Combined effects of three independent SNPs greatly increase the risk estimate for RA at 6q23

Gisela Orozco, Anne Hinks, Steve Eyre, Xiayi Ke, Laura J Gibbons, John Bowes, Edward Flynn, Paul Martin, Anthony G Wilson, Deborah E Bax, Ann W Morgan, Paul Emery, Sophia Steer, Lynne Hocking, David M Reid, Paul Wordsworth, Pille Harrison, Wendy Thomson, Anne Barton, Jane Worthington & 1 others Wellcome Trust Case Control Consortium

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Abstract

The most consistent finding derived from the WTCCC GWAS for rheumatoid arthritis (RA) was association to a SNP at 6q23. We performed a fine-mapping of the region in order to search the 6q23 region for additional disease variants. 3962 RA patients and 3531 healthy controls were included in the study. We found 18 SNPs associated with RA. The SNP showing the strongest association was rs6920220 [P = 2.6 x 10(-6), OR (95% CI) 1.22 (1.13-1.33)]. The next most strongly associated SNP was rs13207033 [P = 0.0001, OR (95% CI) 0.86 (0.8-0.93)] which was perfectly correlated with rs10499194, a SNP previously associated with RA in a US/European series. Additionally, we found a number of new potential RA markers, including rs5029937, located in the intron 2 of TNFAIP3. Of the 18 associated SNPs, three polymorphisms, rs6920220, rs13207033 and rs5029937, remained significant after conditional logistic regression analysis. The combination of the carriage of both risk alleles of rs6920220 and rs5029937 together with the absence of the protective allele of rs13207033 was strongly associated with RA when compared with carriage of none [OR of 1.86 (95% CI) (1.51-2.29)]. This equates to an effect size of 1.50 (95% CI 1.21-1.85) compared with controls and is higher than that obtained for any SNP individually. This is the first study to show that the confirmed loci from the GWA studies, that confer only a modest effect size, could harbour a significantly greater effect once the effect of additional risk variants are accounted for.
Original languageEnglish
Pages (from-to)2693-2699
Number of pages7
JournalHuman Molecular Genetics
Volume18
Issue number14
Early online date5 May 2009
DOIs
Publication statusPublished - 15 Jul 2009

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Single Nucleotide Polymorphism
Rheumatoid Arthritis
Genome-Wide Association Study
Alleles
Introns
Logistic Models
Regression Analysis

Keywords

  • adult
  • arthritis, rheumatoid
  • case-control studies
  • chromosome mapping
  • chromosomes, human, pair 6
  • European continental ancestry group
  • female
  • genetic predisposition to disease
  • genome-wide association study
  • humans
  • intracellular signaling peptides and proteins
  • male
  • middle aged
  • nuclear proteins
  • polymorphism, single nucleotide

Cite this

Orozco, G., Hinks, A., Eyre, S., Ke, X., Gibbons, L. J., Bowes, J., ... Wellcome Trust Case Control Consortium (2009). Combined effects of three independent SNPs greatly increase the risk estimate for RA at 6q23. Human Molecular Genetics, 18(14), 2693-2699. https://doi.org/10.1093/hmg/ddp193

Combined effects of three independent SNPs greatly increase the risk estimate for RA at 6q23. / Orozco, Gisela; Hinks, Anne; Eyre, Steve; Ke, Xiayi; Gibbons, Laura J; Bowes, John; Flynn, Edward; Martin, Paul; Wilson, Anthony G; Bax, Deborah E; Morgan, Ann W; Emery, Paul; Steer, Sophia; Hocking, Lynne; Reid, David M; Wordsworth, Paul; Harrison, Pille; Thomson, Wendy; Barton, Anne; Worthington, Jane; Wellcome Trust Case Control Consortium.

In: Human Molecular Genetics, Vol. 18, No. 14, 15.07.2009, p. 2693-2699.

Research output: Contribution to journalArticle

Orozco, G, Hinks, A, Eyre, S, Ke, X, Gibbons, LJ, Bowes, J, Flynn, E, Martin, P, Wilson, AG, Bax, DE, Morgan, AW, Emery, P, Steer, S, Hocking, L, Reid, DM, Wordsworth, P, Harrison, P, Thomson, W, Barton, A, Worthington, J & Wellcome Trust Case Control Consortium 2009, 'Combined effects of three independent SNPs greatly increase the risk estimate for RA at 6q23', Human Molecular Genetics, vol. 18, no. 14, pp. 2693-2699. https://doi.org/10.1093/hmg/ddp193
Orozco, Gisela ; Hinks, Anne ; Eyre, Steve ; Ke, Xiayi ; Gibbons, Laura J ; Bowes, John ; Flynn, Edward ; Martin, Paul ; Wilson, Anthony G ; Bax, Deborah E ; Morgan, Ann W ; Emery, Paul ; Steer, Sophia ; Hocking, Lynne ; Reid, David M ; Wordsworth, Paul ; Harrison, Pille ; Thomson, Wendy ; Barton, Anne ; Worthington, Jane ; Wellcome Trust Case Control Consortium. / Combined effects of three independent SNPs greatly increase the risk estimate for RA at 6q23. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 14. pp. 2693-2699.
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abstract = "The most consistent finding derived from the WTCCC GWAS for rheumatoid arthritis (RA) was association to a SNP at 6q23. We performed a fine-mapping of the region in order to search the 6q23 region for additional disease variants. 3962 RA patients and 3531 healthy controls were included in the study. We found 18 SNPs associated with RA. The SNP showing the strongest association was rs6920220 [P = 2.6 x 10(-6), OR (95{\%} CI) 1.22 (1.13-1.33)]. The next most strongly associated SNP was rs13207033 [P = 0.0001, OR (95{\%} CI) 0.86 (0.8-0.93)] which was perfectly correlated with rs10499194, a SNP previously associated with RA in a US/European series. Additionally, we found a number of new potential RA markers, including rs5029937, located in the intron 2 of TNFAIP3. Of the 18 associated SNPs, three polymorphisms, rs6920220, rs13207033 and rs5029937, remained significant after conditional logistic regression analysis. The combination of the carriage of both risk alleles of rs6920220 and rs5029937 together with the absence of the protective allele of rs13207033 was strongly associated with RA when compared with carriage of none [OR of 1.86 (95{\%} CI) (1.51-2.29)]. This equates to an effect size of 1.50 (95{\%} CI 1.21-1.85) compared with controls and is higher than that obtained for any SNP individually. This is the first study to show that the confirmed loci from the GWA studies, that confer only a modest effect size, could harbour a significantly greater effect once the effect of additional risk variants are accounted for.",
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AU - Hinks, Anne

AU - Eyre, Steve

AU - Ke, Xiayi

AU - Gibbons, Laura J

AU - Bowes, John

AU - Flynn, Edward

AU - Martin, Paul

AU - Wilson, Anthony G

AU - Bax, Deborah E

AU - Morgan, Ann W

AU - Emery, Paul

AU - Steer, Sophia

AU - Hocking, Lynne

AU - Reid, David M

AU - Wordsworth, Paul

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KW - male

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