Investigating the viability of genetic screening/testing for RA susceptibility using combinations of five confirmed risk loci

Annie McClure, Mark Lunt, Steve Eyre, Xiayi Ke, Wendy Thomson, Anne Hinks, John Bowes, Laura Gibbons, Darren Plant, Anthony G Wilson, Ioanna Marinou, Ann W Morgan, Paul Emery, Sophia Steer, Lynne Hocking, David M Reid, Paul Wordsworth, Pille Harrison, Jane Worthington, Anne Barton & 1 others BIRAC consortium

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Abstract

OBJECTIVE: Five loci-the shared epitope (SE) of HLA--DRB1, the PTPN22 gene, a locus on 6q23, the STAT4 gene and a locus mapping to the TRAF1/C5 genetic region--have now been unequivocally confirmed as conferring susceptibility to RA. The largest single effect is conferred by SE. We hypothesized that combinations of susceptibility alleles may increase risk over and above that of any individual locus alone. METHODS: We analysed data from 4238 RA cases and 1811 controls, for which genotypes were available at all five loci. RESULTS: Statistical analysis identified eight high-risk combinations conferring an odds ratio >6 compared with carriage of no susceptibility variants and, interestingly, 10% population controls carried a combination conferring high risk. All high-risk combinations included SE, and all but one contained PTPN22. Statistical modelling showed that a model containing only these two loci could achieve comparable sensitivity and specificity to a model including all five. Furthermore, replacing SE (which requires full subtyping at the HLA-DRB1 gene) with DRB1*1/4/10 carriage resulted in little further loss of information (correlation coefficient between models = 0.93). CONCLUSIONS: This represents the first exploration of the viability of population screening for RA and identifies several high-risk genetic combinations. However, given the population incidence of RA, genetic screening based on these loci alone is neither sufficiently sensitive nor specific at the current time.
Original languageEnglish
Pages (from-to)1369-1374
Number of pages6
JournalRheumatology
Volume48
Issue number11
DOIs
Publication statusPublished - 2009

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Genetic Testing
Epitopes
HLA-DRB1 Chains
TNF Receptor-Associated Factor 1
Genes
Population Control
Population
Alleles
Odds Ratio
Genotype
Sensitivity and Specificity
Incidence

Keywords

  • adult
  • aged
  • arthritis, rheumatoid
  • autoantibodies
  • cost-benefit analysis
  • feasibility studies
  • female
  • genetic loci
  • genetic predisposition to disease
  • genetic testing
  • genotype
  • HLA-DR antigens
  • histocompatibility testing
  • humans
  • male
  • middle aged
  • models, genetic
  • peptides, cyclic
  • sensitivity and specificity
  • sex factors
  • young adult

Cite this

Investigating the viability of genetic screening/testing for RA susceptibility using combinations of five confirmed risk loci. / McClure, Annie; Lunt, Mark; Eyre, Steve; Ke, Xiayi; Thomson, Wendy; Hinks, Anne; Bowes, John; Gibbons, Laura; Plant, Darren; Wilson, Anthony G; Marinou, Ioanna; Morgan, Ann W; Emery, Paul; Steer, Sophia; Hocking, Lynne; Reid, David M; Wordsworth, Paul; Harrison, Pille; Worthington, Jane; Barton, Anne; BIRAC consortium.

In: Rheumatology, Vol. 48, No. 11, 2009, p. 1369-1374.

Research output: Contribution to journalArticle

McClure, A, Lunt, M, Eyre, S, Ke, X, Thomson, W, Hinks, A, Bowes, J, Gibbons, L, Plant, D, Wilson, AG, Marinou, I, Morgan, AW, Emery, P, Steer, S, Hocking, L, Reid, DM, Wordsworth, P, Harrison, P, Worthington, J, Barton, A & BIRAC consortium 2009, 'Investigating the viability of genetic screening/testing for RA susceptibility using combinations of five confirmed risk loci', Rheumatology, vol. 48, no. 11, pp. 1369-1374. https://doi.org/10.1093/rheumatology/kep272
McClure, Annie ; Lunt, Mark ; Eyre, Steve ; Ke, Xiayi ; Thomson, Wendy ; Hinks, Anne ; Bowes, John ; Gibbons, Laura ; Plant, Darren ; Wilson, Anthony G ; Marinou, Ioanna ; Morgan, Ann W ; Emery, Paul ; Steer, Sophia ; Hocking, Lynne ; Reid, David M ; Wordsworth, Paul ; Harrison, Pille ; Worthington, Jane ; Barton, Anne ; BIRAC consortium. / Investigating the viability of genetic screening/testing for RA susceptibility using combinations of five confirmed risk loci. In: Rheumatology. 2009 ; Vol. 48, No. 11. pp. 1369-1374.
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abstract = "OBJECTIVE: Five loci-the shared epitope (SE) of HLA--DRB1, the PTPN22 gene, a locus on 6q23, the STAT4 gene and a locus mapping to the TRAF1/C5 genetic region--have now been unequivocally confirmed as conferring susceptibility to RA. The largest single effect is conferred by SE. We hypothesized that combinations of susceptibility alleles may increase risk over and above that of any individual locus alone. METHODS: We analysed data from 4238 RA cases and 1811 controls, for which genotypes were available at all five loci. RESULTS: Statistical analysis identified eight high-risk combinations conferring an odds ratio >6 compared with carriage of no susceptibility variants and, interestingly, 10{\%} population controls carried a combination conferring high risk. All high-risk combinations included SE, and all but one contained PTPN22. Statistical modelling showed that a model containing only these two loci could achieve comparable sensitivity and specificity to a model including all five. Furthermore, replacing SE (which requires full subtyping at the HLA-DRB1 gene) with DRB1*1/4/10 carriage resulted in little further loss of information (correlation coefficient between models = 0.93). CONCLUSIONS: This represents the first exploration of the viability of population screening for RA and identifies several high-risk genetic combinations. However, given the population incidence of RA, genetic screening based on these loci alone is neither sufficiently sensitive nor specific at the current time.",
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author = "Annie McClure and Mark Lunt and Steve Eyre and Xiayi Ke and Wendy Thomson and Anne Hinks and John Bowes and Laura Gibbons and Darren Plant and Wilson, {Anthony G} and Ioanna Marinou and Morgan, {Ann W} and Paul Emery and Sophia Steer and Lynne Hocking and Reid, {David M} and Paul Wordsworth and Pille Harrison and Jane Worthington and Anne Barton and {BIRAC consortium}",
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TY - JOUR

T1 - Investigating the viability of genetic screening/testing for RA susceptibility using combinations of five confirmed risk loci

AU - McClure, Annie

AU - Lunt, Mark

AU - Eyre, Steve

AU - Ke, Xiayi

AU - Thomson, Wendy

AU - Hinks, Anne

AU - Bowes, John

AU - Gibbons, Laura

AU - Plant, Darren

AU - Wilson, Anthony G

AU - Marinou, Ioanna

AU - Morgan, Ann W

AU - Emery, Paul

AU - Steer, Sophia

AU - Hocking, Lynne

AU - Reid, David M

AU - Wordsworth, Paul

AU - Harrison, Pille

AU - Worthington, Jane

AU - Barton, Anne

AU - BIRAC consortium

PY - 2009

Y1 - 2009

N2 - OBJECTIVE: Five loci-the shared epitope (SE) of HLA--DRB1, the PTPN22 gene, a locus on 6q23, the STAT4 gene and a locus mapping to the TRAF1/C5 genetic region--have now been unequivocally confirmed as conferring susceptibility to RA. The largest single effect is conferred by SE. We hypothesized that combinations of susceptibility alleles may increase risk over and above that of any individual locus alone. METHODS: We analysed data from 4238 RA cases and 1811 controls, for which genotypes were available at all five loci. RESULTS: Statistical analysis identified eight high-risk combinations conferring an odds ratio >6 compared with carriage of no susceptibility variants and, interestingly, 10% population controls carried a combination conferring high risk. All high-risk combinations included SE, and all but one contained PTPN22. Statistical modelling showed that a model containing only these two loci could achieve comparable sensitivity and specificity to a model including all five. Furthermore, replacing SE (which requires full subtyping at the HLA-DRB1 gene) with DRB1*1/4/10 carriage resulted in little further loss of information (correlation coefficient between models = 0.93). CONCLUSIONS: This represents the first exploration of the viability of population screening for RA and identifies several high-risk genetic combinations. However, given the population incidence of RA, genetic screening based on these loci alone is neither sufficiently sensitive nor specific at the current time.

AB - OBJECTIVE: Five loci-the shared epitope (SE) of HLA--DRB1, the PTPN22 gene, a locus on 6q23, the STAT4 gene and a locus mapping to the TRAF1/C5 genetic region--have now been unequivocally confirmed as conferring susceptibility to RA. The largest single effect is conferred by SE. We hypothesized that combinations of susceptibility alleles may increase risk over and above that of any individual locus alone. METHODS: We analysed data from 4238 RA cases and 1811 controls, for which genotypes were available at all five loci. RESULTS: Statistical analysis identified eight high-risk combinations conferring an odds ratio >6 compared with carriage of no susceptibility variants and, interestingly, 10% population controls carried a combination conferring high risk. All high-risk combinations included SE, and all but one contained PTPN22. Statistical modelling showed that a model containing only these two loci could achieve comparable sensitivity and specificity to a model including all five. Furthermore, replacing SE (which requires full subtyping at the HLA-DRB1 gene) with DRB1*1/4/10 carriage resulted in little further loss of information (correlation coefficient between models = 0.93). CONCLUSIONS: This represents the first exploration of the viability of population screening for RA and identifies several high-risk genetic combinations. However, given the population incidence of RA, genetic screening based on these loci alone is neither sufficiently sensitive nor specific at the current time.

KW - adult

KW - aged

KW - arthritis, rheumatoid

KW - autoantibodies

KW - cost-benefit analysis

KW - feasibility studies

KW - female

KW - genetic loci

KW - genetic predisposition to disease

KW - genetic testing

KW - genotype

KW - HLA-DR antigens

KW - histocompatibility testing

KW - humans

KW - male

KW - middle aged

KW - models, genetic

KW - peptides, cyclic

KW - sensitivity and specificity

KW - sex factors

KW - young adult

U2 - 10.1093/rheumatology/kep272

DO - 10.1093/rheumatology/kep272

M3 - Article

VL - 48

SP - 1369

EP - 1374

JO - Rheumatology

JF - Rheumatology

SN - 1462-0324

IS - 11

ER -