of PTPN22, HLA-DRB1 SE, and smoking were defined, with no evidence of departure from a multiplicative model. Within the case population, all 3 factors were independently associated with the generation of CCP antibodies (odds ratio [OR] 11.1, P <0.0001), whereas only HLA-DRB1 SE and smoking were independently associated with RF production (OR 4.4, P <0.0001). There was some evidence of increasing likelihood of antibody positivity with heavier smoking. Finally, we demonstrated that smoking was associated with the generation of both CCP and RF antibodies (OR 1.7, P = 0.0001). CONCLUSION: PTPN22 appears to be primarily associated with anticitrulline autoimmunity, whereas HLA-DRB1 SE is independently associated with RF. This study has confirmed associations of specific gene-environment combinations with a substantially increased risk of developing RA. Further work is needed to determine how these data can be used to inform clinical practice.",
keywords = "adult, aged, aged, 80 and over, alleles, arthritis, rheumatoid, autoantibodies, case-control studies, epitopes, European continental ancestry group, female, genetic predisposition to disease, Great Britain, HLA-DR antigens, humans, logistic models, male, middle aged, models, genetic, peptides, cyclic, protein tyrosine phosphatase, non-receptor type 22, rheumatoid factor, smoking, young adult",
author = "Morgan, {Ann W} and Wendy Thomson and Martin, {Stephen G} and Carter, {Angela M} and Erlich, {Henry A} and Anne Barton and Lynne Hocking and Reid, {David M} and Pille Harrison and Paul Wordsworth and Sophia Steer and Jane Worthington and Paul Emery and Wilson, {Anthony G} and Barrett, {Jennifer H} and {Yorkshire Early Arthritis Register Consortium} and {UK Rheumatoid Arthritis Genetics Consortium}",
year = "2009",
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TY - JOUR

T1 - Reevaluation of the interaction between HLA-DRB1 shared epitope alleles, PTPN22, and smoking in determining susceptibility to autoantibody-positive and autoantibody-negative rheumatoid arthritis in a large UK Caucasian population

AU - Morgan, Ann W

AU - Thomson, Wendy

AU - Martin, Stephen G

AU - Carter, Angela M

AU - Erlich, Henry A

AU - Barton, Anne

AU - Hocking, Lynne

AU - Reid, David M

AU - Harrison, Pille

AU - Wordsworth, Paul

AU - Steer, Sophia

AU - Worthington, Jane

AU - Emery, Paul

AU - Wilson, Anthony G

AU - Barrett, Jennifer H

AU - Yorkshire Early Arthritis Register Consortium

AU - UK Rheumatoid Arthritis Genetics Consortium

PY - 2009/9

Y1 - 2009/9

N2 - OBJECTIVE: To define interactions between the HLA-DRB1 shared epitope (SE), PTPN22, and smoking in cyclic citrullinated peptide (CCP) antibody- and rheumatoid factor (RF)-positive and -negative rheumatoid arthritis (RA). METHODS: Data on approximately 5,000 RA patients and approximately 3,700 healthy controls recruited from 6 centers in the UK were analyzed; not all centers had both genotype data and smoking data available for study. The magnitude of association was assessed in autoantibody-positive and -negative subgroups. The effect of smoking on antibody status among cases was assessed following adjustment for year of birth and center, using Mantel-Haenszel analysis. Analyses of the combined effects of PTPN22, HLA-DRB1 SE, and smoking were performed using additive and multiplicative models of interaction within a logistic regression framework. RESULTS: The combined effects of PTPN22, HLA-DRB1 SE, and smoking were defined, with no evidence of departure from a multiplicative model. Within the case population, all 3 factors were independently associated with the generation of CCP antibodies (odds ratio [OR] 11.1, P <0.0001), whereas only HLA-DRB1 SE and smoking were independently associated with RF production (OR 4.4, P <0.0001). There was some evidence of increasing likelihood of antibody positivity with heavier smoking. Finally, we demonstrated that smoking was associated with the generation of both CCP and RF antibodies (OR 1.7, P = 0.0001). CONCLUSION: PTPN22 appears to be primarily associated with anticitrulline autoimmunity, whereas HLA-DRB1 SE is independently associated with RF. This study has confirmed associations of specific gene-environment combinations with a substantially increased risk of developing RA. Further work is needed to determine how these data can be used to inform clinical practice.

AB - OBJECTIVE: To define interactions between the HLA-DRB1 shared epitope (SE), PTPN22, and smoking in cyclic citrullinated peptide (CCP) antibody- and rheumatoid factor (RF)-positive and -negative rheumatoid arthritis (RA). METHODS: Data on approximately 5,000 RA patients and approximately 3,700 healthy controls recruited from 6 centers in the UK were analyzed; not all centers had both genotype data and smoking data available for study. The magnitude of association was assessed in autoantibody-positive and -negative subgroups. The effect of smoking on antibody status among cases was assessed following adjustment for year of birth and center, using Mantel-Haenszel analysis. Analyses of the combined effects of PTPN22, HLA-DRB1 SE, and smoking were performed using additive and multiplicative models of interaction within a logistic regression framework. RESULTS: The combined effects of PTPN22, HLA-DRB1 SE, and smoking were defined, with no evidence of departure from a multiplicative model. Within the case population, all 3 factors were independently associated with the generation of CCP antibodies (odds ratio [OR] 11.1, P <0.0001), whereas only HLA-DRB1 SE and smoking were independently associated with RF production (OR 4.4, P <0.0001). There was some evidence of increasing likelihood of antibody positivity with heavier smoking. Finally, we demonstrated that smoking was associated with the generation of both CCP and RF antibodies (OR 1.7, P = 0.0001). CONCLUSION: PTPN22 appears to be primarily associated with anticitrulline autoimmunity, whereas HLA-DRB1 SE is independently associated with RF. This study has confirmed associations of specific gene-environment combinations with a substantially increased risk of developing RA. Further work is needed to determine how these data can be used to inform clinical practice.

KW - adult

KW - aged

KW - aged, 80 and over

KW - alleles

KW - arthritis, rheumatoid

KW - autoantibodies

KW - case-control studies

KW - epitopes

KW - European continental ancestry group

KW - female

KW - genetic predisposition to disease

KW - Great Britain

KW - HLA-DR antigens

KW - humans

KW - logistic models

KW - male

KW - middle aged

KW - models, genetic

KW - peptides, cyclic

KW - protein tyrosine phosphatase, non-receptor type 22

KW - rheumatoid factor

KW - smoking

KW - young adult

U2 - 10.1002/art.24752

DO - 10.1002/art.24752

M3 - Article

VL - 60

SP - 2565

EP - 2576

JO - Arthritis & Rheumatism

JF - Arthritis & Rheumatism

SN - 0004-3591

IS - 9

ER -